COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND, OR A RESPECTIVE PHARMACEUTICALLY ACCEPT

专利摘要:
compound, pharmaceutical composition, and, use of a compound, or a respective pharmaceutically acceptable salt or n-oxide, or a solvate or hydrate thereof, or a composition, substituted pyridine compounds are disclosed, as well as pharmaceutical compositions and methods of use. an embodiment consists of a compound having the structure, wherein e, j, t, the ring system designated "b", t, r3, r4, w and x are as described herein. in certain embodiments, a compound disclosed here activates the ampk pathway, and can be used for the treatment of disorders and conditions related to metabolism.
公开号:BR112013002112B1
申请号:R112013002112-8
申请日:2011-07-29
公开日:2021-04-06
发明作者:Dane Goff；Donald Payan；Simon Shaw；David Carroll；Yasumichi Hotoshi；Rajinder Singh
申请人:Rigel Pharmaceuticals, Inc.；
IPC主号:

专利说明:

[0001] [001] This application claims the benefit of the previous registration date of U.S. Provisional Patent Application serial number 61 / 368,928, filed on July 29, 2010, which is hereby incorporated by reference in its entirety. BACKGROUND Domain
[0002] [002] This disclosure refers, in general, to compounds, pharmaceutical compositions and methods of using the compounds and compositions that contain them. This disclosure relates, more in particular, to certain substituted pyridine compounds and their pharmaceutical compositions, and to methods of treating and preventing metabolic disorders, such as type II diabetes, atherosclerosis and cardiovascular disease, using certain substituted pyridine compounds. Technical Background
[0003] [003] The 5'-AMP-activated protein kinase kinase (AMPK) is well established as an important sensor and regulator of cellular energy homeostasis. As a multi-substrate enzyme, AMPK regulates a variety of metabolic processes, such as glucose transport, glycolysis and lipid metabolism. It acts as a sensor for cellular energy homeostasis and is activated in response to certain hormones and muscle contraction, as well as to signs of intracellular metabolic stress, such as exercise, ischemia, hypoxia and nutrient deprivation. Once activated, AMPK turns on catabolic pathways (such as fatty acid oxidation and glycolysis) and turns off ATP-consuming pathways (such as lipogenesis). Activation of the AMPK pathway improves insulin sensitivity by directly stimulating glucose uptake in adipocytes and muscle and by increasing the oxidation of fatty acids in the liver and muscle, resulting in reduced levels of circulating fatty acids and reduced levels of triglycerides intracellular. In addition, the activation of the AMPK pathway decreases the concentration of glycogen by reducing the activity of glycogen synthase. Activation of the AMPK pathway also plays a protective role against inflammation and atherosclerosis. It suppresses the expression of adhesion molecules in vascular endothelial cells and production of cytokines from macrophages, thereby inhibiting the inflammatory processes that occur during the early stages of atherosclerosis.
[0004] [004] Compounds, pharmaceutical compositions and methods are needed for its use to treat disease states where AMPK activation is beneficial, such as type II diabetes, atherosclerosis and cardiovascular disease. SUMMARY
[0005] [005] Compounds having structural formula (I) are disclosed here
[0006] [006] Pharmaceutical compositions are also disclosed here. Examples of such compositions include those having at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound, pharmaceutically acceptable salt, prodrug or N-oxide (or solvate or hydrate) disclosed herein.
[0007] [007] Another aspect of the present disclosure includes methods of modulating metabolism in individuals. Accordingly, methods of treating metabolic disorders using the presently disclosed compounds and pharmaceutical compositions are also disclosed.
[0008] [008] Another aspect of the present disclosure includes methods of modulating sphingolipid metabolism, for example, modulating ceramide signaling, in individuals. In one aspect, modulation of sphingolipid metabolism includes modulation of ceramidase activity, for example, through positive regulation of ceramidase function. Accordingly, methods of treating ceramide-related diseases and disorders using the presently disclosed compounds and pharmaceutical compositions are also disclosed. DETAILED DESCRIPTION
[0009] [009] One aspect of the disclosure provides compounds with structural formula (I):
[0010] [0010] In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the compound has structural formula (II):
[0011] [0011] In one embodiment, the compounds presently disclosed are not compounds disclosed in Darwish et al., International Patent Application No. PCT / US10 / 22411, filed January 28, 2010, which is incorporated herein by reference in its entirety.
[0012] [0012] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, D1, D2 and D3 are independently CH or C substituted with one of w R3. In other embodiments, D1 is N and D2 and D3 are independently CH or C substituted with one of w R3. In other embodiments, D2 is N and D1 and D3 are independently CH or C substituted with one of w R3. In other embodiments, D3 is N and D1 and D2 are independently CH or C substituted with one of w R3.
[0013] [0013] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, J is -C (O) -, -NR13-, -NR13C (O) - or -C (O ) NR13-, where R13 is selected from -H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) and -C (O) O- (C1-C4 alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, R13 is H. In other embodiments, R13 is unsubstituted (C1-C4 alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, J is -C (O) -. In other embodiments, J is -NR13- (for example, -NH-). In still other embodiments, J is -NR13C (O) - (for example, -NHC (O) -). In other embodiments, J is -C (O) NR13- (for example, -C (O) NH-). In still other embodiments, J is absent.
[0014] [0014] In the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system designated as "B" is absent, is arylene, heteroarylene,
[0015] [0015] For example, in certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, those described below in relation to structural formula (IV)), the designated ring system “B” is arylene or heteroarylene. In certain embodiments, the ring system referred to as "B" is arylene (for example, phenylene, such as 1,4-phenylene). In other embodiments, the ring system designated "B" is heteroarylene (for example, 1H-pyrazolylene, 1H-1,2,3-triazolylene, pyridylene, furanylene or thienylene). In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system designated "B" is arylene or monocyclic heteroarylene.
[0016] [0016] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system designated as "B" is absent.
[0017] [0017] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system designated as "B" is
[0018] [0018] In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system designated as "B" is
[0019] [0019] In the presently disclosed compounds of structural formula (I) and (II) as described above, x, the number of substituents in the ring system designated "B", is 0, 1, 2, 3 or 4. In a embodiment, x is 0, 1, 2 or 3. For example, in certain embodiments, x is 0. In other embodiments, x can be 1 or 2.
[0020] [0020] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system designated "B" is
[0021] [0021] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system designated "B" is
[0022] [0022] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system designated "B" is
[0023] [0023] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, when x is 4, not all four R4 groups are (C1-C6 alkyl).
[0024] [0024] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, each R4 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (for example , difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C ( O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl) , - (C1-C6 haloalkyl), - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) -NR9 (C0-C6 alkyl), - (C0-C6 alkyl) - O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl) and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl ), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, each R4 is - (C1-C3 alkyl), - (C1-C3 alkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, in that each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -L- (C0-C2 alkyl), - (C0- C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, each R4 is independently halogen (for example, F, Cl), unsubstituted (C1-C6 alkoxy) (for example, methoxy, ethoxy), - (C1-C6 haloalkoxy) (for example, trifluoromethoxy) , -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (unsubstituted C1-C4 alkyl), -N ( C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with a (C1-C6 alkyl not substituted) and heteroaryl optionally substituted with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (unsubstituted C3-C8 cycloalkyl) or (C3-C8 heterocycloalkyl ) optionally substituted with one (unsubstituted C1-C6 alkyl), and two R4s are optionally combined to form oxo. In certain embodiments, each R4 is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2 or -CN, and two R4 are optionally combined to form oxo .
[0025] [0025] In the presently disclosed compounds of structural formula (I) and (II) as described above, E is -R2, -C (O) NR1R2, -NR1R2 or -NR1C (O) R2, where R1 and R2, in together with the nitrogen to which they are attached, they form Hca, or R1 is H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) or -C (O) O- (C1-C4 alkyl) ); and R2 is -C (O) Hca, - (C0-C3 alkyl) -Ar, - (C0-C3 alkyl) -Het, - (C0-C3 alkyl) -Cak or - (C0-C3 alkyl) -Hca. In certain embodiments, E is -C (O) NR1R2. In other embodiments, E is -NR1R2. In other embodiments, E is -R2. In still other embodiments, E is -NR1C (O) R2.
[0026] [0026] In certain embodiments of the compounds of structural formula (I) and (II) as described above, R1 is H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) or - C (O) O- (C1-C4 alkyl); and R2 is -C (O) Hca, - (C0-C3 alkyl) -Ar, - (C0-C3 alkyl) -Het, - (C0-C3 alkyl) -Cak or - (C0-C3 alkyl) -Hca. In some of the compounds of structural formula (I) as described above, R1 is H. In other embodiments, R1 is (C1-C4 alkyl), for example methyl, ethyl, n-propyl or isopropyl. In still other embodiments, R1 is -C (O) -O- (C1-C4 alkyl), for example -C (O) OCH3 or -C (O) -O-t-butyl. In certain embodiments, no alkyl of R1 is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, any alkyl of R1 is not substituted.
[0027] [0027] In some of the compounds of structural formula (I) and (II) as described above, R2 is -Hca. In certain embodiments, R2 is an optionally substituted monocyclic heterocycloalkyl. By way of example, such optionally substituted R2 fractions include, without limitation, - (optionally substituted azetidinyl), - (optionally substituted pyrrolidinyl), - (optionally substituted piperidinyl), - (optionally substituted piperazinyl) or - (optionally substituted azepanila). For example, in one embodiment, R2 can be - (optionally substituted piperidinyl) or - (optionally substituted pyrrolidinyl). In one embodiment, R2 is - (optionally substituted piperidinyl). In another embodiment, R2 is - (optionally substituted pyrrolidinyl). In another embodiment, R2 is - (optionally substituted piperazinyl).
[0028] [0028] In certain particular embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, R2 is - (optionally substituted azetidin-3-yl), - (optionally substituted piperidin-4-yl) , - (optionally substituted piperazin-4-yl), - (optionally substituted pyrrolidin-3-yl) or - (optionally substituted azepan-4-yl). For example, in one embodiment, R2 is - (optionally substituted piperidin-4-yl). In another embodiment, R2 is - (optionally substituted pyrrolidin-3-yl). In another embodiment, R2 is - (optionally substituted piperazin-4-yl).
[0029] [0029] In certain particular embodiments, when R2 is - (optionally substituted piperidin-4-yl), it is not substituted in its 2 and 3 positions.
[0030] [0030] In other embodiments, when R2 is - (optionally substituted piperidin-4-yl), it is substituted with F in position 3. For example, R2 can be
[0031] [0031] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanyl R2 fractions described above are substituted, for example, in their positions 1 In certain alternative embodiments, they can be substituted at their 4 positions (for example, when it is piperidin-1-yl) or 3 positions (for example, when it is pyrrolidin-5-yl). For example, in one embodiment, R2 is replaced (for example, at its position 1) with - (C0-C3 alkyl) -Ar or - (C0-C3 alkyl) -Het, for example - (C0-C3 alkyl unsubstituted) -Ar or - (C0-C3 unsubstituted alkyl) -Het. For example, in a particular embodiment, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its 1 position) with an optionally substituted benzyl or optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 fraction is replaced (for example, in its 1 position) with a benzyl substituted with an electron acceptor group; or a phenyl substituted with an electron acceptor group. For example, benzyl or phenyl may be substituted with an electron acceptor group selected from the group consisting of halo, cyano, - (C1-C4 fluoroalkyl), -O- (C1-C4 fluoroalkyl), -C (O) - ( C0-C4 alkyl), -C (O) O- (C0-C4 alkyl), -C (O) N (C0-C4 alkyl) (C0-C4 alkyl), -S (O) 2O- (C0-C4 alkyl), SF5, NO2 and -C (O) -Hca where Hca includes a nitrogen atom to which is attached the -C (O) -, where no alkyl, fluoroalkyl or heterocycloalkyl is substituted with a group containing aryl , heteroaryl, cycloalkyl or heterocycloalkyl. In other embodiments, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its 1 position) with an unsubstituted benzyl or an unsubstituted phenyl. In other embodiments, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with -CH (CH3) Ar, CH (C (O) OCH3) Ar or -C ( CH3) 2 Ar.
[0032] [0032] In other embodiments of the compounds disclosed here of structural formula (I) and (II) as described above, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with an optionally substituted pyridinylmethyl, an optionally substituted furanylmethyl, an optionally substituted thienylmethyl, an optionally substituted oxazolylmethyl, or an optionally substituted imidazolylmethyl. For example, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 may be substituted with an unsubstituted pyridinylmethyl, an unsubstituted furanylmethyl, an unsubstituted thienylmethyl, an unsubstituted oxazolylmethyl, or an unsubstituted imidazolylmethyl. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 fraction may be substituted with a pyridinylmethyl, furanylmethyl, thienylmethyl, oxazolylmethyl or imidazolylmethyl substituted with an electron acceptor group as described above.
[0033] [0033] In certain embodiments of the compounds disclosed here of structural formula (I) and (II) as described above, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with -L-Ar or -L-Het, where Ar and Het can be, for example, as described above with respect to - (C0-C3 alkyl) -Ar or - (C0-C3 alkyl) -Het. In that embodiment, L is -C (O) -NR9-, such as -C (O) -NH-. In other embodiments of the presently disclosed compounds of structural formula (I) as described above, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with -C (O) -O (C0-C6 alkyl), -C (O) -Het, -C (O) -Ar, -S (O) 2-Het, -S (O) 2-Ar or -S (O) 2-O ( C0-C6 alkyl), where Ar and Het can be, for example, as described above with respect to - (C0-C3 alkyl) -Ar or - (C0-C3 alkyl) -Het. In one embodiment, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with -C (O) -Het or -C (O) -Ar; in another embodiment, it is replaced (for example, in its position 1) with -S (O) 2-Het or -S (O) 2-Ar. For example, in certain embodiments, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with an optionally substituted benzoyl (for example, replaced with an electron acceptor group as described above); or with an optionally substituted nicotinyl, isonicotinyl or picolinyl (for example, optionally substituted with an electron acceptor group as described above). In other embodiments, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with an unsubstituted benzoyl; or an unsubstituted nicotinoil, isonicotinoil or picolininoil.
[0034] [0034] In other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the fraction azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2 is replaced (for example, in its position 1) with - (C0-C3 alkyl) -Cak, for example - (C0-C3 unsubstituted alkyl) -Cak (for example, -CH2-Cak) or -C (O) -Cak.
[0035] [0035] In one embodiment, R2 is not an oxo-substituted heterocycloalkyl. In another embodiment, R2 is not a tetramethyl substituted heterocycloalkyl.
[0036] [0036] In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is -C (O) NR1R2), R1 and R2, together with nitrogen at to which they are attached, form Hca. In such embodiments, Hca can be, for example, an optionally substituted piperidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted piperazinyl. When R1 and R2 are joined to form Hca, it can be defined and substituted as described above for R2 where that is Hca.
[0037] [0037] In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is -R2, or -NR1R2), R2 is -C (O) Hca. In certain of these embodiments, Hca is linked to -C (O) - via nitrogen. In other of these embodiments, Hca can be linked to -C (O) - via a carbon atom. Hca can be defined and replaced, for example, as described above with respect to R2 when that is Hca.
[0038] [0038] In certain embodiments of the compounds of structural formula (I) as described above (for example, those in which E is -R2, -NR1R2 or -C (O) NR1R2), R2 is - (C0-C3 alkyl ) -Ar or - (C0-C3 alkyl) -Het. For example, in certain embodiments, R2 is Ar, where Ar can be, for example, monocyclic, such as optionally substituted phenyl. In other embodiments, R2 is - (C1-C3 alkyl) - (optionally substituted phenyl), for example optionally substituted benzyl. In other embodiments, R2 is Het, where the Het can be, for example, monocyclic, such as optionally substituted pyridinyl or optionally substituted 1H-pyrazolyl. In other embodiments of the compounds of structural formula (I) as described above (for example, those where E is -C (O) NR1R2), R2 is - (C0-C3 alkyl) -Cak, where Cak can be, for example, monocyclic, such as optionally substituted cyclohexyl. The aryl, heteroaryl or cycloalkyl of R2 can be substituted, for example, as described above with respect to R2 when that is Hca. For example, in certain embodiments, the aryl, heteroaryl or cycloalkyl of R2 is substituted with - (C0- C3 alkyl) -Ar or - (C0-C3 alkyl) -Het, substituted as described above. In other embodiments, the aryl, heteroaryl or cycloalkyl of R2 is substituted with -O- (C0-C3 alkyl) -Ar or -O- (C0-C3 alkyl) -Het. In other embodiments, the aryl, heteroaryl or cycloalkyl of R2 is substituted with an optionally substituted heterocycloalkyl, such as a morpholin-1-yl, a 4-methylpiperazin-1-yl, or a pyrrolidin-1-yl. The ring system of fraction R2 can be replaced in any position. For example, in certain embodiments, the ring of a monocyclic R2 moiety is substituted at position 4, counted from the bond to the central pyridine, pyrazine, pyridazine or pyrimidine, or the fraction E nitrogen or carbonyl. In this embodiment, the ring of a monocyclic R2 fraction is substituted in position 3, counted from the bond to the central pyridine, pyrazine, pyridazine or pyrimidine, or the fraction E nitrogen or carbonyl.
[0039] [0039] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (III)
[0040] [0040] In certain embodiments of compounds of the formulas (I) - (III) as described above (for example, those in which E is -C (O) NR1R2), when R2 is Hca (for example, pyrrolidine or piperidine), is substituted with at least one fluorine, and also optionally substituted, for example, as described below. In certain embodiments of compounds of structural formula (III) (for example, those in which E is -C (O) NR1R2), when R2 is Hca (for example, pyrolidine or piperazine), it is substituted (for example, in nitrogen) with -C (O) -R22, -S (O) 2-R22, -C (O) -Cak, -CH2-Cak, -CH (CH3) -R22, -C (CH3) 2-R22, -CH (C (O) -O (C1-C4 alkyl)) Het, where R22 is Ar or Het, and also optionally substituted, for example, as described below.
[0041] [0041] In certain embodiments of the compounds of the formulas (I) - (III) as described above (for example, those in which E is -C (O) NR1R2), R1 and R2, together with nitrogen at which they are linked to, form Hca, as described below. For example, R1 and R2 can be combined to form an optionally substituted piperazine or an optionally substituted pyrrolidine, as described below. In other embodiments, R1 and R2, together with the nitrogen to which they are attached, form an optionally substituted spirocyclic heterocycloalkyl (for example, 2,8-diazospiro [4.5] decanyl), as described below.
[0042] [0042] In certain embodiments of the compounds of the formulas (I) - (III) as described above (for example, those in which E is -C (O) NR1Hca), T is H, -C (O) - (C1-C6 alkyl) or (C1-C6 alkyl), for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is -C (O) NR1Hca), T is -C (CH3) 2Ar, -CH2-Het, -Het, -CH2- Cak or Hca, for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is -C (O) NR1Hca), T is
[0043] [0043] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (IV)
[0044] [0044] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (V)
[0045] [0045] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VI)
[0046] [0046] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VII)
[0047] [0047] In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VIII)
[0048] [0048] In certain embodiments of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, T is
[0049] [0049] In these embodiments, Q is -O- (C0-C3 alkyl) -, -S (O) 2-, L or - (C0-C3 alkyl) - where each carbon of the (C0-C3 alkyl) ) is optional and independently substituted with one or two R16, where each R16 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl), - (C0-C6 alkyl) -Ar, - (C0- C6 alkyl) -Het, - (C0-C6 alkyl) -Cak, - (C0-C6 alkyl) -Hca, - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - ( C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C (O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, and optionally two of R16 on the same carbon are combined to form oxo. In certain embodiments, each R16 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C (O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, and two R16 on the same carbon are optionally combined to form an oxo, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl), - (C1-C6 haloalkyl), - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) -NR9 (C0-C6 alkyl), - (C0-C6 alkyl) -O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl), and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), and where no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in particular compounds, each R16 is - (C1-C3 alkyl), - (C1-C3 haloalkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - ( C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, and two R16 on the same carbon they are optionally combined to form an oxo, where each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -L - (C0-C2 alkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and where no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl , cycloalkyl or heterocycloalkyl. In certain embodiments, each R16 is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2, N3, - SF5, or -CN, and two R16 are optionally combined to form oxo. In certain embodiments, Q has at most one R16 or one oxo substituted therein. Q can be, for example, an unsubstituted - (C0-C3 alkyl) - (for example, a single bond, -CH2- or -CH2-CH2-). In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments of the compounds of formulas (I) - (VII) as described above, Q is -CH2-; -CH2CH2 -; - OCH2CH2-; O; a simple connection; -S (O) 2-; -C (O) -; -CHF-; -CH (OH) -, -C (CH3) 2-, or -CH (CH3) -.
[0050] [0050] In certain embodiments of the compounds of the formulas (I) - (VIII) as described above, T is
[0051] [0051] In certain embodiments of the compounds of the formulas (I) - (VIII) as described above (for example, those in which T is not bound to a nitrogen), T is
[0052] [0052] In certain embodiments of the compounds of structural formulas (I) - (VIII) as described above (for example, those in which the ring system designated as "B" is absent), T is
[0053] [0053] The number of substituents, y, in the ring system designated “A”, is 0, 1, 2, 3 or 4. For example, in some embodiments of the currently disclosed compounds of structural formulas (I) - (VIII) as described above, y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R5 is halo, cyan, - (C1-C4 haloalkyl), - O- (C1-C4 haloalkyl), - (C1-C4 alkyl), -O- (C1-C4 alkyl), -C (O) - (C0-C4 alkyl), -C (O) O- (C0- C4 alkyl), -C (O) N (C0-C4 alkyl) (C0-C4 alkyl), -N3, -SF5, NO2 or -C (O) -Hca where Hca contains a ring nitrogen atom through of which it is attached to -C (O) -, and in which no alkyl, haloalkyl or heterocycloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
[0054] [0054] In certain embodiments of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, each R5 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (for example , difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C ( O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -N3, -SF5, -NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl), - (C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) - NR9 (C0-C6 alkyl), - (C0-C6 alkyl) -O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl) and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, each R5 is - (C1-C3 alkyl), - (C1-C3 haloalkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -N3, -SF5, - NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -L- (C0-C2 alkyl ), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl) -C (O) - (C0 -C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, each R5 is independently halogen (for example, F, Cl), unsubstituted (C1-C6 alkoxy) (for example, methoxy, ethoxy), - (C1-C6 haloalkoxy) (for example, trifluoromethoxy) , -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (unsubstituted C1-C4 alkyl), -N ( C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with a (C1-C6 alkyl not substituted) and heteroaryl optionally substituted with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (unsubstituted C3-C8 cycloalkyl) or (C3-C8 heterocycloalkyl ) optionally substituted with an unsubstituted (C1-C6 alkyl) .In certain embodiments, each R5 is independently methyl, ethyl, n-propyl, isopropyl a, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2, N3, -SF5, or -CN.
[0055] [0055] In one embodiment of the compounds of the formulas (I) - (VIII) as described above, y is 0. In another embodiment, y is 1. In another embodiment, y is 2.
[0056] [0056] In the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the ring system designated "A" is heteroaryl, aryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, the ring system designated "A" is an aryl or a heteroaryl. The ring system designated "A" can be, for example, a monocyclic aryl or heteroaryl. In one embodiment, when the "A" ring system is aryl, Q is a - (C0-C3 alkyl) - optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a - (C1-C3 alkyl) - having as its only substitution a single oxo, or an - (C0-C3 alkyl) - unsubstituted. In certain embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -CH2-; -CH2CH2-; a simple connection; -S (O) 2-; -C (O) -; or -CH (CH3) -. In other embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -CF-, -CH (OH) - or -C (CH3) 2-. In other embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -O-, -OCH2- or -OCH2CH2-.
[0057] [0057] For example, in certain embodiments of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the ring system designated "A" is monocyclic aryl, such as phenyl. In one embodiment, y is 1 and R5 is linked to phenyl in the para position relative to Q. In one embodiment, y is 1 and R5 is linked to phenyl in the meta position relative to Q. In certain embodiments, y is 1 and R5 is selected from the group consisting of halo, cyano, - (C1-C4 haloalkyl), -O- (C1-C4 haloalkyl), - (C1-C4 alkyl), -O- (C1-C4 alkyl) , -C (O) - (C0-C4 alkyl), -C (O) O- (C0-C4 alkyl), -C (O) N (C0-C4 alkyl) (C0-C4 alkyl), NO2 and - C (O) -Hca where Hca contains a nitrogen atom in the ring through which it is attached to -C (O) -, and where neither (C0-C4 alkyl) or (C1-C4 alkyl) is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. R5 can be, for example, -Cl, -F, cyano, -N3, SF5, -C (O) CH3, -C (O) OH, -C (O) NH2, methoxy, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy . In another embodiment, the fraction
[0058] [0058] In another embodiment of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the ring system designated "A" is a heteroaryl. For example, in certain embodiments, the ring system designated "A" is a pyridyl, a thienyl, or a furanyl. In another embodiment, the ring system designated "A" is an isoxazolyl. In one embodiment, when the "A" ring system is heteroaryl, Q is a - (C0-C3 alkyl) - optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a - (C1-C3 alkyl) - having as its only substitution a single oxo, or an - (C0-C3 alkyl) - unsubstituted. In certain embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -CH2-; a simple connection; -S (O) 2-; -C (O) -; or -CH (CH3) -. In other embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -O-, -CF-, -CH (OH) - or -C (CH3) 2-. In other embodiments, the ring system designated "A" is an aryl or a heteroaryl and Q is -O-, -OCH2- or -OCH2CH2-.
[0059] [0059] In another embodiment of the presently disclosed compounds of formulas (I) - (VIII) as described above, the ring system designated "A" is a heterocycloalkyl. For example, in certain embodiments, the ring system designated "A" is a tetrahydro-2H-pyranyl or a morpholino. In this embodiment, when the “A” ring system is a heterocycloalkyl, Q is a single bond. In another such embodiment, Q is -CH2- or -C (O) -. In another such embodiment, Q is -O-, -OCH2- or -OCH2CH2-.
[0060] [0060] In another embodiment of the presently disclosed compounds of formulas (I) - (VIII) as described above, the ring system designated "A" is a cycloalkyl. For example, in certain embodiments, the ring system designated "A" is cyclohexyl. In this embodiment, when the “A” ring system is a cycloalkyl, Q is -CH2- or -C (O) -. In another such embodiment, Q is a simple link. In another such embodiment, Q is -O-, -OCH2- or -OCH2CH2-.
[0061] [0061] In certain embodiments of the compounds of formulas (I) - (VIII) as described above, T is H, - (C1-C6 alkyl) or -C (O) (C1-C6 alkyl). In certain of these embodiments, the alkyl fractions of T are not substituted. In other such embodiments, the alkyl fractions of T are optionally substituted as described below. For example, in certain embodiments, T is H, ispropropyl, or -C (O) -t-butyl.
[0062] [0062] In certain embodiments of the compounds of formulas (I) - (VIII) as described above, T is -C (CH3) 2Ar, -CH2-Het, -Het, -CH2-Cak or -Hca. The fractions -Ar, -Het, -Cak and -Hca can, for example, be replaced with y fractions R5, as described above for the ring system designated "A".
[0063] [0063] In certain embodiments of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, fraction T is selected from the group consisting of
[0064] [0064] For example, in certain embodiments of the compounds of formulas (I) - (VIII) as described above, the T fraction is selected from
[0065] [0065] In an embodiment of the presently disclosed compounds of structural formulas (I) - (VII) as described above, the compound has structural formula (IX):
[0066] [0066] In another embodiment of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the compound has structural formula (X):
[0067] [0067] In another embodiment of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the compound has the structural formula (XI):
[0068] [0068] In another embodiment of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the compound has structural formula (XII):
[0069] [0069] In another embodiment of the presently disclosed compounds of structural formulas (I) - (VIII) as described above, the compound has the structural formula (XIII):
[0070] [0070] In the compounds of any of the structural formulas (I) - (XIII) as described above, w, the number of substituents on the pyridine, pyridazine, pyrazine or central pyrimidine is 0, 1, 2 or 3. For example, in a embodiment, w is 0, 1 or 2. In another embodiment, w is 0. In other embodiments, w is at least 1, and at least one R3 is selected from the group consisting of halo, cyan, - (C1-C4 fluoroalkyl), -O- (C1-C4 fluoroalkyl), -C (O) - (C0-C4 alkyl), -C (O) O- (C0-C4 alkyl), -C (O) N (C0-C4 alkyl) (C0-C4 alkyl), -S (O) 2O- (C0-C4 alkyl), NO2 and -C (O) -Hca where Hca includes a nitrogen atom to which is attached -C (O) -, where no alkyl, fluoroalkyl or heterocycloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in certain embodiments, at least one R3 is halo (for example, chlorine) or - (C1-C4 alkyl) (for example, methyl, ethyl or propyl). In certain embodiments, an R3 is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine at the meta position with respect to fraction J.
[0071] [0071] In certain embodiments of the compounds of any of the structural formulas (I) - (XIII) as described above, each R3 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (for example , difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C ( O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl) , - (C1-C6 haloalkyl), - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) -NR9 (C0-C6 alkyl), - (C0-C6 alkyl) - O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl), and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, each R3 is - (C1-C3 alkyl), - (C1-C3 alkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, in that each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -L- (C0-C2 alkyl), - (C0- C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in certain embodiments, each R3 is halo (for example, chlorine) or - (C1-C4 alkyl) (for example, methyl, ethyl or propyl). In certain embodiments, each R3 is independently halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (for example, trifluoromethoxy) , -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (unsubstituted C1-C4 alkyl), -N ( C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with a (C1-C6 alkyl not substituted) and heteroaryl optionally substituted with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (unsubstituted C3-C8 cycloalkyl) or (C3-C8 heterocycloalkyl ) optionally substituted with an unsubstituted (C1-C6 alkyl) .In certain embodiments, each R3 is independently methyl, ethyl, n-propyl, isopropyl a, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2 or -CN.
[0072] [0072] In certain embodiments of the compounds of any of the structural formulas (I) - (XIII) as described above, w is at least one, and at least one R3 is -NR8R9. For example, in one embodiment, w is 1. In certain of these embodiments, an R3 is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine at the meta position with respect to fraction J.
[0073] [0073] In other embodiments of the compounds of any of the structural formulas (I) - (XIII) as described above, w is at least one, and at least one R3 is - (C0-C3 alkyl) -Y1- (C1 -C3 alkyl) -Y2- (C0-C3 alkyl), where each of Y1 and Y2 is independently L, -O-, -S- or -NR9-. For example, in one embodiment, w is 1. In certain of those embodiments, R3 is substituted in the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position with respect to fraction J. In a particular embodiment, R3 is - CH2-N (CH3) -CH2-C (O) -OCH3.
[0074] [0074] In certain embodiments of the presently disclosed compounds of structural formulas (I) - (XIII) as described above, the compound has the structural formula (XIV):
[0075] [0075] In certain embodiments of the presently disclosed compounds of structural formula (XIV) as described above (for example, those in which E1 is -C (O) - or is absent, Y3 is N and Y4 is N. In other embodiments (for example, those in which E1 is -C (O) -NR1-), Y3 is C or CH and Y4 is N. In other embodiments, Y3 is N and Y4 is C or CH. embodiments, Y3 is C or CH and Y4 is C or CH; in such embodiments, the fractions E1 and G may be arranged, for example, cis in the cycloalkyl ring. of the structural formula (XIV) as described above, z is 1. In other embodiments, z is 0.
[0076] [0076] In certain embodiments of the presently disclosed compounds of structural formulas (I) - (XIV) as described above, all D1, D2 and D3 are CH or C substituted with one of the w R3, and the fraction R2 is a optionally substituted piperidine. For example, in one embodiment, a compound has the structural formula (XV):
[0077] [0077] In other embodiments of compounds according to structural formula (XV), one of the R15's is F. For example, F may be substituted on the alpha carbon with respect to the E1 fraction. Accordingly, in certain embodiments, a compound has the structural formula (XVI):
[0078] [0078] In certain embodiments of the compounds of the structural formulas (XV) - (XX), the compound has the structural formula (XXI):
[0079] [0079] In the compounds of structural formulas (XV) - (XXI), the regiochemistry around the central pyridine can be as described in relation to any of the claims (IX) - (XI). In addition, the E1 fraction of any of these compounds may be absent, it may be -C (O) -, -C (O) NR1-or -NR1C (O) -. In this embodiment, a compound of any of the structural formulas (XV) - (XXI) has the structural formula (XXII):
[0080] [0080] In the compounds of structural formulas (XV) - (XXIX) as described above, G and Q can be as described above with respect to structural formulas (I) - (XIV). For example, in certain embodiments, G is CH2, CO, or SO2. In certain embodiments, Q is CH2, CO, SO2 or O.
[0081] [0081] In the compounds of structural formulas (XV) - (XXIX) as described above, R17 and T can be as described above with respect to structural formulas (I) - (XIV). For example, in certain embodiments, R17 is an optionally substituted phenyl, for example, substituted with 0-2 groups R30 as described above. In other embodiments, R17 is an optionally substituted heteroaryl, for example, substituted with 0-2 groups R30 as described above. In certain embodiments, T is
[0082] [0082] As examples, in certain embodiments, the compounds have one of the structural formulas (XXX) - (XXXV):
[0083] [0083] In other embodiments of the presently disclosed compounds of structural formulas (I) - (XIII) as described above, the compound has the structural formula (XXXVI):
[0084] [0084] In other embodiments of the presently disclosed compounds of structural formulas (I) - (XIII) as described above, the compound has structural formula (XVI):
[0085] [0085] In certain embodiments of the presently disclosed compounds of the structural formula (XXXVII) as described above (for example, those in which E1 is -C (O) - or is absent), Y5 is N and Y6 is N. In other embodiments (for example, those in which E1 is -C (O) -NR1-), Y5 is C or CH and Y6 is N. In other embodiments, Y5 is N and Y6 is C or CH. In other embodiments, Y5 is C or CH and Y6 is C or CH. In certain embodiments of the presently disclosed compounds of the structural formula (XXXVII) as described above, z1 is 1 and z2 is 0. In other embodiments, z1 is 0 and z2 is 1.
[0086] [0086] In an embodiment of the compounds of the structural formulas (XIV) - (XXXVII) as described above, Q is a single bond. In another embodiment, Q is -CH2-. In other embodiments, Q is -C (O) - or -S (O) 2-. In other embodiments, Q is -NH-C (O) - or -CH2-NH-C (O) -. In other embodiments, Q is -C (CH3) 2-, -CH2CH2-, -CH (CH3) -, -CH (OH) - or -CHF-. In other embodiments, Q is -O-. In other embodiments, Q is -CH2O- or -OCH2CH2-. In other embodiments, Q is -CH (COOMe) - or -CH (COOEt) -.
[0087] [0087] In an embodiment of the compounds of the structural formulas (XIV) - (XXXVII) as described above, G is -CH2-. In other embodiments, G is -C (O) - or -S (O) 2-. In other embodiments, G is -CH (CH3) - or -C (CH3) 2-. In other embodiments, G is -O-. In other embodiments, G is -C (O) -NH- or -C (O) -NH-CH2-. In other embodiments, G is -CH2CH2-. In other embodiments, G is a single bond. In other embodiments, G is -O-. In other embodiments, G is -OCH2- or -CH2CH2O-. In other embodiments, G is -CH (COOMe) - or -CH (COOEt) -.
[0088] [0088] In the presently disclosed compounds of structural formulas (XIV) - (XXXVII) as described above, the fractions Q and G described above can be combined in any possible combination. For example, in one embodiment, Q is a single bond and G is -CH2-or -C (O) -. In another embodiment, Q is -CH2- or -C (O) - and G is a single bond. In yet another embodiment, Q is -CH2- or -C (O) - and G is -CH2- or -C (O) -.
[0089] [0089] In certain embodiments of the compounds of the structural formulas (XIV) - (XXXVII) as described above, the ring system designated "A" is aryl or heteroaryl, as described above. In one embodiment, the ring system designated "A" is replaced with one or more electron acceptor groups as described above. In another embodiment, R17 is replaced with one or more electron acceptor groups as described above. In certain embodiments, the ring system designated "A", R17 or both are not substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, the azacycloalkyl to which it is attached -G-R17 is a piperidinyl; in other embodiments, it is a pyrrolidinyl.
[0090] [0090] In the presently disclosed compounds of structural formulas (XIV) - (XXXVII) as described above, v is 0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For For example, v can be 0, or it can be 1 or 2.
[0091] [0091] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XXXVII) as described above, two R15's are combined to form an oxo. The oxo can be linked, for example, in the alpha position with respect to the nitrogen of an azacycloalkyl ring. In other embodiments, two R15's are not combined to form an oxo.
[0092] [0092] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XXXVII) as described above, v is at least 1 (for example, 1) and at least one R15 is F. In certain embodiments , the F can be arranged, for example, in an alpha position with respect to the E1 fraction. When F and E1 are both arranged in saturated carbons, they can be arranged in a cis relationship with each other. For example, in certain embodiments, a compound has the structural formula (XXXVIII)
[0093] [0093] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XLI) as described above, when v is 4, not all four fractions R15 are (C1-C6 alkyl).
[0094] [0094] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XLI) as described above, each R15 is independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (for example , difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C ( O) R10, - (C0-C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN and two R15 on the same carbon are optionally combined to form oxo, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl), - (C1-C6 haloalkyl), - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) -NR9 (C0- C6 alkyl), - (C0-C6 alkyl) -O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl) and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, each R15 is - (C1-C3 alkyl), - (C1-C3 alkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN and two R15 on the same carbon are optionally combined to form oxo, where each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -L - (C0-C2 alkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and where no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl , cycloalkyl or heterocycloalkyl. In certain embodiments, each R15 is independently halogen (for example, F, Cl), unsubstituted (C1-C6 alkoxy) (for example, methoxy, ethoxy), - (C1-C6 haloalkoxy) (for example, trifluoromethoxy) , -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (unsubstituted C1-C4 alkyl), -N ( C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with a (C1-C6 alkyl not substituted) and heteroaryl optionally substituted with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (unsubstituted C3-C8 cycloalkyl) or (C3-C8 heterocycloalkyl ) optionally substituted with one (unsubstituted C1-C6 alkyl), and two R4s are optionally combined to form oxo. In certain embodiments, each R15 is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2, N3, -SF5, or -CN, and two R15 on the same carbon are optionally combined to form oxo. In some embodiments, an R15 is -C (O) NR9R7, which can be linked, for example, in an alpha position with respect to piperidine nitrogen, or in the position linked to the E1 fraction.
[0095] [0095] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XLI) as described above, R17 is an unsubstituted aryl or heteroaryl. In other embodiments, R17, Ar or Het is substituted with 1, 2 or 3 substituents independently selected from - (C1-C6 alkyl), - (C1-C6 haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L-R7, - (C0-C6 alkyl) -NR8R9, - (C0-C6 alkyl) -OR10, - (C0-C6 alkyl) -C (O) R10, - (C0- C6 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C6 alkyl), - (C1-C6 haloalkyl) , - (C0-C6 alkyl) -L- (C0-C6 alkyl), - (C0-C6 alkyl) -NR9 (C0-C6 alkyl), - (C0-C6 alkyl) -O- (C0-C6 alkyl) , - (C0-C6 alkyl) -C (O) - (C0-C6 alkyl) and - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, R17, Ar or Het is substituted with 1, 2 or 3 substituents independently selected from - (C1-C3 alkyl), - (C1-C3 haloalkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O ) 0-2R10, -halogen, -NO2 and -CN, where each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl ) -L- (C0-C2 alkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl) -O- (C0-C2 alkyl), - (C0-C2 alkyl ) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halo, cyano, - (C1-C4 haloalkyl), -O- (C1-C4 haloalkyl), - (C1-C4 alkyl), -O - (C1-C4 alkyl), -C (O) - (C0-C4 alkyl), -C (O) O- (C0-C4 alkyl), -C (O) N (C0-C4 alkyl) (C0- C4 alkyl), NO2 and -C (O) -Hca in which no alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (C1-C4 unsubstituted alkyl), -N (C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O) N (Unsubstituted C1-C4 alkyl) 2, -C (O) OH, C (O) O (unsubstituted C1-C6 alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, optionally substituted heterocycloalkyl with one (C1-C6 unsubstituted alkyl) and heteroaryl optionally substituted with one (C1-C6 unsubstituted alkyl), where each R33 is (C1-C6 unsubstituted alkyl), (C1-C6 haloalkyl (C3-C8 cycloalkyl not substituted) or (C3-C8 heterocycloalkyl) optionally substituted with one (unsubstituted C1-C6 alkyl), and two R4s are optionally combined to form oxo. certain embodiments, each R17 is substituted with 1, 2 or 3 substituents selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, - halogen, -NO2, N3, -SF5, or -CN. R17 can be substituted, for example, with one of these substituents, or two of these substituents.
[0096] [0096] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XLI) as described above, at least one of R17 and the ring system designated "A" is replaced with -C (O) NR27R29 , where R27 is selected from H, - (C1-C6 alkyl), - (C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), - (C0-C6 alkyl) -L- (C0-C6 alkyl ), - (C0-C6 alkyl) -NR9 (C0-C6 alkyl), - (C0-C6 alkyl) -O- (C0-C6 alkyl), - (C0-C6 alkyl) -C (O) - (C0 -C6 alkyl), - (C0-C6 alkyl) -S (O) 0-2- (C0-C6 alkyl), where no heterocycloalkyl, alkyl or haloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and R29 is -H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) or -C (O) -O- (C1-C4 alkyl) where none (C1-C4 alkyl) is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl, or R27 and R29, together with the nitrogen to which they are attached, form Hca (eg, morpholino, pip erazinyl, pyrrolidinyl or piperidinyl). In certain embodiments, heterocycloalkyl, alkyl or haloalkyl groups of R27 and R29 are substituted with 1, 2 or 3 substituents selected from halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy ) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (C1-C6 unsubstituted alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, -NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -N3, -SF5, -C (O) -NH2, C (O) NH (C1-C4 alkyl unsubstituted), C (O) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - ( NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and heteroaryl optionally substituted with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1 -C6 haloalkyl (unsubstituted C3-C8 cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with one (unsubstituted C1-C6 alkyl ), and two R4 are optionally combined to form oxo. In certain embodiments, the heterocycloalkyl, alkyl or haloalkyl groups of R27 and R29 are optionally substituted with acetyl, -NH2, -OH, methoxy, ethoxy, trifluoromethoxy, -SO2Me, -halogen, -NO2, N3, -SF5, or - CN. In one embodiment, R27 and R29 are both H. In another embodiment, R27 is CH3 and R29 is H.
[0097] [0097] In certain embodiments of the presently disclosed compounds of structural formulas (XIV) - (XLI) as described above, the -G-R17 fraction is selected from the group consisting of
[0098] [0098] For example, in certain embodiments of the compounds of formulas (XIV) - (XLI) as described above, the fraction -G-R17 is selected from
[0099] [0099] In certain embodiments, the compounds presently disclosed have the structural formula (XLII):
[0100] [00100] In certain embodiments, the compounds presently disclosed have the structural formula (XLIII):
[0101] [00101] In certain embodiments, the compounds currently disclosed have the structural formula (XLIV):
[0102] [00102] In certain embodiments, the compounds currently disclosed have the structural formula (XLV):
[0103] [00103] In certain embodiments, the compounds currently disclosed have the structural formula (XLVI):
[0104] [00104] In certain embodiments, the compounds currently disclosed have the structural formula (XLVII):
[0105] [00105] In certain embodiments, the compounds currently disclosed have the structural formula (XLVIII):
[0106] [00106] In certain embodiments, the compounds currently disclosed have the structural formula (XLIX):
[0107] [00107] In certain embodiments, the compounds presently disclosed have the structural formula (L):
[0108] [00108] In certain embodiments, the compounds presently disclosed have the structural formula (LI):
[0109] [00109] In certain embodiments, the compounds presently disclosed have the structural formula (LII):
[0110] [00110] In certain embodiments, the compounds currently disclosed have the structural formula (LIII):
[0111] [00111] In certain embodiments, the compounds currently disclosed have the structural formula (LIV):
[0112] [00112] In certain embodiments, the compounds presently disclosed have the structural formula (LV):
[0113] [00113] In certain embodiments, the compounds presently disclosed have the structural formula (LVI):
[0114] [00114] In certain embodiments, the compounds currently disclosed have the structural formula (LVII):
[0115] [00115] In certain embodiments, the compounds currently disclosed have the structural formula (LVIII):
[0116] [00116] where one or two of X1, X2, X3 and X4 are N, and the others are CH or C replaced with one of w R3, and all other variables are independently defined as described above with respect to structural formulas (I ) - (XLIII). In one embodiment, X1 is N and X2, X3 and X4 are CH or C replaced with one of w R3. For example, in certain embodiments, the fraction
[0117] [00117] In certain embodiments, the compounds presently disclosed have the structural formula (LX):
[0118] [00118] In certain embodiments, the compounds currently disclosed have the structural formula (LXI):
[0119] [00119] In certain embodiments, the compounds currently disclosed have the structural formula (LXII):
[0120] [00120] In certain embodiments, the compounds currently disclosed have the structural formula (LXIII):
[0121] [00121] In certain embodiments, the compounds currently disclosed have the structural formula (LXIV):
[0122] [00122] In certain embodiments, the compounds currently disclosed have the structural formula (LXV):
[0123] [00123] In certain embodiments, the compounds presently disclosed have the structural formula (LXVI):
[0124] [00124] In certain embodiments, the compounds presently disclosed have the structural formula (LXVII):
[0125] [00125] In certain embodiments, the compounds currently disclosed have the structural formula (LXVIII):
[0126] [00126] In certain embodiments, the compounds currently disclosed have the structural formula (LXVIII):
[0127] [00127] For example, in certain embodiments, the fraction
[0128] [00128] In certain embodiments, the compounds currently disclosed have the structural formula (LXIX):
[0129] [00129] In certain embodiments, the compounds currently disclosed have the structural formula (LXX):
[0130] [00130] In certain embodiments, the compounds presently disclosed have the structural formula (LXXI):
[0131] [00131] In certain embodiments, the compounds currently disclosed have the structural formula (LXXII):
[0132] [00132] In certain embodiments, the compounds currently disclosed have the structural formula (LXXIII):
[0133] [00133] In certain embodiments, the compounds currently disclosed have the structural formula (LXXIV):
[0134] [00134] In certain embodiments, the compounds currently disclosed have the structural formula (LXXV):
[0135] [00135] In certain embodiments, the compounds presently disclosed have the structural formula (LXXVI):
[0136] [00136] In certain embodiments, the compounds presently disclosed have the structural formula (LXXVII):
[0137] [00137] In certain embodiments, the compounds presently disclosed have the structural formula (LXXVIII):
[0138] [00138] In certain embodiments, the compounds currently disclosed have the structural formula (LXXIX):
[0139] [00139] In certain embodiments, the compounds presently disclosed have the structural formula (LXXX):
[0140] [00140] In certain embodiments, the compounds currently disclosed have the structural formula (LXXXI):
[0141] [00141] In certain embodiments, the compounds currently disclosed have the structural formula (LXXXII):
[0142] [00142] In certain embodiments, the compounds currently disclosed have the structural formula (LXXXIII):
[0143] [00143] In certain embodiments, the compounds currently disclosed have the structural formula (LXXXIV):
[0144] [00144] In certain embodiments of compounds having structural formulas (XIII) - (LXXVIII), the fraction
[0145] [00145] Another aspect of the disclosure provides compounds of the structural formula (LXXXV):
[0146] [00146] In certain embodiments of compounds having structural formulas (XIII) - (LXXVI) as described above, the -G-R17 fraction is p-chlorobenzyl, p-fluorobenzyl, p-cyanobenzyl, p-cyano-m- fluorobenzyl, p-cyanobenzoyl, p-cyanobenzenesulfonyl, cyclohexanocarbonyl, benzoyl, benzyl, phenyl, cyclohexylmethyl, phenoxy, phenylmethoxy, 1-phenylethyl, p-nitrophenyl, cyanophenyl, p- (trifluoromethyl-pyridyl-3-pyril, 3-pyril) - ila, 4-morpholinyl, 4-methylpiperazin-1-yl, p-cyanobenzylcarbamofla, m, m-difluorobenzyl, p-fluoro-m-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-methylbenzoxi, m-fluorophen, m-fluorophen -fluorophenoxy, m-cyanophenoxy, m-methoxyphenoxy, m-methylphenoxy, p-cyanophenoxy, p-fluorophenoxy, pyrid-3-yl, thien-3-yl, phenethyl, α-carboethoxybenzyl, pyrid-4-ylmethyl, 1- ( p-cyanophenyl) -1-methylethyl, p- (trifluoromethyl) benzenesulfonyl, p- (trifluoromethyl) phenoxy, p- (trifluoromethyl) benzyl, m- (trifluoromethyl) benzyl, p-methylsulfonylbenxyl, p-methylsulfonylphenylphenyl p-pyrrolidinylbenzyl, or p-methoxybenzyl.
[0147] [00147] As will be recognized by the professional, the various forms of realization and characteristics described above can be combined to form other forms of realization contemplated by the disclosure. For example, in an embodiment of the compounds of some of the formulas (I) - (LXXV) as described above, Q is -CH2-, as described above, and G is -CH2-, as described above. In another embodiment of the compounds of some of the formulas (I) - (LXXV) as described above, x is 0 and each w is 0. In another embodiment of the compounds of some of the formulas (I) - (LXXVI ), x is 0, each w is 0 and each v is 0.
[0148] [00148] In addition, the various fractions -E and T- fractions (“B” ring system) - J- described above in relation to any of the structural formulas (I) - (LXXVI) can be combined around the pyridine, pyrazine , pyridazine or central pyrimidine (for example, in any of the ways described with respect to structural formulas (IX) - (XIII)) to give rise to additional embodiments of compounds specifically contemplated by such disclosure.
[0149] [00149] Examples of compounds according to structural formula (I) include those listed in Table 1. These compounds can be prepared according to the general schemes described below, for example, using procedures analogous to those described below in the Examples.
[0150] [00150] For reasons of simplicity, chemical fractions are defined and referred to in this document mainly as univalent chemical fractions (for example, alkyl, aryl, etc.). However, these terms are also used to refer to the corresponding multivalent fractions in the appropriate structural circumstances that will be clear to practitioners. For example, while an “alkyl” moiety may refer to a monovalent radical (eg CH3-CH2-), in some circumstances a bivalent bond moiety may be “alkyl”, in which case professionals will understand that alkyl is a radical divalent (for example, C2 alkylene -CH2-CH2- can be described as a C2 alkyl group), which is equivalent to the term "alkylene". (Similarly, in circumstances where a divalent fraction is required and is said to be "aryl", practitioners will understand that the term "aryl" refers to the corresponding divalent fraction, arylene.) It is understood that all atoms have its normal number of valences for bonding (that is, 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S). Nitrogens in the compounds presently disclosed can be hypervalent, for example, an N-oxide or tetra-substituted ammonium salt. Sometimes a fraction can be defined, for example, as (A) aB-, where a is 0 or 1. In such cases, when a is 0 the fraction is B-, and when a is 1 the fraction is AB -.
[0151] [00151] As used herein, the term "alkyl" includes the alkyl, alkenyl and alkynyl groups having a designated number of carbon atoms, desirably from 1 to about 12 carbons (i.e., including 1 and 12). The term "Cm-Cn alkyl" means an alkyl group having from m to n carbon atoms (that is, including m and n). The term "Cm-Cn alkyl" means an alkyl group having from m to n carbon atoms. For example, "C1-C6 alkyl" is an alkyl group having from one to six carbon atoms. Alkyl and alkyl groups can be linear or branched and, depending on the context, can consist of a monovalent radical or a divalent radical (i.e., an alkylene group). In the case of an alkyl or alkyl group having zero carbon atoms (i.e., "C0 alkyl"), the group is merely a simple covalent bond if it is a divalent radical or it is a hydrogen atom if it is a monovalent radical. For example, the fraction "- (C0-C6 alkyl) -Ar" means the attachment of an optionally substituted aryl via a single bond or an alkylene bridge having from 1 to 6 carbons. Examples of "alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyla, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbon atoms is not specified, the “alkyl” or “alkyl” fraction has from 1 to 12 carbons.
[0152] [00152] The term "haloalkyl" is an alkyl group substituted with one or more halogen atoms, for example F, Cl, Br and I. A more specific term, for example, "fluoroalkyl" is an alkyl group substituted with one or more fluorine atoms. Examples of "fluoroalkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, hexafluoroisopropyl and the like. In certain embodiments of the compounds disclosed herein, each haloalkyl is a fluoroalkyl.
[0153] [00153] The term "aryl" represents an aromatic carbocyclic ring system having a single ring (e.g., phenyl) that is optionally fused to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. "Arila" includes ring systems having multiple condensed rings and at least one of which is aromatic (for example, 1,2,3,4-tetrahydronaftila, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl and 6,7,8,9-tetrahydro-5H-benzo [a] cycloheptenyl. The aryl groups here are not substituted or, when specified as “optionally substituted”, may, unless stated otherwise, be substituted in one or more positions capable of being substituted with several groups, as described below.
[0154] [00154] The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur in an aromatic ring. The heteroaryl may be fused to one or more cycloalkyl or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazol, zazolyl, zazolyl, zazolyl, zazolyl, zazolyl, zazolyl, zazole , benzimidazolila, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolila, tiadiazolila, benzo [1,4] oxazinila, triazolila, tetrazolila, isotiazolila, naftiridinila, isocromanila, cromanila, tetrahidroisoquinolinila, isoindolinila, isobenzotetrahidrofuranila, isobenzotetrahidrotienila, isobenzotienila, benzoxazolila, piridopiridinila, benzotetrahidrofuranila , benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazine, benzyl, chromium, benzine, chromium, benzyl, pyridine quinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl oxide, N-oxide oxide, N-oxide oxide, N-oxide indolyl, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazol N-oxide, oxazol N-oxide N-oxide of thiazolyl, N-oxide of indolizinyl, N-oxide of indazolyl, N-oxide of benzothiazolyl, N-oxide of benzimidazolyl, N-oxide of pyrrolyl, N-oxide of oxadiazolyl, N-oxide of thiadiazolyl, N-oxide of thiadiazolyl triazolyl oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, S, benzothiopyranyl S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tziazolyl, tziazolyl, tziazolyl, tziazolyl, tziazolyl, tziazolyl, tziazolyl, tziazol, , Pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, N -pyrrolyl oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. The heteroaryl groups here are not substituted or, when specified as "optionally substituted", may, unless stated otherwise, be substituted in one or more positions capable of being substituted with several groups, as described below.
[0155] [00155] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing at least one heteroatom which is preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is located in a non-ring aromatic. The heterocycloalkyl can be saturated (i.e., a heterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl). The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings and / or phenyl rings. In certain embodiments, heterocycloalkyl groups have from 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. Examples of heterocycloalkyl groups include, for example, azabicyclo [2.2.2] octyl (in each case also "quinuclidinyl" or a quinuclidine derivative), azabicyclo [3.2.1] octyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, S, Thiomorpholinyl S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrohydrinyl, isohydrohydine, 3-dihydrohydine, 3-dihydroxy , homothiomorpholinyl, S, homothiomorpholinyl S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrimidyl, dihydroxylhydroxyl, hydrochloride, dihydroxylhydroxyl, imidazole, imidazole Especially desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2 (1H) -ila, tetrahydropyranyl, piperidinyl, aza-bicyclo [2.2.2] octyl, γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl), γ- butriolactamila (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, S, thiomorpholinyl S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkyl groups here are not substituted or, when specified as "optionally substituted", may, unless stated otherwise, be substituted in one or more positions capable of being substituted with several groups, as described below.
[0156] [00156] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring or ring system, which can be saturated (ie, a cycloalkyl) or partially unsaturated (ie, a cycloalkenyl). The cycloalkyl ring can optionally be fused or otherwise connected (for example, bridged systems) to other cycloalkyl rings. Preferred cycloalkyl groups have from 3 to 7 members in a single ring. Most preferred cycloalkyl groups have 5 or 6 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaftila and bicyclo [2.2.1] heptane. The cycloalkyl groups here are not substituted or, when specified as “optionally substituted”, they can be substituted in one or more positions capable of being substituted with several groups.
[0157] [00157] The term "oxa" means a divalent oxygen radical in a chain, sometimes called -O-.
[0158] [00158] The term "oxo" means oxygen bonded via a double bond, sometimes called = O or, for example, in the description of a carbonyl "C (O)", can be used to show a substituted carbon with oxo.
[0159] [00159] The term "electron acceptor group" means a group that removes more electronic density from the structure to which it is attached than a similarly bonded hydrogen atom. For example, electron acceptor groups can be selected from the group consisting of halo, cyano, - (C1-C4 fluoroalkyl), -O- (C1-C4 fluoroalkyl), -C (O) - (C0-C4 alkyl), - C (O) O- (C0-C4 alkyl), -C (O) N (C0-C4 alkyl) (C0-C4 alkyl), -S (O) 2O- (C0-C4 alkyl), -SF5, NO2 and -C (O) -Hca in which the Hca includes a nitrogen atom to which the -C (O) - is attached, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with a group containing aryl, heteroaryl, cycloalkyl or heterocycloalkyl .
[0160] [00160] The term "substituted", when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are replaced, each independently of the other, by the same or different substituent groups as defined in low.
[0161] [00161] Substituent groups for replacing hydrogens on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R60, halo, -OM +, = O, -OR70, -SR70, -S-M +, = S, -NR80R80, = NR70, = N-OR70, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, = N2, -N3, -SO2R70, -SO2O M +, -SO2OR70, - OSO2R70, -OSO2O M +, -OSO2OR70, -P (O) (O-) 2 (M +) 2, -P (O) (OR70) O-M +, -P (O) (OR70) 2, -C (O ) R70, -C (S) R70, -C (NR70) R70, -C (O) OM +, -C (O) OR70, -C (S) OR70, -C (O) NR80R80, -C (NR70) NR80R80, -OC (O) R70, -OC (S) R70, -OC (O) O-M +, -OC (O) OR70, - OC (S) OR70, -NR70C (O) R70, -NR70C (S ) R70, -NR70CO2-M +, -NR70CO2R70, -NR70C (S) OR70, -NR70C (O) NR80R80, -NR70C (NR70) R70 and - NR70C (NR70) NR80R80. Each R60 is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, -O-M +, = O, -OR71, -SR71, -S-M +, = S, -NR81R81, = NR71, = N-OR71, trihalomethyl, -CF3, -CN, -OCN, -SCN , -NO, -NO2, = N2, -N3, -SO2R71, -SO2O M +, -SO2OR71, -OSO2R71, -OSO2O-M +, -OSO2OR71, -P (O) (O-) 2 (M +) 2, - P (O) (OR71) O-M +, -P (O) (OR71) 2, -C (O) R71, -C (S) R71, -C (NR71) R71, -C (O) O-M + , -C (O) OR71, -C (S) OR71, -C (O) NR81R81, -C (NR71) NR81R81, -OC (O) R71, -OC (S) R71, -OC (O) O- M +, -OC (O) OR71, -OC (S) OR71, -NR71C (O) R71, -NR71C (S) R71, -NR71CO2-M +, -NR71CO2R71, -NR71C (S) OR71, -NR71C (O) NR81R81, - NR71C (NR71) R71 and -NR71C (NR71) NR81R81. Each R70 is independently hydrogen or R60; each R80 is independently R70 or, alternatively, two R80s, taken together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocycloalkyl that can optionally include from 1 to 4 equal or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have a -H or C1-C3 alkyl substitution; and each M + is a counterion with a single positive global charge. Each R71 is independently hydrogen or R61, where R61 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, -O-M +, = O, -OR72, -SR72, -S-M +, = S, -NR82R82, = NR72, = N-OR72, trihalomethyl, -CF3, -CN, -OCN , -SCN, -NO, -NO2, = N2, -N3, -SO2R71, -SO2O M +, -SO2OR72, -OSO2R72, -OSO2O-M +, -OSO2OR72, -P (O) (O-) 2 (M +) 2, -P (O) (OR72) O-M +, -P (O) (OR72) 2, -C (O) R72, -C (S) R72, -C (NR72) R72, -C (O) O-M +, -C (O) OR72, -C (S) OR72, -C (O) NR82R82, -C (NR72) NR82R82, -OC (O) R72, -OC (S) R72, -OC (O ) O-M +, -OC (O) OR72, -OC (S) OR72, -NR72C (O) R72, -NR72C (S) R72, -NR72CO2-M +, -NR72CO2R72, -NR72C (S) OR72, -NR72C (O) NR82R82, - NR72C (NR72) R72 and -NR72C (NR72) NR82R82; and each R81 is independently R71 or alternatively, two R81s, taken together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocycloalkyl that can optionally include from 1 to 4 additional heteroatoms equal or different selected from the group consisting of O, N and S, of which N may have a -H or C1-C3 alkyl substitution. Each R72 is independently hydrogen, (C1-C6 alkyl) or (C1-C6 fluoroalkyl); each R82 is independently R72 or alternatively, two R82s, taken together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocycloalkyl that can optionally include 1, 2, 3 or 4 additional heteroatoms equal or different selected from the group consisting of O, N and S, of which N may have a -H or C1-C3 alkyl substitution. Each M + can be independently, for example, an alkaline ion, such as K +, Na +, Li +; an ammonium ion, such as + N (R60) 4; or an alkaline earth ion, such as [Ca2 +] 0.5, [Mg2 +] 0.5, or [Ba2 +] 0.5 (”the subscript 0.5 means, for example, that one of the counterions for these divalent alkaline earth ions can be an ionized form of a presently disclosed compound and the other a typical counterion, such as chloride, or two presently ionized molecules may serve as counterions for these divalent alkaline earth ions, or a doubly ionized compound may serve as a counterion for these divalent alkaline earth ions ). As specific examples, -NR80R80 is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, Ν-piperazinyl, 4-methyl-piperazin-1-yl and Ν-morpholinyl. In certain embodiments, each R60 is H or (unsubstituted C1-C6 alkyl). In certain embodiments, each R70 is H or (unsubstituted C1-C6 alkyl). In certain embodiments, each R80 is H or (unsubstituted C1-C6 alkyl).
[0162] [00162] Substituent groups for hydrogens on unsaturated carbon atoms in "substituted" alkene, alkaline, aryl and heteroaryl groups are, unless otherwise specified, -R60, halo, -O-M +, -OR70, -SR70, - S-M +, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3M +, -SO3R70, -OSO2R70, -OSO3M +, -OSO3R70, -PO3 -2 (M +) 2, -P (O) (OR70) O-M +, -P (O) (OR70) 2, -C (O) R70, -C (S) R70, -C (NR70) R70, -CO2-M +, -CO2R70, -C (S) OR70, -C (O) NR80R80, -C (NR70) NR80R80, -OC (O) R70, -OC (S) R70, -OCO2 M +, -OCO2R70, -OC (S) OR70, -NR70C (O) R70, -NR70C (S) R70, -NR70CO2-M +, -NR70CO2R70, -NR70C (S) OR70, -NR70C (O) NR80R80, - NR70C (NR70) R70 and -NR70C (NR70) NR80R80, where R60, R70, R80 and M + are as previously defined.
[0163] [00163] Substituent groups for hydrogen on nitrogen atoms in "substituted" heteroalkyl and heterocycloalkyl groups are, unless otherwise specified, -R60, -O-M +, -OR70, -SR70, -S-M +, -NR80R80, trihalomethyl, -CF3, -CN, -NO, -NO2, -S (O) 2R70, -S (O) 2O-M +, -S (O) 2OR70, -OS (O) 2R70, -OS (O) 2O -M +, -OS (O) 2OR70, -P (O) (O-) 2 (M +) 2, -P (O) (OR70) O-M +, -P (O) (OR70) (OR70), - C (O) R70, -C (S) R70, -C (NR70) R70, -C (O) OR70, -C (S) OR70, -C (O) NR80R80, -C (NR70) NR80R80, -OC (O) R70, -OC (S) R70, -OC (O) OR70, -OC (S) OR70, -NR70C (O) R70, -NR70C (S) R70, -NR70C (O) OR70, -NR70C ( S) OR70, -NR70C (O) NR80R80, -NR70C (NR70) R70 and -NR70C (NR70) NR80R80, where R60, R70, R80 and M + are as previously defined.
[0164] [00164] In certain embodiments as described above, the substituent groups on carbon atoms can also or alternatively be -SF5.
[0165] [00165] In certain embodiments of the compounds disclosed herein, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
[0166] [00166] In certain embodiments, an "optionally substituted alkyl", unless otherwise specified, is substituted with halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, - NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O ) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and optionally substituted heteroaryl with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (C3-C8 unsubstituted cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6 alkyl). action, "optionally substituted alkyl" is also or alternatively optionally substituted with -N3 or -SF5.
[0167] [00167] In certain embodiments, an "optionally substituted aryl", unless otherwise specified, is substituted with halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, - NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O ) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and optionally substituted heteroaryl with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (C3-C8 unsubstituted cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6 alkyl). No, "optionally substituted aryl" is also or alternatively optionally substituted with -N3 or -SF5.
[0168] [00168] In certain embodiments, an "optionally substituted heteroaryl", unless otherwise specified, is substituted with halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (C1-C6 unsubstituted alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, - NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O ) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and optionally substituted heteroaryl with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (C3-C8 unsubstituted cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6 alkyl). In addition, "optionally substituted heteroaryl" is also or alternatively optionally substituted with -N3 or -SF5.
[0169] [00169] In certain embodiments, an "optionally substituted cycloalkyl", unless otherwise specified, is substituted with halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (C1-C6 unsubstituted alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, - NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O ) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and optionally substituted heteroaryl with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (C3-C8 unsubstituted cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6 alkyl). In addition, "optionally substituted cycloalkyl" is also or alternatively optionally substituted with -N3 or -SF5.
[0170] [00170] In certain embodiments, an "optionally substituted heterocycloalkyl", unless specified otherwise, is substituted with halogen (for example, F, Cl), (C1-C6 alkoxy) (for example, methoxy, ethoxy) unsubstituted, - (C1-C6 haloalkoxy) (e.g., trifluoromethoxy), -SH, -S (unsubstituted C1-C6 alkyl), -S (C1-C6 haloalkyl), -OH, -CN, -NO2, - NH2, -NH (unsubstituted C1-C4 alkyl), -N (C1-C4 unsubstituted alkyl) 2, -C (O) -NH2, C (O) NH (C1-C4 unsubstituted alkyl), C (O ) N (C1-C4 unsubstituted alkyl) 2, -C (O) OH, C (O) O (C1-C6 unsubstituted alkyl), - (NH) 0-1SO2R33, - (NH) 0-1COR33, heterocycloalkyl optionally substituted with one (unsubstituted C1-C6 alkyl) and optionally substituted heteroaryl with one (unsubstituted C1-C6 alkyl), where each R33 is (unsubstituted C1-C6 alkyl), (C1-C6 haloalkyl (C3-C8 unsubstituted cycloalkyl) or (C3-C8 heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6 alkyl). In one embodiment, "optionally substituted heterocycloalkyl" is also or alternatively optionally substituted with -N3 or -SF5.
[0171] [00171] The compounds disclosed herein can also be provided as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" or "a respective pharmaceutically acceptable salt" refers to salts prepared from non-toxic and pharmaceutically acceptable acids or bases, including inorganic acids and bases and organic acids and bases. If the compound is basic, salts can be prepared from non-toxic and pharmaceutically acceptable acids. Such salts can be, for example, acid addition salts of at least one of the following acids: benzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic, phosphoric acid, propanoic acid, succinic acid, sulfuric acid, tartaric acid (d, l, or dl), tonic acid (toluenesulfonic acid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethyl succinic acid, fumaric acid, galactaric acid (musclic acid), D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hypuric acid, isetionic acid (ethanolsulfonic acid), lactobionic acid, maleic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfate, 3-hydroxy acid -2-naphthoic, 1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid, (+) - camphoric acid, d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharin, salicylic acid, gentisic acid, and / or 4-acetamidobenzoic acid.
[0172] [00172] The compounds described here can also be provided in prodrug form. “Pro-drug” refers to a derivative of an active compound (drug) that requires a transformation in the conditions of use, such as inside the body, to release the active drug. It is common, but not necessary, for prodrugs to be pharmacologically inactive until they are converted into the active drug. Prodrugs are typically obtained by masking a functional group in the drug, which is believed to be partly required for activity, with a pro-group (defined below) to form a carrier fraction that undergoes a transformation, such as cleavage, under the conditions of use specified to release the functional group, and thus the active drug. Cleavage of the carrier fraction may proceed spontaneously, such as through a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change or exposure to a physical or environmental parameter, such as a change in temperature. The agent can be endogenous to the conditions of use, such as an enzyme present in the cells where the prodrug or acidic conditions of the stomach are administered, or it can be provided exogenously. A wide variety of pro-groups, as well as the resulting carrier fractions, suitable for masking functional groups in active drugs to give rise to prodrugs are well known in the art. For example, a hydroxyl functional group can be masked as a sulfonate, ester or carbonate carrier fraction, which can be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group can be masked as a carrier fraction of amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl, which can be hydrolyzed in vivo to provide the amino group. A carboxyl group can be masked as an ester-carrying fraction (including silyl esters and thioesters), amide or hydrazide, which can be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable pro-groups and their respective carrier fractions will be clear to practitioners.
[0173] [00173] The compounds disclosed here can also be provided in the form of N-oxides.
[0174] [00174] The presently disclosed compounds, salts, prodrugs and Ν-oxides can be provided, for example, in the form of solvate or hydrate.
[0175] [00175] The compounds can be evaluated for binding to a membrane-bound adiponectin receptor by conducting a competitive adiponectin binding assay. In one of these procedures, the HEK 293 cell membrane is coated on a COSTAR 384 plate, which is then blocked with 1% casein. Globular adiponectin with polyhistidine tail and a candidate compound are incubated with the membrane in HEPES buffer. Unbound ligands are removed by washing and the degree of adiponectin binding is determined using anti-polyhistidine conjugated to horseradish peroxidase. Compounds that compete with adiponectin binding to the membrane (i.e., generate a reduced signal compared to a control performed without a candidate compound) can be chosen as hits and further screened using the functional assays described below to identify receptor agonists adiponectin.
[0176] [00176] An In-Cell Western assay can be conducted to demonstrate activation of the AMPK pathway in human liver cells by globular adiponectin using glutathione S-transferase (GST). AMPK activity can be measured by the relative concentration of phosphorylated acetyl Co-A carboxylase, which is one of AMPK's products. An increase in pACC is correlated with an increase in the oxidation rate of fatty acids.
[0177] [00177] The compounds of structural formulas (I) - (LXXXVI) can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in unit dosage formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients . The term parenteral, as used herein, includes techniques for percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection and the like.
[0178] [00178] Pharmaceutical compositions can be prepared using the compounds presently disclosed. For example, in one embodiment, a pharmaceutical composition includes a pharmaceutically acceptable carrier, diluent or excipient, and compound as described above with respect to structural formulas (I) - (LXXXVI).
[0179] [00179] In the pharmaceutical compositions disclosed herein, one or more compounds of structural formulas (I) - (LXXXVI) may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. Pharmaceutical compositions containing compounds of structural formulas (I) - (LXXXVI) may be in a form suitable for oral use, for example, in the form of tablets, troches, sweets, aqueous or oily suspensions, dispersible powders or granules, emulsion, capsules hard or soft, or syrups or elixirs.
[0180] [00180] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions, and these compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents for provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients that are suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated using known techniques. In some cases, these coatings can be prepared using appropriate techniques to delay disintegration and absorption in the gastrointestinal tract and, thus, provide a sustained action for a longer period. For example, a time-delaying material, such as glyceryl monostearate or glyceryl distearate, can be employed.
[0181] [00181] Formulations for oral use can also be presented as hardened gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.
[0182] [00182] Formulations for oral use can also be presented as sweets.
[0183] [00183] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents, such as a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethylene-oxycethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol mono-oleate, or ethylene oxide condensation products with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl p-hydroxybenzoate, or n-propyl, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0184] [00184] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palate-friendly oral preparations. Such compositions can be preserved by adding an antioxidant, such as ascorbic acid.
[0185] [00185] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
[0186] [00186] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase may consist of a vegetable oil or a mineral oil or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example, acacia or tragacanth gum, naturally occurring phosphatides, for example, soy, lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents.
[0187] [00187] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring agents, and dyes. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. Such a suspension can be formulated according to the known technique using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic and parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. For this purpose, any fixed soft oil, including synthetic mono- or diglycerides, can be employed. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.
[0188] [00188] Compounds of structural formulas (I) - (LXXXVI) can be formulated into lotions, oils or powders for application to the skin according to certain methods described below.
[0189] [00189] Compounds of structural formulas (I) - (LXXXVI) can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and thus will melt in the rectum, releasing the drug. These materials include cocoa butter and polyethylene glycols.
[0190] [00190] Compounds of structural formulas (I) - (LXXXVI) can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants, such as local anesthetics, preservatives and buffering agents, can be dissolved in the vehicle.
[0191] [00191] The compounds disclosed here can be prepared using procedures that are familiar to the practitioner and as described here. For example, compounds of structural formula (I) can be prepared according to Schemes 1-6, below, or similar synthetic schemes:
[0192] [00192] Referring to Scheme 1, a monomethyl ester of pyridinodicarboxylic acid (i), for example, is coupled to an amine (here a substituted 1-benzoylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinocarboxamide (ii ). The ester is saponified to form the corresponding carboxylic acid (iii), which is then coupled to a suitable amine (in this case, a substituted 1-benzylpiperazine) to form Compound 4 of Table 1.
[0193] [00193] Referring to Scheme 2, a bromopyridine dicarboxylic acid, for example, is coupled to an amine (here a substituted 1-benzylpiperidine-4-amine) to form a bromine (iv) substituted pyridinocarboxamide, which is then coupled to a suitable amine (in this case, a substituted 4-phenoxypiperidine) using a palladium catalyst to form Compound 17 from Table 1.
[0194] [00194] Referring to Scheme 3, a monomethyl ester of pyridinodicarboxylic acid (v), for example, is coupled to an amine (here a substituted 1-benzylpiperidine-4-amine) to form a carboxymethyl substituted pyridinecarboxamide (vi ). The ester is saponified to form the corresponding carboxylic acid (vii), which is then coupled to a suitable amine (in this case, a substituted 4-benzoylpiperidine) to form Compound 160 of Table 1.
[0195] [00195] Referring to Scheme 4, a pyridine dicarboxylic acid (viii), for example, is coupled to an equivalent of an amine (here, a substituted 1-benzylpiperizine), then to methanol and trimethylsilyl (diazomethane) to form a carbomethoxy substituted pyridinecarboxamide (ix), which is saponified to give a carboxylic acid substituted pyridinocarboxamide (x). An amine (in this case, 1-phenylpiperazine) is coupled to the carboxylic acid substituted pyridinocarboxamide (x) to form Compound 94 in Table 1.
[0196] [00196] Referring to Scheme 5, a bromopyridinecarboxamide (xi) is coupled to a substituted 1-benzylpiperidine-4-carboxamide using a palladium catalyst to form Compound 46 in Table 1. Reactions of this general type are described in more detail , for example, in Wrona, Iwona E. et al., Journal of Organic Chemistry (2010), 75 (9), 2820-2835.
[0197] [00197] Scheme 6 describes a preparation that can be used to obtain gem-dimethylpiperazines for use in the manufacture of compounds analogous to Compound 125 in Table 1. A piperazin-2-one is uniquely protected with trityl chloride, then it is coupled to an appropriate bromide (here, a substituted benzyl bromide) to form a protected 1- (substituted benzyl) piperazin-2-one in position 4. The oxo is converted to a gem-dimethyl using Grignard chemistry, then the trityl is removed to provide the desired gem-dimethyl piperazine. Details are provided in the Examples below, and in Xiao, K-J .; Luo, J-M .; Ye, K-Y .; Wang, Y .; Huang, P-Q. Angew. Chem. Int. Ed. 2010, 49, 3037-3040.
[0198] [00198] The professional can adapt the reaction sequences in Schemes 1-6 to suit the desired target molecule. Obviously, in certain situations, the practitioner will use different reagents to perform one or more of the individual steps or to use protected versions of some of the substituents. Additionally, the practitioner will recognize that compounds of structural formulas (I) - (LXXXVI) can be synthesized using different pathways together.
[0199] [00199] Compounds suitable for use in the pharmaceutical compositions presently disclosed include compounds from Table 1, above. These compounds can be prepared according to the general scheme described above, for example, using a procedure similar to that described below in the Examples.
[0200] [00200] Not wishing to be restricted by theory, the inventors assume that compounds of structural formulas (I) - (LXXXVI) activate the AMPK pathway. Activation of the AMPK pathway has the effect of increasing glucose uptake, decreasing glycogen synthesis and increasing oxidation of fatty acids, thereby reducing the concentration of glycogen, triglycerides and intracellular fatty acids and causing an increase in insulin sensitivity . Since they activate the AMPK pathway, compounds of structural formulas (I) - (LXXXVI) must also inhibit the inflammatory processes that occur during the early stages of atherosclerosis. Accordingly, compounds of structural formulas (I) - (LXXXVI) may be useful in the treatment of type II diabetes and in the treatment and prevention of atherosclerosis, cardiovascular disease, obesity and non-alcoholic fatty liver disease.
[0201] [00201] In one aspect and without limitation to the theory, the present compounds exert AMPK activation activity by binding to an adiponectin receptor, acting as effective adiponectin mimetics. Adiponectin is a protein hormone exclusively expressed in adipose tissue and secreted from it and is the most abundant specific adipose tissue protein. Adiponectin has been implicated in the modulation of glucose and lipid metabolism in insulin sensitive tissues. Decreased levels of adiponectin in the circulation have been demonstrated in some insulin-resistant states, such as obesity and type 2 diabetes mellitus and also in patients with coronary artery disease, atherosclerosis and hypertension. Adiponectin levels are positively correlated with insulin sensitivity, HDL (high-density lipoprotein) levels and insulin-stimulated glucose disposition, and inversely correlated with adiposity and levels of glucose, insulin and triglycerides. The drugs thiazolidinedione, which increase insulin sensitivity by activating the γ receptor activated by peroxisome proliferators, increase the production of endogenous adiponectin in humans.
[0202] [00202] Adiponectin binds to its receptors in the liver and musculoskeletal and thus activates the AMPK pathway. Similarly, in one aspect, the present compounds act as adiponectin receptor agonists. Adiponectin 1 and 2 receptors are membrane-bound proteins present in skeletal muscle and adipose tissue.
[0203] [00203] Accordingly, another aspect of this disclosure relates to a method of activating the AMPK pathway. Accordingly, a method of activating the AMPK pathway in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of the formulas (I) - (LXXXVI).
[0204] [00204] In one embodiment, a method for increasing the oxidation of fatty acids in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate of the same) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI). Acetyl Co-A carboxylase (ACC) catalyzes the formation of malonyl Co-A, a potent inhibitor of oxidation of fatty acids; phosphorylation of ACC greatly reduces its catalytic activity, thereby reducing the concentration of malonyl Co-A and increasing the oxidation rate of fatty acids. Since the compounds presently disclosed can increase the rate of phosphorylation of ACC, then they can reduce the inhibition of fatty acid oxidation and thereby increase its overall rate.
[0205] [00205] In another embodiment, a method for reducing the concentration of glycogen in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, A-oxide (or solvate or hydrate thereof) ) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0206] [00206] In another embodiment, a method for increasing glucose uptake in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) ) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0207] [00207] In another embodiment, a method for reducing triglyceride levels in an individual includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0208] [00208] In another embodiment, a method for increasing an individual's insulin sensitivity includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0209] Accordingly, the compounds and compositions disclosed herein can be used to treat a variety of metabolic disorders. For example, in one embodiment, a method of treating type II diabetes in an individual in need of such treatment includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, solvate, hydrate, N-oxide or composition described above. In another embodiment, a method of treating or preventing atherosclerosis or cardiovascular disease in an individual includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0210] [00210] As described above, the compounds disclosed here can act as activators of the AMPK pathway. Accordingly, in another embodiment, a method comprises modulating the AMPK pathway (in vitro or in vivo) by contacting a cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above, or administration of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above, to a mammal (e.g., a human) in an amount sufficient to modulate the AMPK pathway and study the effects induced in this way. These methods are useful for studying the AMPK pathway and its role in biological mechanisms and disease states in vitro and in vivo.
[0211] [00211] In certain embodiments, the compounds disclosed herein affect lipid signaling pathways. For example, in some embodiments, the compounds up-regulate the activity of ceramidase. Ceramide plays a central role in the mechanism of sphingolipids, and is the immediate precursor to sphingomyelin and glycosphingolipid, as well as the bioactive products sphingosine and sphingosine-1-phosphate. In addition, endogenous ceramide itself mediates, at least in part, the actions of a variety of stimuli in cell differentiation, apoptosis, and growth suppression. Ceramide is deacylated by ceramidase to form sphingosine, which in turn is phosphorylated into sphingosine-1-phosphate by sphingosine kinase.
[0212] [00212] Increased levels of ceramide have been shown to induce cellular apoptosis, differentiation and senescence. In addition, increased levels of ceramide are linked to a variety of diseases and disorders, including, for example, Batten's disease, inflammatory bowel diseases, diffuse intravascular coagulation, fever, protein catabolism and / or lipid depletion, hepatosplenomegaly associated with inflammatory or metabolic diseases of the liver, endomyocarditis, activation of endothelial cells and leukocytes, capillary thrombosis, meningo-encephalitis due to infectious agents, complications in organ transplantation, rheumatoid arthritis and connective tissue diseases, autoimmune diseases, hyperthyroidism, damage caused by agents radiation / chemotherapy and chronic fatigue syndrome.
[0213] [00213] Positive regulation of ceramidase function (and thus reduction of ceramide concentration) can be used to treat disorders involving deficient cell proliferation (growth) or in which cell proliferation is desired for other reasons, for example, disorders degenerative, growth failure, injuries, physical trauma, and diseases in which ceramide accumulates in cells, such as Fabry's disease. Other disorders that may benefit from ceramidase activation include neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis, and aging disorders, such as immune dysfunction, as well as disorders like those listed above linked to increased levels of ceramide.
[0214] [00214] The compounds, salts, prodrugs, N-oxides, solvates and hydrates described herein can be administered, for example, to a mammalian host to delay cellular responses associated with the activation of the ceramide-mediated signal transduction pathway. The compounds can be useful, for example, to provide protection against senescence or cellular apoptosis, as occurs as a result of trauma (for example, radiation-induced dermatitis) and aging (for example, of the skin or other organs).
[0215] [00215] Another embodiment consists of a method of positive regulation of the function of ceramidase in a cell (in vivo or in vitro), in which the method includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, pro - drug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of the formulas (I) - (LXXXVI).
[0216] [00216] In another embodiment, a method for decreasing the concentration of ceramide in a cell (in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, such as a compound of one of formulas (I) - (LXXXVI).
[0217] [00217] In another embodiment, a method for inhibiting responses, activated by ceramide, to stimuli in a cell (in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug , N-oxide (or solvate or hydrate thereof) or composition described above. The stimuli can be, for example, stimuli for cellular senescence and / or apoptosis.
[0218] [00218] Another embodiment consists of a method of treating or preventing a disease or disorder in which cell proliferation is deficient or desired in an individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically salt acceptable, prodrug, N-oxide (or solvate or hydrate thereof) or composition of that compound described above, for example, a compound of one of the formulas (I) - (LXXXVI). Several applicable diseases and disorders are described above.
[0219] [00219] Another embodiment consists of a method of treating a disease or disorder linked to increased levels of ceramide in an individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug. , N-oxide (or solvate or hydrate thereof) or composition as described herein. Several applicable diseases and disorders are described above. In certain embodiments, the individual has a ceramide level greater than about 50 pmol / 106 cells.
[0220] [00220] Furthermore, since some drugs can induce high levels of ceramide, the compounds, salts, prodrugs, N-oxides, solvates and hydrates described here can be usefully co-administered with these drugs to improve, at least partially, that effect. For example, in certain embodiments, an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein is co-administered with a corticosteroid (for example, dexamethasone ), an anti-inflammatory (for example, indomethacin), an antiviral (for example, interferon), an immunosuppressant (for example, cyclosporine), a chemotherapy agent (for example, adriamycin), and an immunopotentiator (for example, an immunoglobulin or a vaccine), or an endocrinological agent (for example, methimazole). As will be appreciated by the professional, co-administration contemplates not only administration at the same time, but also administration at different times, but with pharmacological effects overlapping over time.
[0221] [00221] Another embodiment is a method to reduce the effect of aging on an individual's skin, wherein the method includes contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, Α-oxide (or solvate or hydrate thereof) or composition as described herein.
[0222] [00222] Another embodiment consists of a method of treatment or prevention of radiation-induced dermatitis on the skin of an individual, wherein the method includes contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, Α-oxide ( or solvate or hydrate thereof) or composition as described herein.
[0223] [00223] To identify and select therapeutic compounds for use in the treatment of conditions associated with ceramide, cells (or intracellular components, such as microsomes) that have not been exposed to a senescence-inducing agent or apoptosis (for example, cytokines, such as TNF- α, or exogenous stimuli, such as heat, radiation or chemical agents) are exposed to this agent and the candidate compound. The inhibition of senescence or apoptosis is measured as a function of cell growth. The practitioner will be familiar with techniques for obtaining such measurements.
[0224] [00224] For example, inhibition of cell senescence can be measured after serum deprivation in serum-dependent cells. The growth of many cell types depends on factors in the serum. Thus, serum deprivation of these cells provides a model for evaluating compounds to modulate cellular responses to intracellular ceramide-mediated signal transduction. In particular, removal of serum from serum-dependent cell cultures produces increased intracellular levels of endogenous ceramide and may also increase intracellular levels of endogenous diacyl glycerol (see, for example, Jayadev, et al., J. Biol. Chem., 270 , 2047-2052 (1995)). To evaluate the inhibitory effect of the compounds described here under conditions associated with ceramide in vitro, the serum removal model can be used. Specifically, 3T3 fibroblasts can be seeded in 96-well microtiter plates in DMEM in the presence of 10% fetal bovine serum. The cells are incubated to 90% confluence. The medium is removed, and the cells are washed and re-incubated in DMEM devoid of serum. A test compound, at a variety of concentrations (for example, 0, 4, 40 or 400 μM), and cell permeable ceramide (for example, 0, 5 or 10 μM) are added to the wells. After 24 hours of incubation, 0.5 μCi of [3 H] thymidine is added to each well for 2 hours. DNA synthesis in the tested cell population is assessed using conventional [3 H] thymidine incorporation detection techniques. The results of this assay can be used to establish the cell senescence inhibitory efficacy of the test compound.
[0225] [00225] The inhibition of cell apoptosis can be determined, for example, using stimulation via CD95. The recruitment of the CD95 cell surface receptor (also called the Fas / Apo-1 antigen) triggers cell apoptosis. DX2 is a functional anti-FAS (CD95) antibody that, by means of CD95 binding, will activate the catalysis, by sphingomyelinase, of sphingomyelin hydrolysis and ceramide production (see, for DX2, Cifone, et al., J Exp. Med., 177, 1547-1552 (1993)). Thus, the binding of CD95 is a model of conduction of apoptosis through the sphingomyelin signal transduction pathway. To assess the inhibitory effect of the compounds disclosed here on ceramide-mediated cell apoptosis, human T lymphoblasts (Jurkat) are suspended, at 2x106 cells / mL, in RPMI-1640 supplemented with insulin, transferrin, selenium and glutamine. After incubation for 2 hours at room temperature with a test compound, pentoxifylline, or a control compound (Ro-1724), 25 ng / mL of anti-FAS antibody is added to each suspension. After an additional 2 hours, cell apoptosis is measured as a function of the number of cells (counted by hemocytometer) that excluded the vital dye erythrosine B. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound.
[0226] [00226] To assess the inhibitory effect of the compounds disclosed here on the death of human lymphocytes, human lymphocytes from peripheral blood are isolated from normal human blood and individuals from monocyte depletion by adhering to a plastic substrate. The lymphocytes are then cultured in RPMI-1640 medium with 10% autologous plasma at an initial concentration of 2x106 cells / mL. Aliquots of the cell samples are divided and half of the samples are incubated with a test compound or 6,7-dimethoxy-1 (2H) -isoquinoline (Aldrich) for four days. The remaining half of the samples are left to stand for four days. Cell viability after four days is determined by excluding the dye erythrosine B in a hemocytometer. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound in human lymphocytes compared to untreated lymphocytes.
[0227] [00227] The ceramide-activated protein kinase (CaPK) is a 97 kDa protein that is exclusively bound to membranes and is believed to serve a role in the sphingomyelin signal transduction pathway. In particular, CaPK is believed to mediate the phosphorylation of a peptide derived from the amino acid sequence involving Thr.sup.669 of the epidermal growth factor receptor (i.e., amino acids 663-681). This site is also recognized by the MAP kinase activated by mitogens (also called a family of kinases regulated by extracellular signals). Thus, the effect of the compounds disclosed here on CaPK activity in cells may be an indicator of the effect that the compounds exert on signal transduction in the sphingomyelin pathway. Accordingly, Jurkat cells are suspended, at 2x106 cells / ml, in RPMI-1640 medium as described above for the cell apoptosis experiment. After incubation for 2 hours, a test compound; 20 μM ceramide or 25 ng / mL anti-FAS DX2 antibody is added to each suspension and incubated for 15 minutes. After centrifugation and washing, the cells were homogenized separately in a Dounce homogenizer. The levels of ceramide kinase in each test sample can be assessed as described by Liu, et al., J. Biol. Chem., 269, 3047-3052 (1994), which is hereby incorporated by reference in its entirety. In summary, the membrane fraction is isolated from each homogenate test sample of cells treated by means of ultracentrifugation and is processed on a 10% PAGE gel. The gel is washed with guanadine-HCl, and is renatured in HEPES buffer. Then [32P] -ATP is added to the gel and remains there for 10 minutes. Then, the gel is extensively washed with 5% TCA. The autophosphorylated kinase is detected by means of autoradiography. The results of this assay can be used to establish the CaPK inhibitory efficacy of the compounds disclosed here.
[0228] [00228] The activity of ceramidase can be measured in a variety of ways. For example, a sample from an individual or a sample of cells can be evaluated in vitro for RNA levels or proteins, structure, and / or activity of the expressed RNA or ceramidase proteins. Thus, many methods common in the field can be employed, including but not limited to enzymatic ceramidase assays.
[0229] [00229] Cellular levels of ceramide can be monitored directly, or by indirectly monitoring the concentrations of a ceramide metabolite in a cell. For example, ceramide levels can be measured directly by isolating lymphocytes from an individual's peripheral blood. The cells are centrifuged to remove supernatant, and lipids are removed from the cell pellet. The organic phase containing ceramide can be evaluated using the diacylglycerase kinase assay for phosphorylation of ceramide, which is then evidenced by autoradiography. Methods of conducting diacylglycerase kinase assays are described, for example, in Cifone, M.G. et al., J. Exp. Med., 180 (4), 1547-52 (1993), Jayadev et al., J. Biol. Chem., 270, 2047-2052 (1995), and Perry, D.K. et al., Methods Enzymology, 312, 22-31 (2000), each of which is incorporated herein by reference in its entirety.
[0230] [00230] The AMPK activating compounds currently disclosed are useful for increasing metabolic efficiency, for example, by increasing the oxidative capacity of fibers, resistance and aerobic workload. In particular, the present compounds are useful for the treatment and regulation of disorders of mitochondrial function, including, without limitation, exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonic epilepsy, as associated with torn red fiber syndrome , Kearns-Sayre syndrome, Leigh syndrome, mitochondrial myopathy and encephalopathy syndrome, lactic acidosis, stroke (MELAS) and stroke-like episodes. The disclosed compounds are also useful for the treatment of muscular dystrophy states, such as Duchenne and Becker muscular dystrophies and Friedreich's ataxia.
[0231] [00231] The function of the AMPK activating compounds currently disclosed is also to reduce oxidative stress and side effects of that stress. Many diseases, including several of those listed above, have side effects caused by damage due to excessive oxidative stress, which can be treated using the compounds disclosed here. For example, free radical damage has been implicated in neurological disorders, such as Parkinson's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Alzheimer's disease. Additional diseases where excessive damage due to free radicals occur include, in general, hypoxic conditions and a variety of other disorders. More specifically, these disorders include ischemia, ischemic reperfusion injury (such as coronary or cerebral reperfusion injury), myocardial ischemia or infarction, cerebrovascular accidents (such as thromboembolic or hemorrhagic stroke) that can lead to ischemia in the brain, ischemia operative, traumatic bleeding (for example, a hypovolemic stroke that can lead to CNS hypoxia or anoxia), resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders (such as rheumatoid arthritis or systemic lupus erythematosus), Down, Hallervorden-Spatz disease, Huntington's chorea, Wilson's disease, diabetic angiopathy (such as peripheral vascular disease or retinal degeneration), uveitis, chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, asthma, neoplasia, disease Crohn's disease, inflammatory bowel disease and pancreatitis. Free radical damage is also implicated in a variety of age-related disorders, in particular ophthalmic conditions, such as cataracts and age-related macular degeneration.
[0232] [00232] In particular, the present compounds are useful for the treatment of neurological disorders associated with reduced mitochondrial function, oxidative stress, or both. For example, Alzheimer's disease, dementia and Parkinson's disease can be treated using the present AMPK activating compounds.
[0233] [00233] Metabolic efficiency is increased by the AMPK activating compounds disclosed. Thus, the compounds can be administered to an individual to improve exercise efficiency and athletic performance. In addition, conditions including, without limitation, hypoxic states, angina pectoris, coronary ischemia and damage to organs secondary to coronary vessel occlusion, intermittent claudication, multi-stroke dementia, myocardial infarction, stroke, high altitude sickness and heart failure , including congestive heart failure, can be treated using the disclosed compounds.
[0234] [00234] Disorders and inflammatory effects can be treated using the present compounds. For example, in one aspect, the present compounds are particularly useful for the treatment of lung inflammation, such as that involved in asthma, COPD and transplant rejection. Similarly, the present compounds are useful in reducing inflammation of organs, in particular inflammation associated with macrophages, such as inflammation of the kidney, liver and other organs. The anti-inflammatory activity of the compounds currently disclosed can be assessed as is known to those skilled in the art, for example, using the mixed lymphocyte response in vitro.
[0235] [00235] Accordingly, one aspect of the disclosure refers to a method of treating or ameliorating a disorder or condition related to oxidative stress, mitochondrial dysfunction, free radical damage and / or metabolic inefficiency in a needy individual, where the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.
[0236] [00236] Another aspect of the present disclosure relates to a method of treating or ameliorating a disorder of mitochondrial dysfunction in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, a pharmaceutically acceptable salt, drug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the disorder is selected from the group consisting of exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonic epilepsy (as associated with torn red fiber syndrome), Kearns-Sayre syndrome, Leigh, myopathy syndrome and mitochondrial encephalopathy, lactic acidosis, stroke (MELAS) and stroke-like episodes.
[0237] [00237] Another aspect of the disclosure relates to a method of increasing metabolic efficiency in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide ( or solvate or hydrate thereof) or pharmaceutical composition described above. These methods can be used to increase the oxidative capacity of fibers, strength, aerobic workload, or any combination of these. These methods can be used, for example, to improve exercise efficiency, resistance to exercise and / or athletic performance in an individual.
[0238] [00238] Another aspect of the present disclosure relates to methods for mimicking the effects of exercise in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.
[0239] [00239] Another aspect of the disclosure concerns a method of treating or ameliorating a disorder in a needy individual, in which the disorder is selected from the group consisting of hypoxic states, angina pectoris, coronary ischemia and damage to organs secondary to occlusion of coronary vessels, intermittent claudication, multi-stroke dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure, in which the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt , prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.
[0240] [00240] Another aspect of the disclosure relates to a method of treating or ameliorating a state of muscular dystrophy in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug , N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the state of muscular dystrophy is Duchenne muscular dystrophy, Becker muscular dystrophy, or Freidreich's ataxia.
[0241] [00241] Another aspect of the disclosure relates to a method for increasing the oxidative capacity of a muscle fiber, wherein the method includes contacting the muscle fiber with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate) or hydrate thereof) or pharmaceutical composition described above. Contact can be made in vitro or in vivo.
[0242] [00242] Another aspect of the disclosure relates to a method for reducing oxidative stress in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.
[0243] [00243] Another aspect of the disclosure relates to a method for reducing free radical damage to a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N- oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.
[0244] [00244] Another aspect of the disclosure refers to a method of treating or ameliorating a disorder or condition in a needy individual, in which the disorder or condition is selected from the group consisting of neurological disorders, hypoxic conditions, ischemia, reperfusion injury ischemic, ischemic or myocardial infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders, Down syndrome, Hallervorden-Spatz disease, Huntington's chorea, Wilson's disease, diabetic angiopathy, uveitis, chronic obstructive pulmonary disease (COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease, pancreatitis and age-related disorders, in which the method includes administering to the individual an effective amount of a compound, pharmaceutically salt acceptable, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of these disorders and conditions are discussed above.
[0245] [00245] Another aspect of the disclosure consists of a method of treating or ameliorating a neurological disorder in a needy individual, in which the neurological disorder is associated with reduced mitochondrial function, oxidative stress, or both, in which the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of these neurological disorders are discussed above.
[0246] [00246] Another aspect of the disclosure relates to a method for reducing oxidative stress in a cell, wherein the method includes contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate of the same) or pharmaceutical composition described above. Contact can be made in vitro or in vivo.
[0247] [00247] Another aspect of the disclosure concerns a method to reduce damage caused by free radicals in a cell, wherein the method includes contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate) or hydrate thereof) or pharmaceutical composition described above. Contact can be made in vitro or in vivo.
[0248] [00248] Another aspect of the disclosure is a method of treating an inflammatory disorder or effect in a needy individual, wherein the method includes administering to the individual an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. For example, in one embodiment, the inflammatory disorder or effect is lung inflammation, such as that involved in asthma, COPD and transplant rejection. In another embodiment, the inflammatory disorder or effect is inflammation of organs, in particular inflammation associated with macrophages, such as inflammation of the kidney, liver and other organs.
[0249] [00249] Another embodiment is the use of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described above in the manufacture of a medicament for any of the therapeutic purposes described above. For example, the drug may be aimed at reducing triglyceride levels in an individual, treating type II diabetes in an individual, or treating or preventing atherosclerosis or cardiovascular disease in an individual. In other embodiments, the drug can be used to reduce levels of cellular ceramide in an individual, for example, in the treatment of Batten's disease.
[0250] [00250] The compounds disclosed here can be linked to labeling agents, for example, for use in a variety of experiments exploring their receptor binding, efficacy and metabolism. Accordingly, another embodiment consists of a labeled conjugate comprising a compound as disclosed herein covalently linked to a labeling agent, optionally via a linker. Suitable labeling and binding agents will be clear to practitioners in consideration of this disclosure. The labeling agent can be, for example, an affinity tag, such as biotin or streptavidin, a hapten, such as digoxygenin, an enzyme, such as a peroxidase, or a fluorophoric or chromophoric marker. Any suitable connector can be used. For example, in some embodiments, an ethylene glycol, oligo (ethylene glycol) or poly (ethylene glycol) linker is used. Other examples of linkers include amino acids, which can be used alone or in combination with other linker groups, such as ethylene glycol, oligoethylene glycol or polyethylene glycol. Suitable linkers include, without limitation, isolated amino acids, as well as di- and tripeptides. In one embodiment, the linker includes a glycine residue. The practitioner will, of course, understand that other binders and labeling agents can be used. In other embodiments, the linker is an alkylene chain. In other embodiments, the linker has the structure - [(C0-C3 alkyl) -Ym-] m-, where each Ym is -O-, -N (R9) -, or L, and is located in the range 1-40. For example, in certain embodiments, a labeled conjugate has the structural formula (LXXXVII):
[0251] [00251] For example, in a particular embodiment, a labeled conjugate has the structural formula (LXXXVIII):
[0252] [00252] Another disclosed embodiment of a labeled conjugate has the formula (LXXXIX):
[0253] [00253] The connection to the compound in parentheses can be made, for example, in pyridine, pyridazine, pyrimidine or central pyrazine.
[0254] [00254] Compounds of formulas (LXXXIX) can be synthesized by organic chemistry professionals, for example, by reducing amination of the N-Boc-glycine aldehyde with a primary amine H2NR2, providing R2NHCH2CH2NHBoc, which can be coupled to a pyridinocarboxylic acid to build the target structure as described here. The Boc protecting group can be removed, and the resulting amine can be further elaborated to provide the labeled species.
[0255] [00255] In another particular embodiment, a labeled conjugate has the structural formula (XC):
[0256] [00256] Compounds according to structural formula (XC) can be prepared according to Scheme 7, below, and as described with respect to Examples 159 and 164.
[0257] [00257] Referring to Scheme 7, a monoethyl ester of chloropyridine dicarboxylic acid (xii) is coupled to an amine (here, a substituted 1-benzylpiperazine) to form a carboxymethyl substituted chloropyridinecarboxamide (xiii), which is coupled to one propargyl amine protected to form a carboxyethyl substituted alkynylpyridinecarboxamide (xiv). Compound (xiv) is saponified, then it is coupled to an amine (here, a substituted 1-benzylpiperidine), to form a pyridinodicarboxamide substituted with (3-amino-1-propine), Compound 164 from Table 1. Compound 164 is deprotected, and the free amine is coupled to a biotinyl-bound acid to form Compound 159 of Table 1.
[0258] [00258] The following Examples are intended to further illustrate certain embodiments, and are not intended to limit the scope of the disclosure. EXAMPLES Example 1
[0259] [00259] The following compounds were prepared using methods analogous to Schemes 1-7; in certain cases, exemplary synthesis procedures are provided.
[0260] [00260] Compound 1 N- (4- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-fluorobenzyl) piperizino-1-carbonyl) picolinamide. 1H nmr (CD3OD) δ 8.96 (1H, s), 8.29 (1H, dd, J 8.0, 2.0 Hz), 7.71-7.64 (3H, m), 7.55 (2H, d, J 8.0 Hz), 7.38-7.32 ( 2H, m), 7.04 (2H, t, J 8.5Hz), 3.96-3.85 (1H, m), 3.82-3.76 (2H, m), 3.62 (2H, s), 3.54 (2H, s), 3.48- 3.43 (2H, m), 2.91 (2H, m), 2.56 (2H, m), 2.45 (2H, m), 2.19 (2H, m), 1.95 (2H, m), 1.74-1.63 (3H, m) ; m / z: 542 [M + H] +.
[0261] [00261] Compound 2: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (piperazine-1-carbonyl) picolinamide. 1H nmr (CD3OD) δ 8.67 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J 8.0, 2.0), 7.68 (2H, d, J 8.0 Hz), 7.54 (2H , d, J 8.0 Hz), 3.97-3.87 (1H, m), 3.75 (2H, m), 3.62 (2H, s), 3.39 (2H, m), 2.97-2.74 (6H, m), 2.23 (2H , m), 1.96-1.91 (2H, m), 1.80-1.66 (3H, m); m / z: 533 [M + H] +.
[0262] [00262] Compound 3: pyridine-2,5-di-ylbis ((4- (4-fluorobenzyl) piperazin-1-yl) methanone). 1H nmr (CD3OD) δ 8.62 (1H, s), 7.97 (1H, dd, J 8.0, 2.0 Hz), 7.66 (1H, d, J 8.0 Hz), 7.38-7.32 (m, 4H), 7.07-7.01 ( 4H, m), 3.82-3.74 (4H, m), 3.55-3.47 (8H, m), 2.58-2.54 (4H, m), 2.46-2.41 (4H, m); m / z: 520 [M + H] +.
[0263] [00263] Compound 4: N- (1- (4-cyanobenzoyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CD3OD) δ 8.66 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J 8.0, 2.0 Hz), 7.84 (2H, d, J 8.5 Hz), 7.60 ( 2H, d, J 8.5 Hz), 7.37-7.32 (2H, m), 7.04 (2H, t, J 9.0 Hz), 4.63 (1H, m), 4.24-4.17 (1H, m), 3.79 (2H, m ), 3.67-3.52 (4H, m), 3.43 (2H, m), 3.11-3.03 (1H, m), 2.56 (2H, m), 2.43 (2H, m), 2.14-1.85 (2H, m), 1.79-1.62 (2H, m); m / z: 555 [M + H] +.
[0264] [00264] Compound 5: N2- (1- (4-cyanobenzyl) piperidin-4-yl) -N5- (3-benzylphenyl) pyridine-2,5-dicarboxamide. 1H nmr (CDCl3) δ 9.01 (1H, s), 8.26 (2H, s), 7.96 (1H, d, J 8.0 Hz), 7.87 (1H, s), 7.61 (2H, d, J 8.5 Hz), 7.57 (2H, d, J 8.0 Hz), 7.45 (2H, d, J 8.0 Hz), 7.32-7.16 (m, 7H), 3.99 (3H, s), 3.56 (2H, s), 2.84 (2H, m) , 2.22 (2H, m), 2.02 (2H, m), 1.72-1.61 (2H, m); m / z: 530 [M + H] +.
[0265] [00265] Compound 6: N- (4 - ((4-cyanophenyl) sulfonyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.57 (1H, br s), 8.17 (1H, m), 7.91-7.83 (m, 6H), 7.28 (1H, m), 7.01 (2H, m), 3.98-3.77 (5H, m), 3.57-3.30 (4H, m), 2.62-2.31 (6H, m), 2.09 (2H, m), 1.78-1.62 (2H, m); m / z: 591 [M + H] +.
[0266] [00266] Compound 7: N- (1- (cyclohexanocarbonyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. m / z: 537 [M + H] +.
[0267] [00267] Compound 8: N- (1- (benzoyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CD3OD) δ 8.66 (1H, m), 8.15 (1H, d, J 8.0 Hz), 7.98 (1H, dd, J 8.0, 2.0), 7.48-7.40 (5H, m), 7.37-7.31 (2H , m), 7.07-7.01 (2H, m), 4.62 (1H, m), 4.24-4.14 (1H, m), 3.78 (3H, m), 3.54 (2H, s), 3.43 (2H, m), 3.26-3.00 (3H, m), 2.54 (2H, m), 2.42 (m, 2H), 2.10-1.84 (2H, m), 1.69 (2H, m); m / z: 530 [M + H] +.
[0268] [00268] Compound 9: N- (1- (4-cyanobenzyl) -1H-pyrazol-3-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CD3OD) δ 8.68 (1H, m), 8.23 (1H, d, J 8.0 Hz), 8.02 (1H, dd, J 8.0, 2.0 Hz), 7.71-7.64 (3H, m), 7.38-7.30 ( 4H, m), 7.02 (2H, m), 6.80 (1H, m), 5.36 (2H, s), 3.76 (2H, m), 3.52 (2H, s), 3.43 (2H, m), 2.53 (2H , m), 2.41 (2H, m); m / z: 524 [M + H] +.
[0269] [00269] Compound 10: N- (4-benzylphenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.88 (1H, s), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 8.5 Hz), 7.33-7.17 (9H, m), 7.02 (2H, m), 3.98 (2H, s), 3.83 (2H, s), 3.55- 3.40 (4H, m), 2.62-2.36 (4H, m); m / z: 510 [M + H] +.
[0270] [00270] Compound 11: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl-N- (4-phenylphenyl) picolinamide. 1H nmr (D6-DMSO) δ 10.79 (1H, s), 8.73 (1H, m), 8.20 (1H, d, J 8.0 Hz), 8.06 (1H, dd, J 8.0, 2.0), 8.00 (2H, d, J 9.0 Hz), 7.67 (4H, m), 7.44 (2H, t, J 8.0 Hz), 7.35-7.29 (3H, m), 7.13 (2H, t, J 9.0 Hz), 3.66 (2H, m), 3.49 (2H, s), 3.33 (2H, m), 2.44 (2H, m), 2.35 (2H, m); m / z: 495 [M + H] +.
[0271] [00271] Compound 12: 5- (4- (4-fluorobenzyl) piperazmo-1-carboml-N- (3-phenylphenyl) picolinamide. 1H nmr (CDCl3) δ 9.95 (1H, s), 8.60 (1H, m) , 8.28 (1H, d, J 8.0 Hz), 7.96 (1H, m), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.70 (1H, m), 7.57 (2H, d, J 7.0 Hz), 7.42-7.19 (7H, m), 6.95 (2H, m), 3.76 (2H, m), 3.46 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.36 (2H, m) ; m / z: 495 [M + H] +.
[0272] [00272] Compound 13: N- (1- (idohexylmethyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.56 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.98 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.29- 7.24 (2H, m), 7.03-6.95 (2H, m), 4.07 (1H, m), 3.79 (2H, m), 3.50 (2H, s), 3.38 (2H, m), 3.20-3.10 (2H, m), 2.97 (1H, d, J 5.0 Hz), 2.60-2.35 (8H, m), 2.16-2.06 (2H, m), 1.95-1.60 (6H, m), 1.31-1.08 (4H, m), 1.01-0.86 (2H, m); m / z: 522 [M + H] +.
[0273] [00273] Compound 14: 5- (4- (4-fluorobenzyl) piperazmo-1-carboml) -N- (1- (phenyl) piperidin-4-yl) picolinamide. 1H nmr (D6-DMSO) δ 8.73 (1H, d, J 9.0 Hz), 8.62 (1H, m), 8.06 (1H, d, J 8.0 Hz), 7.98 (1H, dd, J 8.0, 2.0 Hz), 7.357.28 (2H, m), 7.21-7.08 (4H, m), 6.96-6.91 (2H, m), 6.73 (1H, m), 3.97 (1H, m), 3.72-3.58 (4H, m), 3.47 (2H, s), 2.82-2.70 (2H, m), 2.41 (2H, m), 2.31 (2H, m), 1.88-1.74 (4H, m); m / z: 503 [M + H] +.
[0274] [00274] Compound 15: 4 - ((8- (5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolininoyl) -2,8-diazaospiro [4.5] decan-2-yl) methyl) benzonitrile. 1H nmr (D6-DMSO) δ 8.56 (1H, s), 7.91 (2H, d, J 8.5 Hz), 7.78 (2H, m), 7.57 (1H, t, J 8.0 Hz), 7.49 (1H, m) , 7.32 (2H, m), 7.13 (2H, m), 3.62 (4H, m), 3.47 (4H, m), 3.40-3.20 (8H, m), 2.44-2.37 (6H, m), 1.58 (4H , m); m / z: 582 [M + H] +.
[0275] [00275] Compound 16: 5- (4- (4-fluorobenzyl) piperazmo-1-carboml) -N- (4-phenoxyphenyl) picolinamide. 1H nmr (CDCl3) δ 9.84 (1H, s), 8.58 (1H, m), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0), 7.67 (2H, d, J 9.0 Hz), 7.307.18 (4H, m), 7.06-6.90 (7H, m), 3.76 (2H, m), 3.46 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m / z: 512 [M + H] +.
[0276] [00276] Compound 17: (4- (4-fluorobenzyl) piperazin-1-yl) (6- (4- (benzyloxy) feml) pyridin-3-yl) methanone. To a mixture of (4- (4-fluorobenzyl) piperazm-1-yl) (6-bromopyridin-3-yl) methanone (0.048 g, 0.13 mmol, 1.0 eq), 4-benzyloxyphenylboronic acid (0.040 g , 0.18 mmol, 1.4 eq), potassium phosphate (0.053 g, 0.25 mmol, 1.9 eq), S-Phos (0.006 g, 0.01 mmol, 0.1 eq), and tris (dibenzylidenoacetone) dipaladium (0) (0.012 g, 0.01 mmol, 0.01 eq) 1-butanol-water (1.25 ml, 4: 1) was added. After a 5 minute purge of the reaction mixture with argon, the reactor was sealed and heated to 100 □ ° C for 10 hours. The reaction mixture was filtered through Celite®, eluting with 5% MeOH-CH2Cl2, and was purified by RP-HPLC, providing Compound 17. 1H nmr (D6-DMSO) δ 8.61 (1H, s), 8.06 (2H, d , J 9.0 Hz), 7.95 (1H, d, J 8.0 Hz), 7.83 (1H, dd, J 8.0, 2.0 Hz), 7.48-7.30 (7H, m), 7.16-7.10 (4H, m), 5.16 ( 2H, s), 3.61 (2H, m), 3.48 (2H, s), 3.37 (2H, m), 2.38 (4H, m); m / z: 483 [M + H] +.
[0277] [00277] Compound 18: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (1- (1-phenylethyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.50 (1H, s), 8.13 (1H, d, J 8.0 Hz), 7.88 (1H, d, J 8.0 Hz), 7.78 (1H, dd, J 8.0, 2.0 Hz), 7.32- 7.18 (7H, m), 6.94 (2H, m), 3.98-3.86 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.32 (2H, m), 3.14 (1H, m) , 2.98-2.85 (1H, m), 2.47 (2H, m), 2.38-2.14 (4H, m), 1.98 (2H, m), 1.86-1.62 (3H, m), 1.48 (4H, m); m / z: 531 [M + H] +.
[0278] [00278] Compound 19: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (2-phenylphenyl) picolinamide. 1H nmr (CDCl3) δ 10.15 (1H, s), 8.56 (1H, d, J 8.0 Hz), 8.35 (1H, m), 8.22 (1H, d, J 8.0 Hz), 7.78 (1H, dd, J 8.0 , 2.0 Hz), 7,467.34 (6H, m), 7.29-7.13 (4H, m), 6.95 (2H, m), 3.73 (2H, m), 3.53-3.22 (4H, m), 2.47 (2H, m), 2.32 (2H, m); m / z: 496 [M + H] +.
[0279] [00279] Compound 20: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (4-nitrophenyl) phenyl) picolinamide. 1H nmr (D6-DMSO) δ 10.93 (1H, s), 8.74 (1H, m), 8.28 (2H, d, J 9.0 Hz), 8.20 (1H, d, J 8.0 Hz), 8.11-8.05 (3H, m), 7.97 (2H, d, J 9.0 Hz), 7.82 (2H, d, J 9.0 Hz), 7.35-7.30 (2H, m), 3.65 (2H, m), 3.49 (2H, s), 3.35 ( 2H, m), 2.43 (2H, m), 2.35 (2H, m); m / z: 541 [M + H] +.
[0280] [00280] Compound 21: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (3-phenoxyphenyl) picolinamide. 1H nmr (CDCl3) δ 9.85 (1H, s), 8.56 (1H, m), 8.24 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.47-7.40 (2H, m), 7,327.18 (5H, m), 7.00-6.91 (5H, m), 6.77-6.71 (1H, m), 3.76 (2H, m), 3.46 (2H, s), 3.36 (2H, m) , 2.49 (2H, m), 2.36 (2H, m); m / z: 512 [M + H] +.
[0281] [00281] Compound 22: (6- (3- (benzyloxy) phenyl) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.72 (1H, br s), 7.84-7.74 (2H, m), 7.96 (1H, s), 7.58 (1H, d, J 8.0 Hz), 7.48-7.25 (8H, m), 7.08 - 6.98 (3H, m), 5.16 (2H, s), 3.80 (2H, m), 3.53 (4H, m), 2.50 (4H, m); m / z: 483 [M + H] +.
[0282] [00282] Compound 23: N- (1- (4-cyanobenzyl) -1H-pyrazol-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.71 (1H, s), 8.56 (1H, m), 8.20 (1H, d, J 8.0 Hz), 8.12 (1H, s), 7.84 (1H, dd, J 8.0, 2.0 Hz) , 7.60-7.54 (3H, m), 7.26-7.18 (4H, m), 6.95 (2H, m), 5.29 (2H, s), 3.76 (2H, m), 3.46 (2H, s), 3.36 (2H , m), 2.60-2.27 (4H, m); m / z: 425 [M + H] +.
[0283] [00283] Compound 24: N- (4- (4-cyanophenyl) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 10.04 (1H, s), 8.67 (1H, m), 8.36 (1H, d, J 8.0 Hz), 7.97-7.88 (3H, m), 7.75-7.61 (6H, m), 7.29 (2H, m), 7.03 (2H, m), 3.84 (2H, m), 3.60-3.34 (4H, m), 2.49 (4H, m); m / z: 521 [M + H] +.
[0284] [00284] Compound 25: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4- (4-trifluoromethylphenyl) phenyl) picolinamide. 1H nmr (CDCl3) δ 10.02 (1H, s), 8.68 (1H, m), 8.37 (1H, d, J 8.0 Hz), 7.95 (1H, d, J 9.0 Hz), 7.89 (2H, d, J 8.5 Hz), 7.71-7.61 (6H, m), 7.28 (2H, m), 7.04 (2H, m), 3.84 (2H, m), 3.60-3.38 (4H, m), 2.56 (2H, m), 2.43 (2H, m); m / z: 564 [M + H] +.
[0285] [00285] Compound 26: N- (4-benzoylphenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 10.15 (1H, s), 8.67 (1H, m), 8.35 (1H, d, J 8.0 Hz), 7.95 (1H, dd, J 8.0, 2.0 Hz), 7.90 (4H, m) , 7.79 (2H, d, J 7.5 Hz), 7.59 (1H, m), 7.49 (2H, m), 7.29 (2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.54 (2H , s), 3.47 (2H, m), 2.56 (2H, m), 2.43 (2H, m); m / z: 524 [M + H] +.
[0286] [00286] Compound 27: N- (4-benzyloxyphenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.75 (1H, s), 8.58 (1H, s), 2.27 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.39-7.18 (7H, m), 6.96-6.90 (4H, m), 5.01 (2H, s), 3.76 (2H, m), 3.52-3.28 (4H, m), 2.60-2.24 ( 4H, m); m / z: 526 [M + H] +.
[0287] [00287] Compound 28: N- (4-bromophenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.93 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.93 (1H, dd, J 8.0, 2.0 Hz), 7.68 (2H, d, J 9.0 Hz), 7.50 (2H, d, J 9.0 Hz), 7.28 (2H, m), 7.02 (2H, m), 3.82 (2H, m), 3.52 (2H, s), 3.42 (2H, m) , 2.49 (4H, m); m / z: 497, 499 [M + H] +.
[0288] [00288] Compound 29: N- (4- (4-methoxyphenyl) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.96 (1H, s), 8.66 (1H, m), 8.36 (1H, d, J 8.0 Hz), 7.93 (1H, dd, J 8.0, 2.0 Hz), 7.83 (2H, d, J 9.0 Hz), 7.60-7.51 (4H, m), 7.29 (2H, m), 7.03 (2H, m), 6.97 (2H, d, J 9.0 Hz), 3.85 (5H, m), 3.60-3.36 ( 4H, m), 2.50 (4H, m); m / z: 526 [M + H] +.
[0289] [00289] Compound 30: (6- (4-benzylphenylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.26 (1H, s), 7.56 (1H, dd, J 9.0, 1.0), 7.32-7.15 (10H, m), 7.06-6.97 (3H, m), 6.77 (1H, d, J 8.5 Hz), 3.96 (2H, s), 3.66 (4H, m), 3.52 (2H, s), 2.47 (4H, m); m / z: 482 [M + H] +.
[0290] [00290] Compound 31: 4 - ((2- (5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) pyridin-2-yl) -2,8-diazaspiro [4.5] decan-8-yl) methyl) benzonitrile. m / z: 554 [M + H] +.
[0291] [00291] Compound 32: N- (4- (3-cyanophenyl) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 10.04 (1H, s), 8.67 (1H, s), 8.35 (1H, d, J 8.0 Hz), 7.95 (1H, dd, J 8.0, 2.0), 7.947.80 (3H, m ), 7.63-7.52 (3H, m), 7.28 (2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.53 (2H, s), 3.44 (2H, m), 2.48 (4H, m); m / z: 521 [M + H] +.
[0292] [00292] Compound 33: (6- (3-phenylphenylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.23 (1H, s), 7,567.47 (4H, m), 7.39-7.18 (9H, m), 6.93 (2H, t, J 9.0 Hz), 6.80 (1H, d, 8.5 Hz ), 3.59 (4H, m), 3.43 (2H, s), 2.39 (4H, m)); m / z: 468 [M + H] +.
[0293] [00293] Compound 34: (4- (4-fluorobenzyl) piperazin-1-yl) (6- (4-phenoxyphenylamino) pyridin-3-yl) methanone. 1H nmr (CDCl3) δ 8.26 (1H, s), 7.58 (1H, dd, J 9.0, 2.0 Hz), 7.35-7.25 (6H, m), 7.12-6.97 (8H, m), 6.73 (1H, d, J 9.0 Hz), 3.66 (4H, m), 3.51 (2H, s), 2.46 (4H, m); m / z: 483 [M + H] +.
[0294] [00294] Compound 35: (6- (4- (4-cyanobenzylcarbamoyl) phenyl) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.64 (1H, br s), 7.96 (2H, d, J 8.0 Hz), 7.83 (2H, d, J 8.0 Hz), 7.75-7.68 (2H, m), 7.56 (2H, d , J 8.0 Hz), 7.40 (2H, d, J 8.0 Hz), 7.26-7.19 (2H, m), 7.01-6.91 (3H, m), 4.65 (2H, d, J 6.0 Hz), 3.73 (2H, m), 3.47 (4H, m), 2.42 (4H, m); m / z: 535 [M + H] +.
[0295] [00295] Compound 36: (6- (4- (cyanobenzyl) piperidin-4-ylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CD3OD) δ 8.06 (1H, s), 7.68 (2H, dd, J 8.0, 2.0 Hz), 7.44 (1H, m), 7.36-7.32 (2H, m), 7.06-6.98 (2H, m) , 6.49 (2H, d, J 9.0 Hz), 3.68-3.56 (6H, m), 3.34 (2H, s), 2.84 (2H, m), 2.46 (4H, m), 2.20 (2H, m), 1.96 (2H, m), 1.60-1.47 (2H, m); m / z: 514 [M + H] +.
[0296] [00296] Compound 37: (6- (4-phenylphenylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.31 (1H, d, J 2.0 Hz), 7.65-7.55 (5H, m), 7.46-7.40 (4H, m), 7.36-7.25 (3H, m), 7.16 (1H, s) , 7.01 (2H, t, J 9.0 Hz), 6.87 (1H, d, J 9.0 Hz), 3.68 (4H, m), 3.52 (2H, s), 2.48 (4H, m); m / z: 467 [M + H] +.
[0297] [00297] Compound 38: N5- (1- (4-cyanobenzyl) -1H-pyrazol-3-yl) -N2- (1- (4-cyanobenzyl) piperidin-4-yl) pyridine-2,5-dicarboxamide. 1H nmr (CDCl3) δ 8.98 (1H, s), 8.57 (1H, s), 8.22 (2H, m), 7.92 (1H, m), 7.59-7.54 (4H, m), 7.46 (2H, m), 7.39 (1H, d, J 2.0 Hz), 7.21-7.16 (2H, m), 6.86 (1H, d, J 1.5 Hz), 5.21 (2H, s), 3.96 (1H, m), 3.57 (2H, s ), 2.89-2.80 (2H, m), 2.23 (2H, m), 1.97 (2H, m), 1.67 (2H, m); m / z: 546 [M + H] +.
[0298] [00298] Compound 39: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4- (1H-pyrrol-3-yl) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.85 (1H, s), 8.58 (1H, s), 8.31 (1H, m), 8.27 (1H, d, J 8.0 Hz), 7.85 (1H, d, J 8.0, 2.0 Hz) , 7.68 (2H, d, J 9.0 Hz), 7.48 (2H, d, J 9.0 Hz), 7.24-7.18 (2H, m), 7.02 (1H, m), 6.95 (2H, t, J 8.5 Hz), 6.77 (1H, m), 6.47 (1H, m), 3.76 (2H, m), 3.46-3.32 (4H, m), 2.48 (2H, m), 2.36 (2H, m); m / z: 485 [M + H] +.
[0299] [00299] Compound 40: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4-morpholinophenyl) picolinamide. 1H nmr (CDCl3) δ 9.74 (1H, s), 8.57 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.22 (2H, m), 6.94 (2H, t, J 9.0 Hz), 6.88 (2H, d, J 9.0 Hz), 3.83-3.53 (6H, m), 3.45 (2H, s), 3.36 ( 2H, m), 3.08 (4H, m), 2.48 (2H, m), 2.35 (2H, m); m / z: 505 [M + H] +.
[0300] [00300] Compound 41: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4- (4-methylpiperazin-1-yl) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.74 (1H, s), 8.57 (1H, m), 8.25 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0), 7.60 (2H, d, J 9.0 Hz), 7.24-7.18 (2H, m), 6.97-6.87 (4H, m), 3.75 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 3.19 (4H, m), 2.60 (4H, m), 2.48 (2H, m), 2.34 (5H, m); m / z: 518 [M + H] +.
[0301] [00301] Compound 42: (6- (3- (4-cyanobenzylcarbamoyl) phenyl) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.64 (1H, br s), 8.40 (1H, s), 8.07 (1H, d, J 8.0 Hz), 7.86 (1H, d, J 8.0 Hz), 7.77 (2H, m), 7.59-7.47 (3H, m), 7.41 (2H, d, J 8.0 Hz), 7.24-7.17 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.88 (1H, m), 4.66 (2H , d, J 6.0 Hz), 3.74 (2H, m), 3.45 (4H, m), 2.42 (4H, m); m / z: 535 [M + H] +.
[0302] [00302] Compound 43: N5- (1- (4-cyanobenzyl) -1H-pyrazol-4-yl) -N2- (1- (4-cyanobenzyl) piperidin-4-yl) pyridine-2,5-dicarboxamide. 1H nmr (D6-DMSO) δ 10.83 (1H, s), 9.08 (1H, s), 8.70 (1H, d, J 8.0 Hz), 8.43 (1H, dd, J 8.0, 2.0 Hz), 8.25 (1H, s), 8.13 (1H, d, J 8.5 Hz), 7.79 (4H, m), 7.67 (1H, s), 7.49 (2H, d, J 8.0 Hz), 7.33 (2H, d, J 8.0 Hz), 5.45 (2H, s), 3.80 (1H, m), 3.55 (2H, s), 2.76 (2H, m), 2.07 (2H, m), 1.71 (4H, m); m / z: 546 [M + H] +.
[0303] [00303] Compound 44: (4- (1- (4-fluorobenzyl) -1H-pyrazol-4-ylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.15 (1H, d, J 2.0 Hz), 7.61 (1, 1H), 7.46 (1H, dd, J 8.0, 2.0 Hz), 7.42 (1H, s), 7.24-7.12 (4H, m), 6.99-6.90 (4H, m), 6.70 (1H, s), 6.45 (1H, d, J 8.5 Hz), 5.17 (2H, s), 3.57 (4H, m), 3.44 (2H, m) , 2.39 (4H, m); m / z: 489 [M + H] +.
[0304] [00304] Compound 45: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (1- (4-fluorobenzyl) -1H-pyrazol-4-ylamino) picolinamide. 1H nmr (CDCl3) δ 7.92 (1H, d, J 3.0 Hz), 7.89 (1H, d, J 9.0 Hz), 7.62 (1H, d, J 8.5 Hz), 7.54 (2H, d, J 8.0 Hz), 7.44-7.38 (3H, m), 7.30 (1H, s), 7.19-7.13 (2H, m), 7.02-6.94 (3H, m), 5.49 (1H, s), 5.19 (2H, s), 3.98- 3.84 (1H, m), 3.52 (2H, s), 2.76 (2H, m), 2.17 (2H, m), 1.93 (2H, m), 1.57 (2H, m); m / z: 511 [M + H] +.
[0305] [00305] Compound 46: (4- (1- (4-cyanobenzyl) piperidine-4-carboxamido) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. To a mixture of (4- (4-fluorobenzyl) piperazin-1-yl) (6-bromopyridin-3-yl) methanone (0.040 g, 0.11 mmol, 1.0 eq), 1- (4-cyanobenzyl) piperidine-4-carboxamide (0.028 g, 0.12, 1.1 eq), and N, N'-dimethylethylenediamine (0.012 ml, 0.11 mmol, 1.0 eq) anhydrous toluene (1.0 ml) was added . This mixture was purged with argon for 5 minutes and copper (I) iodide (0.011 g, 0.058 mmol, 0.5 eq) and potassium carbonate (0.044 g, 0.23 mmol, 2.1 eq) were added. The reaction mixture was heated to 100 ° C for 4.5 hours and was then absorbed on silica gel. Purification by column chromatography (silica, 0 → 5% MeOH-CH2Cl2) provided a green solid (0.070 g). Further purification using preparative TLC (silica, 4% MeOH-CH2Cl2) provided Compound 46 as a white solid (0.040 g, 67%). 1H nmr (D6-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H, m) , 7.31 (2H, t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99-1.87 ( 2H, m), 1.79-1.54 (4H, m); m / z: 542 [M + H] +. More information on this type of coupling is provided in Wrona, Iwona E .; Gozman, Alexander; Taldone, Tony; Chiosis, Gabriela; Panek, James S. Journal of Organic Chemistry (2010), 75 (9), 2820-2835.
[0306] [00306] 1H nmr (D6-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H , m), 7.31 (2H, t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99 -1.87 (2H, m), 1.79-1.54 (4H, m); m / z: 542 [M + H] +.
[0307] [00307] Compound 47: N- (4- (4-cyanobenzylcarbamoyl) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 10.03 (1H, s), 8.58 (1H, s), 8.24 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.78 (4H, m) , 7.57 (2H, d, J 8.0 Hz), 7.40 (2H, d, J 8.0 Hz), 7.26-7.19 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.68 (1H, m) 4.64 (2H, d, J 6.0 Hz), 3.76 (2H, m), 3.47 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.36 (2H, m); m / z: 578 [M + H] +.
[0308] [00308] Compound 48: (6- (4- (4- cyanobenzylcarbamoyl) phenylamino) pyridin-3-yl) (4- (4-fluorobenzyl) piperazin-1-yl) methanone. 1H nmr (CDCl3) δ 8.25 (1H, s), 7.81 (1H, s), 7.70 (1H, d, J 9.0 Hz), 7.53-7.33 (8H, m), 7.28-7.23 (2H, m), 6.99 (2H, t, J 9.0 Hz), 6.73 (1H, d, J 8.5 Hz), 4.60 (2H, d, J 6.0 Hz), 3.60 (4H, m), 3.48 (2H, s), 2.43 (4H, m); m / z: 550 [M + H] +.
[0309] [00309] Compound 49: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.52 (1H, s), 8.16 (1H, d, J 8.0 Hz), 7.86 (1H, d, J 8.0 Hz), 7.81-7.78 (1H, m), 7.23-7.07 (3H, m), 7.06-6.91 (4H, m), 4.20-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.43 (2H, s), 3.33 (2H, m), 2.78 (2H, m), 2.47 (2H, m), 2.321 (2H, m), 2.16 (2H, m), 1.96 (2H, m), 1.62 (2H, m); m / z: 553 [M + H] +.
[0310] [00310] Compound 50: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (1- (4-fluoro-3-methylbenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.51 (s, 1H), 8.16 (1H, d, J 8.0 Hz), 7.85 (1H, d, J 9.0 Hz), 7.79 (1H, d, J 8.0 Hz), 7.23-7.18 ( 2H, m), 7.10-7.01 (2H, m), 6.97-6.84 (3H, m), 3.99-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.40 (2H, s), 3.33 (2H, m), 2.79 (2H, m), 2.47 (2H, m), 2.32 (2H, m), 2.20 (3H, s), 2.13 (1H, m), 1.94 (2H, m ), 1.60 (3H, m); m / z: 549 [M + H] +.
[0311] [00311] Compound 51: N- (1- (4-chlorobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H NMR (CD3OD) δ 8.67 (1H, m, major isomer), 8.63 (1H, m, minor isomer), 8.16 (1H, d, J 8.0 Hz), 8.00 (1H, dd, J 8.0, 2.0 Hz), 7.38-7.32 (2H, m), 7.09-7.00 (5H, m), 6.81 (2H, d, J 9.0 Hz), 4.10 (m), 3.80 (m), 3.57 (s), 3.45 ( m), 3.30 (m), 2.96 (s), 2.58-2.44 (m), 1.94-1.60 (m), 1.39-1.28 (m); m / z: 546 [M + H] +.
[0312] [00312] Compound 52: N- (1- (4-chlorobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.57 (1H, s), 8.21 (1H, d, J 8.0 Hz), 7.90 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0), 7.28-7.22 (6H, m), 6.99 (2H, m), 4.04-3.92 (1H, m), 3.79 (2H, m), 3.49 (2H, s), 3.46 (2H, s), 3.38 (2H, m), 2.81 (2H, m), 2.52 (2H, m), 2.37 (2H, m), 2.17 (2H, m), 1.98 (2H, m), 1.62 (2H, m); m / z: 551, 553 [M + H] +.
[0313] [00313] Compound 53: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4- (4-methylphenoxy) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.88 (1H, s), 8.64 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.91 (1H, dd, J 8.0, 2.0 Hz), 7.71 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m), 7.13 (2H, d, J 8.0 Hz), 7.03-6.96 (4H, m), 6.91 (2H, d, J 8.5 Hz), 3.82 (2H, m ), 3.51 (2H, s), 3.42 (2H, m), 2.54 (2H, m), 2.41 (2H, m), 2.33 (3H, s); m / z: 526 [M + H] +.
[0314] [00314] Compound 54: 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (4- (4-methoxyphenoxy) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.87 (1H, m), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz), 7.91 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m), 7.03-6.95 (6H, m), 6.87 (2H, m), 3.80 (5H, m), 3.51 (2H, s), 3.42 (2H, m) , 2.54 (2H, m), 2.41 (2H, m); m / z: 541 [M + H] +.
[0315] [00315] Compound 55: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (3-fluorophenoxy) feml) picolinamide. 1H nmr (CDCl3) δ 9.86 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0 Hz), 7.70 (2H, d, J 9.0 Hz), 7.24-7.15 (3H, m), 7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 9.0 Hz), 6.74- 6.60 (3H, m), 3.75 (2H, m ), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m / z: 530 [M + H] +.
[0316] [00316] Compound 56: N- (4- (3-cyanophenoxy) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.90 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.74 (2H, d, J 9.0 Hz), 7.38-7.25 (2H, m), 7.24-7.14 (4H, m), 7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m ), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m / z: 537 [M + H] +.
[0317] [00317] Compound 57: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (3-methoxyphenoxy) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.84 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0 Hz), 7.67 (2H, d, J 9.0 Hz), 7.24-7.11 (3H, m), 7.01-6.91 (4H, m), 6.60-6.48 (3H, m), 3.76 (2H, m), 3.70 (3H, s), 3.45 (2H, s), 3.37 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m / z: 542 [M + H] +.
[0318] [00318] Compound 58: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (3-methylphenoxy) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.90 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.73 (2H, d, J 9.0 Hz), 7.31-7.25 (2H, m), 7.21 (1H, t, J 7.5 Hz), 7.06-6.96 (4H, m), 6.90 (2H, d, J 7.5 Hz), 6.82 (2H, m ), 3.82 (2H, m), 3.51 (2H, s), 3.42 (2H, s), 2.54 (2H, m), 2.41 (2H, m), 2.32 (3H, s); m / z: 526 [M + H] +.
[0319] [00319] Compound 59: N- (4- (4-cyanophenoxy) phenyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 9.91 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.5 Hz), 7.87 (1H, dd, J 8.0, 1.5 Hz), 7.76 (2H, d, J 9.0 Hz), 7.53 (2H, d, J 8.5 Hz), 7.24-7.18 (2H, m), 7.04 (2H, d, J 9.0 Hz), 6.98-6.91 (4H, m), 3.76 (2H, m ), 3.45 (2H, s), 3.36 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m / z: 537 [M + H] +.
[0320] [00320] Compound 60: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (4-fluorophenoxy) feml) picolinamide. 1H nmr (CDCl3) δ 9.84 (1H, s), 8.58 (1H, s), 8.27 (1H, d, J 8.5 Hz), 7.88-7.84 (1H, m), 7.66 (2H, d, J 9.0 Hz) , 7.24-7.18 (3H, m), 6.99-6.88 (7H, m), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H , m); m / z: 530 [M + H] +.
[0321] [00321] Compound 61: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (pyridine-3-yl) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.97 (1H, s), 8.80 (1H, s), 8.61 (1H, s), 8.51 (1H, d, J 5.0 Hz), 7.90-7.80 (4H, m), 7.56 (2H , d, J 8.5 Hz), 7.33-7.27 (1H, m), 7.25-7.18 (2H, m), 6.95 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s) , 3.37 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m / z: 497 [M + H] +.
[0322] [00322] Compound 62: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (4- (thiophen-3-yl) phenyl) picolinamide. 1H nmr (CDCl3) δ 9.91 (1H, s), 8.59 (1H, m), 8.28 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.75 (2H, d, J 8.5 Hz), 7.56 (2H, d, J 8.5 Hz), 7.38-7.31 (2H, m), 7.24-7.16 (3H, m), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m ), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m / z: 502 [M + H] +.
[0323] [00323] Compound 63: 5- (4- (4-fluorobenzyl) piperazine-1-carboml) - (6- (4-cyanophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.89 (1H, s), 8.60 (1H, m), 8.40 (1H, d, J 2.5 Hz), 8.35 (1H, dd, J 9.0, 3.0 Hz), 8.26 (1H, dd, J 8.5, 1.0 Hz), 7.88 (1H, dd, J 8.0, 2.0 Hz), 7.61 (2H, d, J 9.0 Hz), 7.25-7.13 (4H, m), 7.00 (1H, d, J 9.0 Hz) , 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.35 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m / z: 538 [M + H] +.
[0324] [00324] Compound 64: 5- (4- (4-fluorobenzyl) piperazmo-1-carboml) - (6- (3-cyanophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.87 (1H, s), 8.60 (1H, m), 8.36 (2H, m), 8.26 (1H, d, J 8.5 Hz), 7.87 (1H, dd, J 8.0, 2.0 Hz) , 7.46-7.31 (3H, m), 7.23-7.18 (3H, m), 7.02-6.90 (3H, m), 3.76 (2H, m), 3.45 (2H, s), 3.35 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m / z: 538 [M + H] +.
[0325] [00325] Compound 65: 5- (4- (4-fluorobenzyl) piperazmo-1-carboml) -N- (6- (4-fluorophenoxy) pyridm-3-yl) picolmamide. 1H nmr (CDCl3) δ 9.83 (1H, s), 8.58 (1H, m), 8.37-8.21 (4H, m), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.24-7.17 (2H, m) , 7.05-6.86 (6H, m), 3.75 (2H, m), 3.44 (2H, s), 3.34 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m / z: 531 [M + H] +.
[0326] [00326] Compound 66: 5- (4- (4-cyano-2-methoxyphenoxy) piperidmo-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidm-4-yl) picolmamide. 1H nmr (CDCl3) δ 8.54 (1H, m), 8.18 (1H, d, J 8.0 Hz), 7.87-7.80 (2H, m), 7.55 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz), 7.21-7.15 (1H, m), 7.05 (1H, m), 6.87 (1H, d, J 8.0 Hz), 4.66-4.58 (1H, m), 3.97-3.78 (6H, m), 3.60 (1H, m), 3.50 (2H, s), 3.41 (2H, m), 3.31 (1H, m), 2.76 (2H, m), 2.16 (2H, m), 2.20-1.57 (4H, m) , 1.63-1.52 (2H, m); m / z: 580 [M + H] +.
[0327] [00327] Compound 67: 5- (4- (4-fluoro-4-fluorobenzoyl) piperidmo-1-carboml) -N- (6- (4-fluorophenoxy) pyridm-3-yl) picolmamide. 1H nmr (CDCl3) δ 9.83 (1H, s), 8.64 (1H, s), 8.36-8.24 (3H, m), 8.11-8.05 (2H, m), 7.92 (1H, dd, J 8.0, 2.0 Hz) , 7.11-6.97 (6H, m), 6.89 (1H, d, J 9.0 Hz), 4.62 (1H, m), 3.70-3.41 (3H, m), 2.36-1.91 (4H, m); m / z: 562 [M + H] +.
[0328] [00328] Compound 68: N- (1- (4-thianobenzyl) piperidin-4-yl) -5- (4- (4-fluoro-4-fluorobenzofl) piperidmo-1-carboml) picolmamide. 1H nmr (CDCl3) δ 8.57 (1H, s), 8.19 (1H, d, J 8.0 Hz), 8.09-8.04 (2H, m), 7.88-7.82 (2H, m), 7.54 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz), 7.08 (2H, t, J 8.5 Hz), 4.60 (1H, m), 3.99-3.90 (1H, m), 3.60-3.30 (4H, m), 2.75 (2H, m), 2.28-2.07 (6H, m), 1.95 (3H, m), 1.65-1.53 (2H, m); m / z: 573 [M + H] +.
[0329] [00329] Compound 69: 5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) - N- (6- (4-fluorophenoxy) pyridm-3-yl) picolmamide. 1H nmr (CDCl3) δ 9.85 (1H, s), 8.62 (1H, s), 8.37-8.25 (3H, m), 7.92-7.85 (3H, m), 7.06-6.99 (4H, m), 6.90 (3H , m), 4.62 (1H, m), 3.81 (3H, s), 3.72 (1H, m), 3.49 (1H, s), 3.28- 2.98 (2H, m), 1.97 (1H, m), 1.77 ( 3H, m); m / z: 556 [M + H] +.
[0330] [00330] Compound 70: 5- (4- (4-methoxyphenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.84 (1H, s), 8.61 (1H, s), 8.35-8.25 (2H, m), 7.89 (1H, dd, J 8.0, 2.0 Hz), 7.06-7.01 (4H, m) , 6.90 (1H, d, J 9.0 Hz), 6.83-6.75 (4H, m), 4.43 (1H, m), 3.84 (2H, m), 3.70 (3H, m), 3.31 (1H, m), 1.93 (2H, m), 1.79 (2H, m); m / z: 544 [M + H] +.
[0331] [00331] Compound 71: trans-N- (4- (4-cyanophenoxy) cyclohexyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.53 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.86-7.80 (2H, m), 7.51 (2H, d, J 9.0 Hz), 7.00 (2H, t, J 8.5 Hz), 4.27 (1H, m), 4.07-3.40 (7H, m), 2.65 (4H, m), 2.13 (4H, m), 1.68-1.57 (2H, m), 1.49-1.38 (2H, m); m / z: 543 [M + H] +.
[0332] [00332] Compound 94: (4- (4-fluorobenzyl) piperazin-1-yl) (6- (4-phenylpiperazine-1-carbonyl) pyridin-2-yl) methanone. To a suspension of pyridine-2,6-dicarboxylic acid (0.200 g, 1.20 mmol, 1.0 eq) in tetrahydrofuran (6.0 mL) was added 4-fluorobenzylpiperazine (0.116 g, 0.60 mmol, 0, 5 eq). Triethylamine (0.33 mL, 2.40 mmol, 2.0 eq) was added, followed by HATU (0.319 g, 0.84 mmol, 0.7 eq), and the reaction was stirred at room temperature for 14 hours. . The reaction mixture was diluted with methanol (3.0 ml) and (trimethylsilyl) diazomethane (2.0 ml of a 2 M solution in hexane, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 minutes before being concentrated under reduced pressure. The residue was partitioned between NaHCO3 (50 ml) and EtOAc (50 ml). The organics were washed with saline (50 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 2 → 5% MeOH-CH2Cl2) provided methyl 6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate (0.214 g, 50%) as a white solid; m / z: 358 [M + H] +. To a solution of methyl 6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate (0.214 g, 0.60 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) was added a solution of lithium hydroxide monohydrate (0.050 g, 1.20 mmol, 2.0 eq) in water (3.0 mL). The reaction was stirred at room temperature for 25 minutes before being neutralized with HCl (approximately 0.6 ml of a 2 M solution). The reaction mixture was concentrated to dryness, providing 6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinic acid, which was used without further purification; m / z: 344 [M + H] +. To a solution of crude 6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinic acid (approximately 0.200 mmol, 1.0 eq) and triethylamine (0.083 mL, 0.600 mmol, 3.0 eq) in dimethylformamide ( 2.0 ml) 1-phenylpiperazine (0.036 ml, 0.240 mmol, 1.2 eq) was added. HATU was added and the reaction was stirred at room temperature for 2.5 hours before being partitioned between EtOAc (50 mL) and NaHCO3-water (1: 1, 50 mL). The organics were additionally washed with saline solution (50 ml), water (50 ml) and saline solution (50 ml) before drying (Na2SO4) and concentration under reduced pressure. Column chromatography (silica, 3 → 7% MeOH-CH2Cl2) provided Compound 94 as a colorless oil; 1H nmr (CDCl3) δ 7.92 (1H, t, J 7.5 Hz, pyH-4), 7.73 (1H, d, J 8.0 Hz, pyH-3 or pyH-5), 7.70 (1H, d, J 7.5 Hz, pyH-3 or pyH-5), 7.33-7.22 (4H, m, 2H of C6H4F and 2H of C6H5), 7.01-6.90 (5H, m, 2H of C6H4F and 3H of C6H5), 3.97 (2H, dd, J 5.5, 5.0 Hz, 2H of piz), 3.81 (2H, dd, J 5.0, 4.5 Hz, 2H of piz), 3.74 (2H, t, J 5.0 Hz, 2H of piz), 3.55 (2H, dd, J 5.0 , 4.5 Hz, 2H of piz), 3.46 (2H, s, CH2C6H4F), 3.29 (2H, t, J 5.0 Hz, 2H of piz), 3.17 (2H, dd, J 5.5, 4.5 Hz, 2H of piz), 2.52 (2H, t, J 5.0 Hz, 2H piz), 2.39 (2H, dd, 5.0, 4.5 Hz, 2H piz); m / z: 488 [M + H] +.
[0333] [00333] Compound 140: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3,5-difluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.58 (1H, br s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.87 (2H, d, J 6.5 Hz, H-2 and H-6 of C6H3F2), 6.70 (1H, t, J 9.0 Hz, H-4 of C6H3F2), 4.00 (1H, m, pipH-4), 3.82 (2H, m, 2H of piz), 3.56 (2H, s, 1 x CH2Ar), 3.51 (2H, s, 1 x CH2Ar), 3.41 (2H, m, 2H of piz), 2.81 (2H, m, 2H of pip), 2.55 (2H , m, 2H of piz), 2.40 (2H, m, 2H of piz), 2.22 (2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.64 (2H, m , 2H of pip); m / z: 560 [M + H] +.
[0334] [00334] Compound 141: 5- (4- (4-carbamoyl benzyl) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (D6- DMSO) δ 8.65 (2H, m, NH, 1 x pyH), 8.04 (1H, m, 2 x pyH), 7.81 (1H, d, J 8.5 Hz, 2H of C6H4CN or C6H4CONH2), 7.78 (2H, d, J 8.0 Hz, 2H of C6H4CN or C6H4CONH2), 7.49 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.01 (2H, d, J 9.0 Hz, 2H of C6H4CONH2), 4.75 (1H, m, oxypipH-4), 4.09 (1H, m, 1H of oxypipH-2, H-6), 3.80 (1H, m, pipH-4), 3.54 (2H, s, CH2C6H4CN), 3.48 (2H, m, 2H of oxypipH-2, H-6), 3.25 (1H, m, 1H of oxypipH-2, H-6), 2.75 (2H, m, 2H of pipH-2, H-6), 2.06 (3H, m , 2H of pipH-2, H-6, 1H of oxypipH-3, H-5), 1.91 (1H, m, 1H of oxypipH-3, H-5), 1.71 (6H, m, 4H of pipH-3 , H-5, 2H of oxypipH-3, H-5); m / z: 568 [M + H] +.
[0335] [00335] Compound 142: N- (1- (4-rianobenzyl) piperidin-4-yl) -5- (4 - ((4-fluorophenyl) (hydroxy) methyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.56 (1H, br s, pyH-6), 8.21 (1H, d, J 7.0 Hz, pyH-3), 7.91 (1H, d, J 8.5 Hz, NH), 7.85 (1H, m, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.26 (2H, m, 2H of C6H4F), 7.04 ( 2H, t, J 8.5 Hz, 2H of C6H4F), 4.75 (1H, m, 1H of BnpipH-2, H-6), 4.43 (1H, d, J 7.0 Hz, CH (OH) C6H4F), 3.99 (1H , m, pipH-4), 3.66 (1H, m, 1H of BnpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.01 (1H, m, 1H of BnpipH-2, H-6) , 2.81 (2H, m, 2H of pipH-2, H-6) 2.71 (1H, m, 1H of BnpipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH- 2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.86 (1H, m, BnpipH-4), 1.62 (2H, m, 2H of pipH-3, H-5 ), 1.44-1.30 (4H, m, 4H of BnpipH-3, H-5); m / z: 556 [M + H] +.
[0336] [00336] Compound 143: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-methoxyphenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, d, J 1.5 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.87 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.82 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.47 (1H, m, 1H of oxypip), 4.00 (1H, m, pipH-4), 3.88 ( 2H, m, 2H of oxypip), 3.77 (3H, s, OCH3), 3.63 (1H, m, 1H of oxypip), 3.56 (2H, s, CH2C6H4CN), 3.35 (1H, m, 1H of oxypip), 2.81 (2H, m, 2H of pip), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.01 (4H, m, 2H of pip, 2H of oxypip), 1.82 (2H, m, 2H of oxypip), 1.63 (2H, m, 2H of pip); m / z: 555 [M + H] +.
[0337] [00337] Compound 144: N2- (2- (4-cyanobenzyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -N 5 - (4-fluorobenzyl) pyridine-2,5-dicarboxamide. 1H nmr (CDCl3) δ 9.86 (1H, s, IsoqH-8), 8.99 (1H, d, J 1.0 Hz, pyH-6), 8.28 (1H, d, J 8.0 Hz, pyH-3), 8.22 (1H , dd, J 8.0, 1.5 Hz, pyH-4), 7.51 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.51 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.42 (1H, dd, J 8.5, 1.5 Hz, IsoqH-6), 7.33 (2H, m, 2H of C6H4F), 7.12 (1H, d, J 8.5 Hz, IsoqH-5), 7.04 (2H, t, J 8.5 Hz, 2H of C6H4F ), 6.71 (1H, t, J 5.5 Hz, NH), 4.63 (2H, d, J 6.0 Hz, NHCH2C6H4F), 3.72 (2H, s, CH2C6H4CN IsoqH-1), 3.62 (2H, s, IsoqH-1 or CH2C6H4CN), 2.89 (2H, t, J 5.5 Hz, IsoqH-3 or IsoqH-4), 2.75 (2H, t, J 6.0 Hz, IsoqH-3 or H-4); m / z: 520 [M + H] +.
[0338] [00338] Compound 145: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-methylbenzyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.56 (1H, s, pyH-6), 8.21 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd , J 8.0, 1.5 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.09 (2H, d, J 8.0 Hz, 2H of C6H4CH3), 7.02 (2H, d, J 8.0 Hz, 2H of C6H4CH3), 4.69 (1H, m, 1H of BnpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.60 (1H, m, 1H of BnpipH-2, H-6), 3.58 (2H, s, CH2C6H4CN), 3.00 (1H, m, 1H of BnpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.74 (1H, m, 1H of BnpipH-2, H-6), 2.53 (2H, m, CH2C6H4CH3), 2.04 (3H, s, CH3), 2.24 (2H, t , J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.79-1.63 (4H, m, 2H of pipH-3, H-5 , BnpipH-4 ', 1H of BnpipH-3, H-5), 1.31-1.13 (3H, m, 3H of BnpipH-3, H-5); m / z: 537 [M + H] +.
[0339] [00339] Compound 146: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3-fluoro-4-methoxybenzyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.56 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.85 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.20 (1H, t, 8.0 Hz , 1 x ArH), 6.73 (1H, dd, J 8.0, 7.0 Hz, 1 x ArH), 6.68 (1H, br s, 1 x ArH), 4.69 (1H, m, 1H Bnpip), 4.00 (1H, m, pipH-4), 3.79 (3H, s, OCH3), 3.62 (1H, m, 1H from Bnpip), 3.56 (2H, s, CH2C6H4CN), 3.01 (1H, m, 1H from Bnpip), 2.81 (2H , m, 2H of pip), 2.75 (1H, m, 1H of Bnpip), 2.55 (2H, t, J 6.0 Hz, CH2C6H3FOCH3), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.82 (2H, m, 2H of Bnpip), 1.64 (2H, m, 2H of pip), 1.33-1.18 (3H, m, 3H of Bnpip); m / z: 570 [M + H] +.
[0340] [00340] Compound 147: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3-methoxybenzyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.56 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.84 (1H, br d, J 8.0 Hz, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.85 (4H, m, 4H of C6H4OCH3), 4.69 (1H, m, 1H of BnpipH-2, H-6), 3.99 (1H, m, pipH-4), 3.86 (3H, s, OCH3), 3.62 (1H, m, 1H of BnpipH- 2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.02 (1H, m, 1H of BnpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.75 (1H, m, 1H of BnpipH-2, H-6), 2.51 (2H, m, CH2C6H4OCH3), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.77 (2H, m, 2H of BnpipH-3, H-4, H-5), 1.64 (2H, m, 2H of pipH-3, H -5), 1.30-1.16 (3H, m, 3H of BnpipH-3, H-4, H-5); m / z: 552 [M + H] +.
[0341] [00341] Compound 148: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.98 (2H, dd, J 9.5 , 8.0 Hz, 2H of C6H4F), 6.86 (2H, m, 2H of C6H4F), 4.52 (1H, m, oxypipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of oxypipH-2, H-6), 3.64 (1H, m, 1H of oxypipH-2, H-6), 3.58 (2H, s, CH2C6H4CN), 3.32 (1H, m, 1H of oxypipH-2, H-6 ), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (3H, m, 2H of pipH- 3, H-5, 1H of oxypipH-3, H-5), 1.83 (3H, m, 3H of oxypipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5) ; m / z: 542 [M + H] +.
[0342] [00342] Compound 149: N2- (1- (4-cyanobenzyl) piperidin-4-yl) -N5- (2- (4-fluorophenoxy) ethyl) pyridine-2,5-dicarboxamide. 1H nmr (CDCl3) δ 8.94 (1H, s, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.19 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (1H, d, J 8.5 Hz, NHpip), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.98 (2H, dd, J 9.5 , 8.0 Hz, 2H of C6H4F), 6.85 (2H, dd, J 9.5, 4.5 Hz, 2H of C6H4F), 6.67 (1H, br s, NHCH2CH2O), 4.13 (2H, t, J 5.0 Hz, NHCH2CH2O), 4.00 (1H, m, pipH-4), 3.89 (2H, q, J 5.5 Hz, NHCH2CH2O), 3.56 (2H, s, CH2C6H4CN), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 11.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.69 (2H, m, 2H of pipH-3 , H-5); m / z: 502 [M + H] +.
[0343] [00343] Compound 150: N- (cis-4- (4-cyanophenoxy) cyclohexyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.58 (1H, m, pyH-6), 8.23 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.86 (1H , dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.26 (2H, m, 2H of C6H4F), 7.00 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4CN), 4.59 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.80 (2H, m, 2H of piz), 3.50 (2H, s, CH2C6H4F), 3.39 (2H, m, 2H of piz), 2.53 (2H, m, 2H of piz), 2.38 (2H, m, 2H of piz), 2.06 (2H, m, 2H of cHexH-2, H-6), 1.90-1.72 (4H, m, 2H of cHexH2, H-6, 2H of cHexH-3, H-5), 1.24 (2H, m, 2H of cHexH- 3, H-5); m / z: 542 [M + H] +.
[0344] [00344] Compound 151: N- (trans-4- (4-cyanophenoxy) cyclohexyl) -5- (4- (4-fluorobenzoyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.02-7.96 (3H, m, 2H of C6H4F, NH), 7.89 (1H , dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.16 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN), 4.66 (1H, m, 1H of pipH-2, H-6), 4.60 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.76 (1H, m, 1H of pipH-2, H-6), 3.54 (1H, m, pipH-4), 3.24 (1H, m, 1H of pipH-2, H-6), 3.11 (1H, m, 1H of pipH-2, H-6), 2.07 (3H, m, 3H of cHexH-2, H-6), 1.90-1.79 (8H, m, 1H of cHexH-2, H-6, 3H of cHexH- 3, H-5, 4H of pipH-3, H-5), 1.25 (1H, m, 1H of cHexH-3, H-5); m / z: 555 [M + H] +.
[0345] [00345] Compound 152: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-fluorobenzyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.48 (1H, br s, pyH-6), 8.17 (1H, d, J 8.0 Hz, NH or pyH-3), 7.87 (1H, d, J 7.5 Hz, NH or pyH-3 ), 7.80 (1H, m, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.03 (2H, m, 2H of C6H4F), 6.93 (2H, m, 2H of C6H4F), 4.52 (1H, br s, 1H of Bnpip), 4.02 (1H, m, pipH-4), 3.57 (2H, s, CH2C6H4CN), 2.95 (1H , m, 1H of Bnpip), 2.81 (2H, m, 2H of pip), 2.68 (1H, dd, J 13.0, 10.5 Hz, 1H of Bnpip), 2.50 (1H, m, 1H of Bnpip), 2.26 (2H , td, J 11.5, 2.0 Hz, 2H of pip), 2.04 (2H, m, 2H of pip), 1.90-1.58 (5H, m, 2H of pip, 3H of Bnpip), 1.27 (2H, m, 2H of Bnpip); m / z: 541 [M + H] +. ** 2H of Bnpip missing, probably due to the peak width in the 3-5 region **
[0346] [00346] Compound 153: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (2- (4-fluorobenzyl) piperidine-1-carbonyl) picolinamide. m / z: 540 [M + H] +. 1H nmr (CDCl3) δ 8.19 (1H, br s, pyH-6), 8.10 (1H, d, J 7.5 Hz, 1H NH, pyH-3 or pyH-4), 7.86 (1H, d, J 8.0 Hz , 1H of NH, pyH-3 or pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.05 (2H, m wide , 2H of C6H4F), 6.96 (2H, t, J 8.0 Hz, 2H of C6H4F), 4.00 (1H, m, pipH-4), 3.57 (2H, s, CH2C6H4CN), 3.08 (2H, m, 2H of Bnpip ), 2.80 (3H, m, 2H of pip, 1H of Bnpip), 2.25 (2H, m, 2H of pip), 2.02 (2H, m, 2H of pip), 1.76-1.60 (8H, m, 2H of pip , 6H Bnpip); m / z: 540 [M + H] +. ** 2H of Bnpip does not appear, probably too wide to be observed **
[0347] [00347] Compound 154: 5- (4- (4-chlorobenzoyl) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.94-7.87 (4H, m, NH, pyH-4, 2H of C6H4Cl), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.46 (4H, m, 2H of C6H4CN, 2H of C6H4Q), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.58 (2H, s, CH2C6H4CN), 3.53 (1H, m, BzpipH-4), 3.17 ( 2H, m 2H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 10.5 Hz, 2H of pipH-2, H-6 ), 2.02 (2H, m, 2H of BzpipH-3, H-5), 1.82 (2H, m, 2H of pipH-3, H-5), 1.71-1.61 (4H, m, 2H of pipH-3, H-5, BzpipH-3, H-5); m / z: 570 [M + H] +.
[0348] [00348] Compound 155: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3-cyanophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.39 (1H, t, J 7.5 Hz, 1H OC6H4CN), 7.26 (1H, m, 1H OC6H4CN), 7.14 (2H, m, 2H OC6H4CN), 4.65 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4) , 3.90 (2H, m, 2H of PhoxypipH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.39 (1H, m, 1H of PhoxypipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6) , 2.04-1.70 (6H, m, 2H of pipH-3, H-5, PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 549 [M + H] +.
[0349] [00349] Compound 156: 5- (4- (3-chloro-4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H ,, m pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.59 (1H, d, J 9.0 Hz, H-5 or H-6 of C6H3ClCN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.03 (1H, d, J 2.0 Hz, H-2 of C6H3ClCN), 6.87 (1H, dd, J 8.5, 2.0 Hz, H-5 or H-6 of C6H3ClCN), 4.69 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhoxypipH-2, H-6), 3.62 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.42 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 ( 2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.69 (6H, m, 2H of pipH-3, H-5, PhoxypipH-3, H-5), 1.64 ( 2H, m, 2H of pipH-3, H-5); m / z: 583, 585 [M + H] +.
[0350] [00350] Compound 157: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (trifluoromethyl) phenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.87 (2H, m, NH, pyH-4), 7.61 (2H , d, J 8.5 Hz, 2H of C6H4CN), 7.55 (2H, m, 2H of C6H4CF3), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.97 (2H, d, J 9.0 Hz, 2H of C6H4CF3), 4.70 (1H, m, 1H of Phoxypip), 4.01 (1H, m, 1H of Phoxypip or pipH-4), 3.95-3.87 (1H, m, 1H of Phoxypip or pipH-4), 3.64 (1H, m, 1H of Phoxypip), 3.58 (2H, s, CH2C6H4CN), 3.50 (1H, m, 1H of Phoxypip), 3.35 (1H, m, 1H of Phoxypip), 2.83 (2H, m, 2H of pip), 2.24 (2H, t, J 11.0 Hz, 2H of pip), 2.14-1.84 (6H, m, 2H of pip, 4H of Phoxypip), 1.65 (2H, m, 2H of pip); m / z: 592 [M + H] +.
[0351] [00351] Compound 158: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3,4-difluorophenoxy) piperidmo-1-carboml) picolmamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.07 (1H, q, J 9.5 Hz, H- 5 of C6H3F2), 6.74 (1H, m, H-1 of C6H3F2), 6.61 (1H, m, H-6 of C6H3F2), 4.51 (1H, m, PhoxypipH- 4), 4.01 (1H, m, pipH- 4), 3.88 (2H, m, 2H of PhoxyH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.37 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6) , 2.04-1.84 (6H, m, 2H of pipH-3, H-5, 4H of PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 560 [M + H] +.
[0352] [00352] Compound 159: N- (1- (4-cyanobenzyl) piperidin-4-yl) -3- (5,20-dioxo-24 - ((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) - 7,10,13,16-tetraoxa-4,19-diazatetracos-1-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl ) picolinamide. Hydrogen chloride (0.054 mL of a 4.0 M solution in dioxane, 0.216 mmol, 5.0 eq) was added to a solution of Compound 164 (see below) (0.030 g, 0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 90 minutes before removing the solvent under a stream of nitrogen. The residue was dried in vacuo, providing 3- (3-aminoprop-1-ynyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine trihydrochloride -1-carbonyl) picolinamide, which was used without further purification; m / z 594 [M + H] +. To a suspension of 3- (3-aminoprop-1-ynyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl hydrochloride ) picolinamide (0.043 mmol, 1.0 eq) in dichloromethane (1.0 ml) triethylamine (0.018 ml, 0.129 mmol, 3.0 eq) was added, forming a brown solution. 15 - [(D) - (+) - biotinylamino] -4,7,10,13-tetraoxapentadecanoic acid (0.023 g, 0.047 mmol, 1.1 eq) and HATU (0.018 g, 0.047 mmol, 1, 1 eq), followed by dimethylaminopyridine (0.005 g, 0.043 mmol, 1.0 eq). The reaction was stirred at room temperature for 3 hours before being poured into water (20 mL). The organics were extracted with CH2Cl2 (3 x 25 mL). The combined organics were washed with saline (35 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by means of RP-HPLC, providing Compound 159; m / z 1068 [M + H] +.
[0353] [00353] Compound 160: 5- (4- (4-fluorobenzoyl) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. To a solution of 5- (methoxycarbonyl) pyridine-2-carboxylic acid (0.209 g, 1.18 mmol, 1.0 eq) and 1- (4-methoxybenzyl) piperidine dihydrochloride (0.373 g, 1.27 mmol, 1 , 1 eq) in dimethylformamide (10 ml) triethylamine (0.40 ml, 2.89 mmol, 2.5 eq) was added, followed by HATU (0.528 g, 1.39 mmol, 1.2 eq). The reaction was stirred at room temperature for 2 days before being partitioned between EtOAc (100 ml) and water (80 ml). The organics were additionally washed with saline solution (80 ml), water (80 ml) and saline solution (80 ml), before drying (Na2SO4) and concentration under reduced pressure, providing 6- (1- (4-methoxybenzyl) piperidin -4-ylcarbamoyl) methyl nicotinate as a white solid (0.378 g, 84%) which was used without further purification; 1H nmr (CDCl3) 9.13 (1H, m, pyH-6), 8.43 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.98 ( 1H, d, J 7.5 Hz, NH), 7.26 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.87 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 4.01 (1H, m, pipH-4 ), 3.98 (3H, s, 1 x OCH3), 3.80 (3H, s, 1 x OCH3), 3.53 (2H, s, CH2C6H4OCH3), 2.90 (2H, m, 2H of pip), 2.24 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.02 (2H, m, 2H of pip), 1.69 (2H, m, 2H of pip); m / z 384 [M + H] +. To a solution of methyl 6- (1- (4-methoxybenzyl) piperidin-4-ylcarbamoyl) nicotinate (0.378 g, 0.987 mmol, 1.0 eq) in tetrahydrofuran (6 ml) and methanol (3 ml) was added solution of lithium hydroxide monohydrate (0.166 g, 3.948 mmol, 4.0 eq) in water (3 mL). The reaction mixture was stirred at room temperature for 30 minutes before being neutralized with HCl (approximately 2.0 ml of a 2 M solution). The reaction was concentrated to dryness, providing 6- (1- (4-methoxybenzyl) piperidin-4-ylcarbamoyl) nicotinic acid as a white solid, which was used without purification. To a mixture of 6- (1- (4-methoxybenzyl) piperidin-4-ylcarbamoyl) nicotinic acid (0.036 g, 0.098 mmol, 1.0 eq), 4-fluorobenzoylpiperidine hydrochloride (0.029 g, 0.117 mmol, 1.2 eq), and triethylamine (0.034 ml, 0.244 mmol, 2.5 eq) in dimethylformamide (1.0 eq) was added HATU (0.041 g, 0.244 mmol, 1.1 eq). The reaction was stirred at room temperature for 3 hours before adding water (5 ml). A gum formed, which was dissolved in EtOAc-CH2Cl2 (4: 1, 50 ml). The solution was washed with NaHCO3-water (1: 1, 50 ml), saline (50 ml), water (50 ml) and saline (50 ml). The organics were dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 3 ^ 7% MeOH-CH2CL) provided Compound 160 as a colorless oil (0.037 g, 68%); 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.98 (2H, dd, J 8.5, 5.5 Hz, 2H of C6H4F), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.24 (2H, d, 2H of C6H4OCH3), 7.16 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.86 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 4.66 ( 1H, m, BzpipH-4), 3.99 (1H, m, pipH-4), 3.80 (3H, s, OCH3), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, 1H of BzpipH-2, H-6), 3.48 (2H, s, CH2C6H4OCH3), 3.21-3.11 (2H, m, 2H of BzpipH-2, H-6), 2.86 (2H, m, 2H of pipH -2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.82 (4H, m, BzpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 559 [M + H] +.
[0354] [00354] Compound 161: 5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.24 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.98 (2H, dd, J 9.0, 8.5 Hz, 2H of C6H4F), 6.86 (4H, m, 2H of C6H4F, 2H of C6H4OCH3), 4.51 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH3), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH2C6H4OCH3), 3.34 (1H, m, 1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.06-1.90 (4H, m, 2H of pipH-3, H- 5, 2H of PhOpipH-3, H-5), 1.83 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 547 [M + H] +.
[0355] [00355] Compound 162: 5- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, d, J 1.0 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.90 (1H, m, NH), 7.87 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4OCH3), 7.23 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4OCH3), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4OCH3), 6.86 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4OCH3), 4.70 (1H, m, PhOpipH-4), 3.99 (1H, m, pipH-4 ), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH3), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s , CH2C6H4OCH3), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.82 (6H, m, 2H of pipH-3, H-5 and 4H of PhOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 555 [M + H] +.
[0356] [00356] Compound 163: 5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 9.0 Hz, 2H OC6H4CN or CH2C6H4CN), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.26 (2H, d, J 8.5 Hz, 2H OC6H4CN or CH2C6H4CN), 6.96 (2H, d, J 9.0 Hz, 2H OC6H4CN or CH2C6H4CN), 6.86 (2H, d, J 8.5 Hz, 2H OC6H4CN or CH2C6H4CN), 4.65 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (3H, s, OCH3), 3.80 ( 1H, m, 1H of PhOpipH-2, H-6), 3.53 (3H, m, 1H of PhOpipH-2, H-6, CH2C6H4OCH3), 3.24-3.11 (2H, m, 2H of PhOpipH-2, H- 6), 2.91 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH -3, H-5), 1.89-1.76 (4H, m, 4H of PhOpipH-3, H-5), 1.70 (2H, m, 2H of pipH-3, H-5); m / z: 572 [M + H] +.
[0357] [00357] Compound 164: 3- (2- (1- (4-cyanobenzyl) piperidin-4-ylcarbamoyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) pyridin-3-yl) prop- Tert-butyl 2-inylcarbamate. To a solution of 5-chloro-6- (ethoxycarbonyl) nicotinic acid (0.201 g, 0.875 mmol, 1.0 eq) and 4-fluorobenzylpiperazine (0.204 g, 1.051 mmol, 1.2 eq) in dimethylformamide (4.0 mL ) triethylamine (0.146 ml, 1.051 mmol, 1.2 eq) was added, followed by HATU (0.366 g, 0.963 mmol, 1.1 eq). The reaction was stirred at room temperature for 3 hours before being partitioned between EtOAc (80 mL) and water-NaHCO3 (2: 1, 60 mL). The organics were additionally washed with saline solution (80 ml), water (80 ml) and saline solution (80 ml) before drying (Na2SO4) and concentration under reduced pressure. MPLC (30 → 95% EtOAc-hexane, 2 → 25 minutes) provided ethyl 3-chloro-5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate as a white solid (0.265 g, 75 %). 1H nmr (D6-DMSO) 8.54 (1H, d, J 1.5 Hz, pyH-2 or pyH-4), 7.83 (1H, d, J 1.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m , 2H of C6H4F), 6.99 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.48 (2H, q, J 7.0 Hz, OCH2CH3), 3.55 (4H, m, 4H of piz), 2.45 (4H, m , 4H of piz), 1.43 (3H, t, J 7.0 Hz, OCH2CH3); m / z 406, 408 [M + H] +. A solution of ethyl 3-chloro-5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate (0.265 g, 0.654 mmol, 1.0 eq) and N-Boc-propargylamine (0.122 g, 0.785 mmol , 1.2 eq) in dimethylformamide (7.0 mL) was degassed by bubbling argon through it. Triethylamine (0.14 mL, 0.981 mmol, 1.5 eq) was added, followed by copper (I) iodide (0.006 g, 0.033 mmol, 0.05 eq) and tetrakis (triphenylphosphine) palladium (0.038 g, 0.033 mmol, 0.05 eq). The reaction mixture was further degassed before being heated to 90 ° C for 14 hours. The reaction was cooled and filtered through Celite®, eluting with EtOAc (80 ml). The filtrate was washed with water (100 ml), saline (80 ml), water (100 ml) and saline (80 ml). The organics were dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 70% EtOAc-hexane) provided the starting material 3-chloro-5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate and 3- (3- (tert-butoxycarbonylamino) ) prop-1-ynyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) ethyl picolinate as a colorless oil. 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.87 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H of C6H4F), 6.99 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.87 (1H, br s, NH), 4.47 (2H, q, J 7.0 Hz, OCH2CH3), 4.21 (2H, d, J 5.5 Hz, CH2NHBoc), 3.77 (2H, m, 2H of piz), 3.37 (2H, m, 2H of piz), 2.51 (2H, m, 2H of piz), 2.38 (2H, m, 2H of piz), 1.47 (9H, s, C (CH3) 3), 1.43 (3H, t, J 7.0 Hz, OCH2CH3); m / z 525 [M + H] +. A solution of lithium hydroxide monohydrate (0.010 g, 0.229 mmol, 2.0 eq) in water (0.5 mL) was added to a solution of 3- (3- (tert-butoxycarbonylamino) prop-1-ynyl) - Ethyl 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinate (0.060 g, 0.115 mmol, 1.0 eq) in tetrahydrofuran-methanol (2: 1, 1.5 mL). The reaction was stirred at room temperature for 40 minutes before being neutralized with HCl (approximately 0.2 ml of a 2 M solution). The reaction mixture was concentrated to dryness, providing 3- (3- (tert-butoxycarbonylamino) prop-1-ynyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinic acid, which was used without purification; m / z 497 [M + H] +. To a solution of crude 3- (3- (tert-butoxycarbonylamino) prop-1-ynyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinic acid (0.115 mmol, 1.0 eq) dimethylformamide (2.0 ml) 1- (4-cyanobenzyl) -4-aminopiperidine dihydrochloride (0.040 g, 0.138 mmol, 1.2 eq) and HATU (0.052 g, 0.138 mmol, 1.2 eq) were added. Triethylamine (0.056 mL, 0.403 mmol, 3.5 eq) was added and the reaction mixture was stirred at room temperature for 2.5 hours before being partitioned between EtOAc (100 mL) and water (100 mL). The organics were additionally washed with saline (80 ml), water (80 ml) and saline solution (80 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 3 → 6% MeOH-CH2Cl2) provided Compound 164 as a yellow foam. 1H nmr (CDCl3) δ 8.46 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.85 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.80 (1H, d, J 8.0 Hz, CONH), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.29-7.25 (2H, m, 2H of C6H4F), 7.00 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.88 (1H, m, NHCO2C), 4.23 (2H, d, J 5.5 Hz, CCH2NH), 3.99 (1H, m, pipH-4), 3.80- 3.40 (4H, br m, 4H of piz), 3.56 (2H, s, CH2C6H4CN or CH2C6H4F), 3.51 (2H, s, CH2C6H4CN or CH2C6H4F), 2.80 (2H, m, 2H of pip), 2.46 (4H, m , 4H of piz), 2.23 (2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2H of pip), 1.46 (9H, s, C (CH3) 3); m / z: 694 [M + H] +.
[0358] [00358] Compound 165: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-cyanophenoxy) piperidin-1-yl) picolinamide. To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1- (4-cyanobenzyl) -4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1 , 0 eq) in dimethylformamide (10 ml) was added triethylamine (1.21 ml, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 14 hours before being partitioned between EtOAc (120 ml) and water (100 ml). The organics were washed with saline solution (100 ml), water (100 ml) and saline solution (100 ml), were dried (Na2SO4) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH-CH2Cl2, 0 → 5 → 25 → 35 minutes) provided 5-bromo-N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide as a solid waxy brown: 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.50 (2H, d, J 8.0 Hz, 2H of C6H4CN), 4.00 ( 1H, m, pipH-4), 3.63 (2H, s, CH2C6H4CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip) , 1.70 (2H, m, 2H of pip); m / z 399, 401 [M + H] +. To a mixture of 5-bromo-N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide (0.040 g, 0.100 mmol, 1.0 eq), 4- (4-piperidinyloxy) benzonitrile (0.024 g, 0.120 mmol, 1, 2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) were added toluene (1.0 mL ). The resulting mixture was degassed by bubbling argon into the mixture. Tris (dibenzylidenoacetone) dipaladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture was further degassed before sealing the reaction and heating to 105 ° C for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH-CH2Cl2 (3 x 15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by means of RP-HPLC, providing Compound 165: 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH- 3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H OC6H4CN, 2H CH2C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H CH2C6H4CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H OC6H4CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H , m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H -5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m / z: 522 [M + H] +.
[0359] [00359] Compound 166: N2- (1- (4-cyanobenzyl) piperidin-4-yl) -N5- (1- (4-cyanophenyl) piperidin-4-yl) pyridine-2,5-dicarboxamide. 1H nmr (CDCl3) δ 8.92 (1H, d, J 1.0 Hz, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH- 4), 7.94 (1H, d, J 8.5 Hz, BnpipNH), 7.61 (2H, d, J 8.5 Hz, 2H of CH2C6H4CN), 7.47 (4H, m, 2H of CH2C6H4CN, 2H of NC6H4CN), 6.88 (2H, d, J 9.0 Hz, 2H of NC6H4CN), 6.21 (1H, d, J 7.5 Hz, PhpipNH), 4.26 (1H, m, PhpipH-4), 3.99 (1H, m, BnpipH-4), 3.89 (2H, m, 2H of PhpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.08 (2H, t, J 11.5 Hz, 2H of PhpipH-2, H-6), 2.81 (2H, m, 2H of BnpipH-2, H-6), 2.26-2.16 (4H, m, 2H of PhpipH-3, H-5, 2H of BnpipH-2, H-6), 2.02 (2H, m, 2H of BnpipH-3 , H-5), 1.70-1.59 (4H, m, 2H of PhpipH-3, H-5, 2H of BnpipH-3, H-5); m / z: 548 [M + H] +.
[0360] [00360] Compound 167: N - ((cis) -4- (4-cyanophenoxy) cyclohexyl) -5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.25 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.01-6.94 (4H, m, 2H of C6H4CN, 2H of C6H4F ), 6.89-6.84 (2H, m, 2H of C6H4F), 4.60 (1H, br s, cHexH-1 or PhOpipH-4), 4.52 (1H, m, cHexH-1 or PhOpipH-4), 4.10 (1H, m, cHexH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH -2, H-6), 2.11-1.90 (12H, m, cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5); m / z: 543 [M + H] +.
[0361] [00361] Compound 265: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-cyanophenoxy) piperidin-1-yl) picolinamide. 1H nmr (CDCl3) δ 8.13 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 9.0 Hz, pyH-3), 7.70 (1H, d, J 8.5 Hz, NH), 7.62 - 7.57 (4H, 4 x ArH), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN or OC6H4CN), 7.19 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H of CH2C6H4CN or OC6H4CN), 4.54 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.75 (1H, dd, J 12.5, 3.0 Hz, 1H of PhOpipH-2 , H-6), 3.55 (2H, s, CH2C6H4CN), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 3.31 (1H, dd, J 13.0, 7.5 Hz, 1H of PhOpipH-2, H-6), 3.23 (1H, m, 1H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pip), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.14 (1H, m, 1H of PhOpip), 1.99 (3H, m, 2H of pip, 1H of PhOpip), 1.79 (2H, m, 2H of PhOpip), 1.62 (2H, m, 2H of pip); m / z: 521 [M + H] +.
[0362] [00362] Compound 266: 5- (4- (4-dorobenzofl) piperidin-1-yl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.18 (1H, br s, 1 x py), 7.98 (1H, d, J 8.5 Hz, NH or 1 x py), 7.98 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4Cl ), 7.96 (1H, m, NH or 1 x py), 7.90 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4Cl), 7.75 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4Q), 7.47 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4Cl), 7.25 (1H, m, NH or 1 x py), 4.26 (2H, s, CH2C6H4CN), 4.19 (1H, m, pipH-4 or BzpipH- 4), 3.90 (2H, m, 2H of pip or Bzpip), 3.62 (2H, m, 2H of pip or Bzpip), 3.45 (1H, m, pipH-4 or BzpipH-4), 3.07 (2H, m, 2H of pip or Bzpip), 2.81 (2H, m, 2H of pip or Bzpip), 2.20-1.85 (8H, m, 4H of pip, 4H of Bzpip); m / z: 542, 544 [M + H] +.
[0363] [00363] Compound 267: N- (1- (4-danobenzyl) piperidin-4-yl) -5- (1- (4-cyanophenyl) piperidin-4-ylamino) picolinamide. 1H nmr (CDCl3) δ 7.99 (1H, d, J 8.5 Hz, pyH-3), 7.89 (1H, d, J 2.0 Hz, pyH-6), 7.65 (1H, d, J 8.5 Hz, NH), 7.66 (2H, d, J 9.0 Hz, 2H of CH2C6H4CN or NC6H4CN), 7.60 (2H, d, J 8.5 Hz, 2H of CH2C6H4CN or NC6H4CN), 7.45 (2H, d, J 7.5 Hz, 2H of CH2C6H4CN or NC6H4CN), 6.94 (1H, dd, J 9.0, 2.5 Hz, pyH-4), 6.89 (2H, d, J 9.0 Hz, 2H of CH2C6H4CN or NC6H4CN), 3.99 (2H, m, 2H of pip), 3.85 (2H, m , 2H of pip), 3.60 (1H, m, 1H of pip), 3.55 (2H, s, CH2C6H4CN), 3.08 (2H, t, J 11.5 Hz, 2H of pip), 2.80 (2H, m, 2H of pip ), 2.21 (4H, m, 4H of pip), 1.99 (2H, m, 2H of pip), 1.59 (3H, m, 3H of pip); m / z: 520 [M + H] +.
[0364] [00364] Compound 268: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (2- (4-fluorophenyl) propan-2-yl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.57 (1H, m, pyH-6), 8.20 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.49-7.29 (4H, m, 2H of C6H4CN, 2H of C6H4F), 6.98 (2H, t, J 9.0 Hz, 2H of C6H4F), 4.00 (1H, m, pipH-4), 3.76 (2H, m, 2H of piz), 3.56 (2H, s, CH2C6H4CN), 3.33 (2H, m, 2H of piz) , 2.81 (2H, m, 2H of pip), 2.57 (2H, m, 2H of piz), 2.40 (2H, m, 2H of piz), 2.22 (2H, dd, J 11.0, 9.5 Hz, 2H of pip) , 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2H of pip), 1.33 (6H, s, C (CH3) 2); m / z: 569 [M + H] +.
[0365] [00365] Compound 269: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (pyridin-4-yloxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.44 (2H, d, J 6.0 Hz, 2H of Opy), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H , m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.81 (2H, d, J 6.5 Hz, 2H of Opy), 4.72 (1H, m, PyOpipH-4), 4.05-3.87 (3H, m, pipH-4, 2H of PyOpipH-2, H-6 ), 3.63 (1H, m, 1H of PyOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.41 (1H, m, 1H of PyOpipH-2, H-6), 2.81 (2H, m , 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5) , 2.00-1.79 (4H, m, 4H of PyOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 525 [M + H] +.
[0366] [00366] Compound 270: (S) -N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide. 1H nmr (CDCl3 @ 50 ° C) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.98 (1H, m, NH or pyH-4), 7.90 (1H, d, J 8.0 Hz, NH or pyH-4), 7.59 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.97 (2H , m, 2H of C6H4F), 6.80 (2H, m, 2H of C6H4F), 4.90 (1H, m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.86 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.80-3.50 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH2C6H4CN), 2.80 (2H, m, 2H of pipH-2, H-6), 2.29-2.14 (4H, m, 2H of pipH-2, H-6, pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3 @ 50 ° C) δ -122.3; m / z: 528 [M + H] +.
[0367] [00367] Compound 271: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.58 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.84 (3H, m, NH, pyH-4, 1H of BzH- 5 or BzH-6), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.99 (1H, m, BzH-5 or BzH-6 ), 6.89 (ddd, J 11.0, 8.5, 2.5 Hz, BzH-3), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.75 (1H , m, BzpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H, m, 1H of BzpipH-2, H-6) , 3.07 (1H, m, 1H of BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, d, J 11.0, 10.0 Hz, 2H of pipH -2, H-6), 2.03 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.86 (1H, m, 1H of BzpipH-3, H-5 ), 1.75-1.58 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); m / z: 572 [M + H] +.
[0368] [00368] Compound 272: 5- (4- (4-fluorobenzoyl) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.91 (1H, s, 1 x NH or ArH), 8.68 (1H, m, 1 x NH or ArH), 8.42-8.33 (3H, m, NH, 2 x ArH or 3 x ArH) , 8.01-7.95 (3H, m, NH, 2 x ArH or 3 x ArH), 7.20-7.08 (5H, m, NH, 4 x ArH or 5 x ArH), 6.97 (2H, d, J 9.0 Hz, 2 x ArH), 4.67 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.76 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.49 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.26 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.14 (1H, m, 1H of BzpipH-2, H-4, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.84 (3H, m, 3H of BzpipH-3, H-5); m / z: 543 [M + H] +.
[0369] [00369] Compound 273: 5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.90 (1H, s, NH or 1 x ArH), 8.68 (1H, m, 1 x ArH), 8.41-8.33 (3H, NH, 2 x ArH or 3 x ArH), 7.96 (1H , dd, J 8.0, 2.0 Hz, 1 x ArH), 7.11-7.08 (4H, m, NH, 3 x ArH or 4 x ArH), 7.02-6.95 (3H, NH, 2 x ArH or 3 x ArH), 6.89-6.85 (2H, m, 2 x ArH), 4.54 (1H, m, PhOpipH-4), 3.91 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH -2, H-6), 3.39 (1H, m, 1H of BzpipH-2, H-6), 2.00 (2H, m, 2H of PhOpipH-3, H-5), 1.86 (2H, m, 2H of PhOpipH-3, H-5); m / z: 531 [M + H] +.
[0370] [00370] Compound 274: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-methoxyphenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, s, pyH-6), 8.23 and 8.11 (1H, 2m, pyH-3), 7.87 (2H, m, NH, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.92-6.73 (4H, m, 4H of C6H4OCH3), 4.24 (2H, m, 1H of PhOpipH-2, H- 6, PhOpipH-3), 3.99 (1H, m, pipH-4), 3.75 (3H, s, OCH3), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.43 (1H, m, 1H of PhOpipH-2, H-6), 3.29 (1H, m, 1H of PhOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H -6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5 ), 1.82 (1H, m, 1H of PhOpipH-4, H-5), 1.65 (3H, m, 2H of pipH-3, H-5, 1H of PhOpipH-4, H-5); m / z: 555 [M + H] +.
[0371] [00371] Compound 275: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (1- (4-methoxyphenyl) piperidin-4-ylamino) picolinamide. 1H nmr (CDCl3) δ 7.98 (1H, d, J 8.5 Hz, pyH-3), 7.88 (1H, d, J 2.0 Hz, pyH-6), 7.68 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.47 (2H, d, J 7.5 Hz, 2H of C6H4CN), 6.93 (3H, m, 2H of C6H4OCH3, pyH-4), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.03-3.97 (2H, m, 2 x pipH-4), 3.77 (3H, s, OCH3), 3.58 (2H, s, CH2C6H4CN), 3.49 (4H, m, 2 x 2H of pipH-2, H-6), 2.83 (4H, m, 2 x 2H of pipH-2, H-6), 2.28-2.15 (4H, m, 2 x 2H of pipH-3, H-5) , 2.00 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m / z: 525 [M + H] +.
[0372] [00372] Compound 276: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (1- (4-fluorophenyl) piperidin-4-ylamino) picolinamide. 1H nmr (CDCl3) δ 8.17 (1H, d, J 3.0 Hz, pyH-6), 8.02 (1H, d, J 8.5 Hz, pyH-3), 7.73 (1H, d, J 8.5 Hz, CONH), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.22 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.89 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.56 (2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 3.98 (1H, m, pipH-4), 3.79 (2H, m, 2H of Phpip), 3.55 (2H, s, CH2C6H4CN), 3.44 (1H, m, PhpipH-4), 3.04 (2H, m, 2H of Phpip), 2.80 (2H, m, 2H of pipH-2, H-6), 2.21 ( 4H, m, 2H of Phpip, 2H of pipH-2, H-6), 1.99 (2H, m, 2H of pipH-3, H-5), 1.76- 1.47 (4H ,, m 2H of pipH-3, H-5, 2H of Phpip); m / z: 513 [M + H] +.
[0373] [00373] Compound 277: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (3-methoxyphenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3 @ 50 ° C) δ 8.58 (1H, s, pyH-6), 8.12 (1H, br s, pyH-3), 7.87 (1H, d, J 8.5 Hz, NH), 7.83 (1H, m, pyH-4), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.12 (1H, t, J 7.5 Hz, 1H of C6H4OCH3 ), 6.49 (1H, d, J 8.5 Hz, 1H of C6H4OCH3), 6.40 (2H, m, 2H of C6H4OCH3), 4.32 (1H, m, PhOpipH-3), 4.00 (1H, m, pipH-4), 3.76 (3H, s, OCH3), 3.59 (1H, m, 1H of PhOpipH-2), 3.56 (2H, s, CH2C6H4CN), 3.37 (2H, m, PhOpipH-6), 2.80 (3H, m, 2H of pipH-2, H-6, 1H of PhOpipH-2), 2.25 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.98 (4H, m, 2H of pipH-3, H- 5.2H of PhOpipH-4, H-5), 1.71-1.59 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5); m / z: 554 [M + H] +.
[0374] [00374] Compound 278: (R) -N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide. 1H nmr (CDCl3 @ 50 ° C) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 7.5 Hz, pyH-3 or H-4), 7.98 (1H, br s, NH) , 7.90 (1H, d, J 8.0 Hz, pyH-3 or H-4), 7.59 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.98 (2H, m, 2H of C6H4F), 6.90-6.78 (2H, m, 2H of C6H4F), 4.92 (1H, m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.85 ( 2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.78- 3.50 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH2C6H4CN), 2.80 (2H , m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16 (2H, m, pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 528 [M + H] +.
[0375] [00375] Compound 279: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5 - ((trans) - 4- (4-cyanophenoxy) -3-fluoropiperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.62 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3), 7.92 (2H, m, NH, pyH-4), 7.63 (2H, d , J 9.0 Hz, 2H OC6H4CN), 7.61 (2H, d, J 8.0 Hz, 2H CH2C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H CH2C6H4CN), 7.01 (2H, d, J 9.0 Hz, 2H OC6H4CN), 4.75 (1H, m, PhOpipH-4), 4.75-4.03 (2H, m, 2H of PhOpipH-2, H-3, H-6), 4.01 (1H, m, pipH-4), 3.78 (1H, m, 1H of PhOpipH-2, H-3, H-6), 3.68-3.37 (2H, m, 2H of PhOpipH-2, H-3, H-6), 3.57 (2H, s, CH2C6H4CN), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H pipH-3, H-5), 1.63 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-6); m / z: 567 [M + H] +.
[0376] [00376] Compound 280: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- ((1R, 3r, 5S) -3- (4-cyanophenoxy) -8-azabicycles [3.2.1] octane-8-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.69 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.97 (1H, dd, J 8.0, 2.0 Hz, pyH- 4), 7.92 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of CH2C6H4CN), 7.57 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN), 6.93 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.67 (1H, m, 1H of PhOpipH-2, H-4, H-6), 4.82 (1H , m, 1H of PhOpipH-2, H-4, H-6), 4.13 (1H ,, m 1H of PhOpipH-2, H-4, H-6), 4.01 (1H, m pipH-4), 3.56 (2H, s, CH2C6H4CN), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, pipH-2, H-6), 2.17 (4H, m, 4H of PhOpip), 2.01 (2H, m, 2H of pipH-3, H-5), 1.86 (2H, d, J 7.5 Hz, 2H of PhOpip), 1.68 (4H, m, 2H of pipH-3, H -5.2H PhOpip); m / z: 575 [M + H] +.
[0377] [00377] Compound 281: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (3,4-difluorobenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.84 (3H, NH, pyH-4, BzH-5 or H- 6), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.99 (1H, m, BzH-5 or H-6), 6.89 ( 1H, ddd, J 11.0, 9.0, 2.0 Hz, BzH-2), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.71 (1H, m , 1H of BzpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H ,, m 1H of BzpipH-2, H-6), 3.08 (1H, m, BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, 11.5, 10.0 Hz, pipH-2, H-6) , 2.12-1.82 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.78-1.59 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); m / z: 572 [M + H] +.
[0378] [00378] Compound 282: N- (1- (4-cyanobenzyl) piperidm-4-yl) -5- (4- (2,4-difluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 9.0 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.98 (1H, td, J 9.0 , 5.5 Hz, PhH-5), 6.87 (1H, ddd, J 11.0, 8.5, 3.0 Hz, PhH-2), 6.80 (1H, m, PhH-6), 4.47 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s , CH2C6H4CN), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.03-1.96 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.85 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 560 [M + H] +.
[0379] [00379] Compound 283: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (pyridin-3-yloxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, m, pyH-6), 8.33 (1H, m, OpyH-2), 8.26-8.23 (2H, m, pyH-3, 1H of OpyH), 7.92 (1H, d , J 9.5 Hz, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.23 (2H, m, 2H of OpyH), 4.66 (1H ,, m pyOpipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of pyOpipH-2, H-6), 3.66 (1H, m, 1H of pyOpipH-2, H-6), 3.40 (1H, m, 1H of pyOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2 , H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.88 (6H, m, 2H of pipH-3, H-5, 4H of pyOpipH -3, H-5), 3.56 (2H, s, CH2C6H4CN), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 525 [M + H] +.
[0380] [00380] Compound 284: ethyl 4- (1- (6- (1- (4-cyanobenzyl) piperidin-4-ylcarbamoyl) nicotinoyl) piperidin-4-yloxy) benzoate. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.99 (2H, d, J 8.5 Hz, 2H of C6H4CO2EO, 7.92 (1H, d, J 9.5 Hz, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz , 2H of C6H4CN), 6.92 (2H, d, J 9.0 Hz, 2H of C6H4CO2Et), 4.72 (1H, m, PhOpipH-4), 4.34 (2H, q, J 7.0 Hz, OCH2CH3), 4.02-3.87 (3H , m, pipH-4, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH2C6H4CN), 3.55 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 10.5 Hz, pipH-2, H-6), 2.03-1.88 (6H, m, pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.37 (3H, t, J 7.0 Hz , OCH2CH3); m / z: 597 [M + H] +.
[0381] [00381] Compound 285: 5- (4- (4-cyanobenzyl) piperazine-1-carboml) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.58 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.90 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.62 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.25 (2H, d, J 8.0 Hz, 2H of C6H4OCH3), 6.86 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 4.00 (1H, m, pipH-4), 3.80 (5H, m, 2H of piz, OCH3), 3.59 (2H, s, 1 x CH2Ar), 3.52 (2H, s, 1 x CH2Ar), 3.41 (2H, m, 2H of piz), 2.90 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, m, 2H of piz), 2.41 (2H, m, 2H of piz), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3 , H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m / z: 553 [M + H] +.
[0382] [00382] Compound 286: 5- (4- (4-cyano-2-methoxyphenoxy) piperidin-1-yl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.18 (1H, d, J 2.5 Hz, pyH-6), 8.02 (1H, d, J 9.0 Hz, pyH-3), 7.73 (1H, d, 8.5 Hz, CONH), 7.61 ( 2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.26-7.21 (2H, m, pyH-4, CoH3 (OCH3) CNH-5), 7.11 (1H, d, J 1.5 Hz, C6H3 (OCH3) CNH-3), 6.95 (1H, d, J 8.5 Hz, C6H3 (OCH3) CNH-6), 4.60 (1H, m, PhOpipH-4), 3.99 ( 1H, m, pipH-4), 3.86 (3H, s, OCH3), 3.69-3.61 (4H, m, 2H of PhOpipH-2, H-6, CH2C6H4CN), 3.30 (2H, m, 2H of PhOpipH- 2 , H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.26 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.14-1.96 ( 6H, m, 2H of pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 552 [M + H] +.
[0383] [00383] Compound 287: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3) , 7.92 (1H, m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.88 (2H, d, J 6.0 Hz, C6H3F2H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m , pipH-4), 3.87 (3H, s, OCH3), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.49 (2H, s, CH2C6H3F2 ), 3.17 (2H, m, 2H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.83 (3H, m, 3H of BzpipH-3, H- 5), 1.66 (2H, m, 2H of pipH-3, H-5); m / z: 577 [M + H] +.
[0384] [00384] Compound 288: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4-fluorobenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.54 (1H, m, pyH-6), 8.17 (1H, d, J 8.0 Hz, pyH-3), 7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F), 7.87 (1H, m, NH), 7.82 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.10 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.82 (2H, d, J 6.5 Hz, C6H3F2H-2 and H-6), 6.62 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 4.60 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH -4), 3.69 (1H, m, 1H of BzpipH-2, H-6), 3.47 (1H, m, BzpipH-4), 3.44 (2H, s, CH2C6H3F2), 3.11 (2H, m, 2H of BzpipH -2, H-6), 2.78 (2H, m, 2H of pipH-2, H-6), 2.17 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.95 ( 2H, m, 2H of pipH-3, H-5), 1.76 (4H, m, 4H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -104.4, -110.5; m / z: 565 [M + H] +.
[0385] [00385] Compound 289: 5- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (3,5-difluorobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 9.69 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.87 (2H, d, J 8.0 Hz, C6H3F2H-2, H- 6), 6.68 (1H, m, C6H3F2H-4), 4.70 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H- 6), 3.49 (2H, s, CH2C6H3F2), 3.41 (1H, m, 1H of PhOpipH-2, H -6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.031.1.83 (6H, m, 2H of pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -110.5; m / z: 560 [M + H] +.
[0386] [00386] Compound 290: 3- (2- (1- (4-cyanobenzyl) piperidin-4-ylcarbamoyl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) pyridin-3-yl) propylcarbamate tert-butyl. 1H nmr (CDCl3) δ 8.42 (1H, d, J 1.5 Hz, pyH-6), 8.03 (1H, d, J 8.5 Hz, PyCONH), 7.61 (3H, m, pyH-4, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.27 (2H, dd, J 8.6, 6.0 Hz, 2H of C6H4F), 7.01 (2H, t, J 8.5 Hz, 2H of C6H4F), 5.02 (1H, m, NHCO2), 3.93 (1H, m, pipH-4), 3.79 (2H, m, 2H of piz), 3.56 (2H, s, CH2C6H4CN or CH2C6H4F), 3.50 (2H, s, CH2C6H4CN or CH2C6H4F), 3.40 (2H, m, 2H of piz), 3.17 (4H, m, PyCH2CH2CH2NH), 2.81 (2H, m, 2H of pipH-2, H-6), 2.79 (2H, m, 2H of piz), 2.53 (2H , m, 2H of piz), 2.21 (2H, t, J 10.5 Hz, 2H of pipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.84 (2H, m, PyCH2CH2CH2NH), 1.66 (2H, m, 2H of pipH-3, H-5), 1.43 (9H, s, C (CH3) 3); m / z: 699 [M + H] +.
[0387] [00387] Compound 291: N- (1- (4-cyanobenzyl) piperidin-4-yl) -3- (5,21-dioxo-25 - ((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) -8,11,14,17-tetraoxa-4,20-diazapentacosil) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide (na form of its trifluoroacetate salt). m / z: 1072 [M + H] +.
[0388] [00388] Compound 292: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5 - ((S) - 3- (4-fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide. m / z: 539 [M + H] + (experimental [M + H] +, 539.2314, C29H29F3N4O3 requires [M + H] + 539.2265).
[0389] [00389] Compound 293: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (p-tolyloxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.09 (2H, d, J 9.0 Hz, 2H of C6H4CH3), 6.88 (2H, d, J 6.5 Hz, C6H3F2H-2, H-6), 6.82 (2H, d, J 8.5 Hz, 2H of C6H4CH3), 6.80 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 4.56 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH2C6H3F2), 2.83 (2H, m, 2H of pipH-2, H-6), 2.29 (3H, s, ArCH3), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.84 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); m / z: 550 [M + H] +.
[0390] [00390] Compound 294: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4- (trifluoromethyl) phenoxy) piperidino-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.55 (2H, d, J 8.5 Hz, 2H of C6H4CF3), 6.98 (2H, d, J 8.5 Hz, 2H of C6H4CF3), 6.88 (2H, d, J 6.0 Hz, C6H3F2H- 2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 4.70 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH2C6H3F2), 3.35 (1H, m, 1H of PhOpipH-2 , H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.12-1.84 ( 6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 603 [M + H] +.
[0391] [00391] Compound 295: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.28 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.98 (2H, t, J 8.0 Hz, 2H of C6H4F), 6.89-6.84 (4H, m, 2H of C6H4F, C6H3F2H-2, H-6), 6.68 (1H, br t , J 8.5 Hz, C6H3F2H-4), 4.52 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH2C6H3F2), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.85 (6H, m, 2H of pipH-3, H-5, PhOpipH- 3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m / z: 525 [M + H] +.
[0392] [00392] Compound 296: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (4-methoxyphenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.0 Hz, NH), 7.88 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 6.90-6.82 (6H, m, C6H4OCH3, C6H3F2H-2, H-6), 6.69 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 4.47 ( 1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.77 (3H, s, OCH3), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.50 (2H, s, CH2C6H3F2), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2 , H-6), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.83 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H -5), 1.66 (2H, m, 2H of pipH-3, H-5); m / z: 565 [M + H] + (experimental [M + H] +, 565.2657, C31H34F2N4O4 requires [M + H] + 565.2621).
[0393] [00393] Compound 297: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (4- (3,4-difluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.07 (1H, q, J 9.5 Hz, 1H of COC6H3F2), 6.91 (2H, d, J 6.0 Hz, C6H3F2H-2, H-6), 6.78-6.17 ( 2H, m, 2H of COC6H3F2), 6.62 (1H, m, C6H3F2H-4), 4.51 (1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.61 (3H, m, CH2C6H3F2, 1H of PhOpipH-2, H-6), 3.37 (1H, m, 1H of PhOpipH-2, H-6), 2.95 (2H, m , 2H of pipH-2, H-6), 2.33 (2H, m, 2H of pipH-2, H-6), 2.08-1.76 (8H, m, pipH-3, H-5, PhOpipH-3, H -5); 19F nmr (CDCl3) δ -75.8, -134.9, -146.9; m / z: 571 [M + H] + (experimental [M + H] +, 571.2402, C30H30F4N4O3 requires [M + H] + 571.2327).
[0394] [00394] Compound 298: 5- (4- (3,4-difluorobenzoyl) piperidine-1-carbonyl) -N- (1- (3,5-difluorobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.96 (1H, d, J 8.5 Hz, NH), 7.93-7.85 (2H , m, pyH-4, COC6H3F2H-5 or H-6), 6.99 (1H, td, J 7.5, 2.0 Hz, COC6H3F2H-5 or H-6), 6.91-6.85 (3H, m, COC6H3F2H-2, CH2C6H3F2H -2, H-6), 6.72 (1H, br t, J 9.0 Hz, CH2C6H3F2H-4), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4 ), 3.70 (1H, m, 1H of BzpipH-2, H-6), 3.61 (2H, s, CH2C6H3F2), 3.41 (1H, m, BzpipH-4), 3.21 (1H, m, BzpipH-2, H -6), 3.07 (1H, m, BzpipH-2, H-6), 2.95 (2H, m, 2H of pipH-2, H- 6), 2.33 (2H, m, 2H of pipH-2, H- 6), 2.04 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.88 (1H, m, 1H of BzpipH-3, H-5), 1.74 (4H , m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -75.8, -101.2, -106.5; m / z: 583 [M + H] + (experimental [M + H] +, 583.2365, C32H34F2N4O4 requires [M + H] + 583.2327).
[0395] [00395] Compound 299: N - ((cis) -4- (3,5-difluorophenoxy) cyclohexyl) -5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.5 Hz, pyH-3), 8.00 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 6.98 (2H, dd, J 9.0, 8.0 Hz, 2H of C6H4F), 6.86 (2H, dd, J 9.5, 4.5 Hz, 2H of C6H4F), 6.45-6.35 ( 3H, m, C6H3F2), 4.52 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 4.46 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 4.09 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 3.89 (2H ,, m 2H of PhOpipH-2, H-6), 3.64 (1H, m, PhOpipH-2, H-6 ), 3.36 (1H, m, PhOpipH-2, H-6), 2.08-1.75 (12H, m, cyHexH-2, H-3, H-5, H-6 and PhOpipH-3, H-5); 19F nmr (CDCl3) δ - 109.4, -122.5; m / z: 525 [M + H] +.
[0396] [00396] Compound 300: N - ((cis) -4- (3,5-difluorophenoxy) cyclohexyl) -5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.5 Hz, pyH-3), 8.00 (1H, d, J 8.5 Hz, NH), 7.93 (2H, d , J 9.0 Hz, 2H of C6H4OCH3), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.45-6.35 (3H, m, C6H3F2), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H, m, cyHexH-1 or H-4), 4.09 (1H, m, cyHexH-1 or H-4), 3.87 (3H, s, OCH3), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.53 (1H, m, BzpipH-4), 3.16 (2H, m, 2H of BzpipH-2, H -6), 2.082.03 (3H, m, 3H of cyHexH-2, H-3, H-5, H-6 and BzpipH-3, H-5), 1.89-1.71 (9H, m, 9H of cyHexH -2, H-3, H-5, H-6 and BzpipH-3, H-5); 19F nmr (CDCl3) δ -109.4; m / z: 578 [M + H] +.
[0397] [00397] Compound 301: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) picolinamide. 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 8.5 Hz, pyH-3), 7.78 (1H, d, J 8.5 Hz, NH), 7.64 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.55 (2H, d, J 9.0 Hz, 2H of C6H4CF3), 7.50 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.23 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.98 (2H, d, J 9.0 Hz, 2H of C6H4CF3), 4.62 (1H, heptet, J 3.0 Hz, PhOpipH-4), 4.04 (1H, m, pipH-4 ), 3.78 (2H, s, CH2C6H4CN), 3.59 (2H, ddd, J 12.5, 8.5, 4.0 Hz, 2H of PhOpipH-2, H-6), 3.34 (2H, ddd, J 12.5, 7.0, 3.5 Hz, 2H of PhOpipH-2, H-6), 3.00 (2H, m, 2H of pipH-2, H-6), 2.43 (2H, m, 2H of pipH-2, H-6), 2.14-1.92 (6H , m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.77 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -61.6; m / z: 564 [M + H] + (experimental [M + H] +, 564.2539, C31H32F3N5O2 requires [M + H] + 564.2581).
[0398] [00398] Compound 302: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-methoxybenzoyl) piperidin-1-yl) picolinamide. 1H nmr (CDCl3) δ 8.17 (1H, d, J 2.5 Hz, pyH-6), 7.99 (1H, d, J 9.0 Hz, pyH-3), 7.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3) , 7.79 (1H, d, J 8.5 Hz, NH), 7.66 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.52 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.22 (1H, dd, J 9.0, 2.5 Hz, pyH-4), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.07 (1H, m, pipH-4), 3.94 - 3.81 (7H, m, 2H of BzpipH-2 , H-6, OCH3, CH2C6H4CN), 3.45 (1H, m, BzpipH-4), 3.13 (2H, m, 2H of BzpipH-2, H-6 or 2H of pipH-2, H-6), 3.05 ( 2H, m, 2H of BzpipH-2, H-6 or 2H of pipH-2, H-6), 2.52 (2H, m, 2H of pipH-2, H-6), 2.10 (2H, m, 2H of pipH-3, H-5), 1.97 (4H, m, BzpipH-3, H-5), 1. 91 (2H, m, 2H of pipH-3, H-5); m / z: 538 [M + H] + (experimental [M + H] +, 538.2831, C32H35N5O3 requires [M + H] + 538.2813).
[0399] [00399] Compound 303: 5- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N - ((cis) -4- (4-fluorophenoxy) cyclohexyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C6H4OCN), 7.00- 6.94 (4H, m, 2H of C6H4CN, 2H of C6H4F), 6.86 (2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 4.70 (1H, m, PhOpipH-4), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.06-2.00 (4H , m, 2H of PhOpipH-2, H-6, 2H of cHexH-2, H-3, H-5, H-6), 1.87-1.75 (8H, 2H of PhOpipH-3, H-5, 6H of cHexH-2, H-3, H-5, H-6); 19F nmr (CDCl3) δ -123.5; m / z: 553 [M + H] + (experimental [M + H] +, 543.2429, C31H31FN4O4 requires [M + H] + 543.2402).
[0400] [00400] Compound 304: 5- (4- (4-fluorobenzoyl) piperidmo-1-carboml) -N - ((cis) -4- (4-fluorophenoxy) cyclohexyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, m, NH), 7.99 (2H, m, 2H of COC6H4F ), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.16 (2H, t, J 9.0 Hz, 2H of COC6H4F), 6.97 (2H, t, J 9.0 Hz, 2H of OC6H4F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of OC6H4F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4), 3.76 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 2.04 (2H, m, 2H of cHexH-2, H-6 ), 1.88-1.75 (10H, m, BzpipH-3, H-5, 6H of cHexH-2, H-3, H-5, H-6); 19F nmr (CDCl3) δ - 104.4, -123.6; m / z: 548 [M + H] + (experimental [M + H] +, 548.2418, C31H31F2N3O4 requires [M + H] + 548.2356).
[0401] [00401] Compound 305: N- (2- (4-fluorophenoxy) ethyl) -5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.62 (1H, m, pyH-6), 8.40 (1H, t, J 6.0 Hz, NH), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.94 (2H, d , J 8.5 Hz, 2H of C6H4OCH3), 7.90 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.00-6.91 (4H, m, 2H of C6H4OCH3, 2H of C6H4F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.12 (2H, t, J 5.0 Hz, CH2OC6H4F), 3.88 (2H, q, J 5.5 Hz , NHCH2), 3.74 (1H, m, BzpipH-2, H-6), 3.53 (1H, pentet, J 7.0 Hz, BzpipH-4), 3.15 (2H, m, 2H of BzpipH-2, H-6) , 2.01 (1H ,, m, 1H of BzpipH-3, H-5), 1.89-1.82 (3H, m, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -123.6; m / z: 506 [M + H] +.
[0402] [00402] Compound 306: 5- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (2- (4-fluorophenoxy) ethyl) picolinamide. 1H nmr (CDCl3) δ 8.62 (1H, m, pyH-6), 3.39 (1H, t, J 6.0 Hz, NH), 8.26 (1H, d, J 7.5 Hz, pyH-3), 7.90 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.00-6.95 (4H, m, 2H of C6H4CN, 2H of C6H4F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 4.70 (1H, m, PhOpipH-4), 4.13 (2H, t, J 5.0 Hz, CH2OC6H4F), 3.89 (4H, m, 2H of PhOpipH-2, H-6 , NHCH2), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.40 (1H, m, 1H of PhOpipH-2, H-6), 1.94 (4H, m, PhOpipH-3, H- 5); 19F nmr (CDCl3) δ -123.4; m / z: 489 [M + H] +.
[0403] [00403] Compound 307: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (3- (4-fluorobenzyloxy) azetidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.76 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (1H, d, J 8.5 Hz, NH), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.30 (2H, dd, J 8.5 , 5.0 Hz, 2H of C6H4F), 7.05 (2H, t, 8.5 Hz, 2H of C6H4F), 4.46 (2H, m, OCH2C6H4F), 4.44 (1H, m, 1H of AzH-2, H-4), 4.38 (1H, d AB system, J 6.0 Hz, 1H of AzH-2, H-4), 4.21 (1H, m, 1H of AzH-2, H-4), 4.13 (1H ,, m 1H of AzH-2 , H-6), 4.01 (1H ,, m pipH-4), 3.56 (2H, s, NCH2C6H4CN), 3.48 (1H, d, J 5.5 Hz, AzH-3), 2.81 (2H, m, 2H of pipH -2, H-6), 2.23 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -113.6; m / z: 528 [M + H] +.
[0404] [00404] Compound 308: N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -5- (3- (4-fluorobenzyloxy) azetidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.70 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.16 (1H, dd, J 8.0, 1.0 Hz, pyH-3, 7.99 (1H, dd, J 8.0, 2.0 Hz , pyH-4), 7.87 (1H, d, J 8.0 Hz, NH), 7.24 (2H, dd, J 8.5, 5.0 Hz, 2H of C6H4F), 6.98 (2H, t, J 8.5 Hz, 2H of C6H4F) , 6.81 (2H, m, C6H3F2H-2, H-6), 6.62 (1H, tt, J 9.0, 2.5 Hz, C6H3F2H-4), 4.40 (2H, m, 2H of AzH-2, H-4 or CH2C6H4F ), 4.37 (1H, m, 1H of AzH-2, H-4 or 1H of CH2C6H4F), 4.31 (1H, d AB system, J 6.0 Hz, 1H of AzH-2, H-4 or 1H of CH2C6H4F), 4.15 (1H, m, 1H of AzH-2, H-4), 4.05 (1H, m, 1H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.44 (2H, s , CH2C6H3F2), 2.98 (1H, m, AzH-3), 2.78 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H- 6), 1.95 (2H, m, pipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ - 110.5, -113.6; m / z : 539 [M + H] +.
[0405] [00405] Compound 309: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. Compound 309 was synthesized as follows: Coupling of benzoylpiperidine
[0406] [00406] To a mixture of 4- (4-methoxybenzoyl) piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5- (methoxycarbonyl) pyridine-2-carboxylic acid (1.42 g , 7.82 mmol, 1.0 eq) in dimethylformamide (55 ml) triethylamine (2.72 ml, 19.55 mmol, 2.5 eq) was added, followed by HATU (2.97 g, 7.82 mmol , 1.0 eq). The reaction was stirred at room temperature for 4 hours before being partitioned between EtOAc (250 mL) and water-NaHCO3 (1: 1, 200 mL). The organics were additionally washed with saline (150 ml), water (150 ml) and saline solution (150 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH-CH2Cl2) provided the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1 x OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1 x OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH- 3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m / z: 383 [M + H] + (experimental [M + H] +, 383.1515, C21H22N2O5 requires [M + H] + 383.1602). Hydrolysis of methyl ester
[0407] [00407] To a solution of the pyridine methyl ester (2.39 g, 6.26 mmol, 1.0 eq) in tetrahydrofuran-methanol (2: 1, 50 mL) was added an aqueous solution of lithium hydroxide monohydrate (0.79 g, 18.77 mmol, 3.0 eq in 10 mL of water). The reaction was stirred at room temperature for 20 minutes before being neutralized with HCl (approximately 2.4 ml of a 6 M solution). The reaction was concentrated to dryness, providing the crude carboxylic acid (3.08 g) as a white solid, which was used without purification; 1H nmr (D6-DMSO) δ 8.97 (1H, m, pyH-6), 8.25 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.98 (2H, d, J 9.0 Hz, 2H of C6H4OCH3) , 7.51 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.04 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.50 (1H, m, 1H of BzpipH-2, H-6), 3.83 (3H, s, 1 x OCH3), 3.76-3.62 (2H, m, 1H of BzpipH-2, H-6, BzpipH-4), 3.20 (1H, m, 1H of BzpipH-2, H-6) , 3.00 (1H, m, 1H of BzpipH-2, H-6), 1.86 (1H, m, 1H of BzpipH-3, H-5), 1.68 (1H, m, 1H of BzpipH-3, H-5 ), 1.54 (2H, m, 2H of BzpipH-3, H-5); m / z: 369 [M + H] +. Coupling of benzylaminopiperidine
[0408] [00408] To a suspension of crude pyridine carboxylic acid (3.08 g, 6.26 mmol, 1.0 eq) and 1- (4-cyanobenzyl) -4-aminopiperidine dihydrochloride (1.80 g, 6.26 mmol, 1.0 eq) in dimethylformamide (50 ml) triethylamine (3.05 ml, 21.91 mmol, 3.5 eq) was added. HATU (2.38 g, 6.26 mmol, 1.0 eq) was added, forming a yellow solution that was stirred at room temperature for 6 hours. The reaction was partitioned between EtOAc (200 ml) and water-NaHCO3 (1: 1, 200 ml). The organics were washed with saline solution (150 ml), water (150 ml) and saline solution (150 ml) before drying (Na2SO4) and concentration under reduced pressure. MPLC (2 → 5% MeOH-CH2Cl2) provided Compound 309 (2.93 g, 83% in two steps) as a white solid; 1H nmr (CDCl3) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.88 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.56 (1H, d, J 7.5 Hz, pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.38 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.89 ( 2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.24 (1H, d, J 7.5 Hz, NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 3.98 (1H, m, pipH -4), 3.87 (1H, m, 1H of BzpipH-2, H-6), 3.81 (3H, s, OCH3), 3.50 (2H, s, CH2C6H4CN), 3.47 (1H, m, BzpipH-4), 3.19 (1H, m, 1H of BzpipH-2, H-6), 3.04 (1H, ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.77 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 1.97 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.85-1.72 (3H, m, 3H of BzpipH-3, H-5), 1.56 (2H, m, 2H of pipH-2, H-6); 13C nmr (CDCl3) δ 200.0, 167.0, 164.6, 163.7, 155.9, 147.4, 144.6, 135.9, 132.1, 130.9, 130.6, 129.3, 128.5, 122.8, 119.0, 114.0, 110.8, 62.4, 55.5, 52.5, 47.4, 46.7, 42.6, 42.0, 32.0, 28.8, 28.5; m / z: 566 [M + H] + (experimental [M + H] +, 566.2749, C33H35N5O4 requires [M + H] + 566.2762).
[0409] [00409] Compound 310: (N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.58 (1H , d, J 8.0 Hz, pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.87 (2H, d, J 6.0 Hz, C6H3F2H-2, H-6), 6.67 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 6.52 (1H, d, J 7.5 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH -4), 3.92 (1H, m, 1H, BzpipH-2, H-6), 3.87 (3H, s, OCH3), 3.53 (1H, m, BzpipH-4), 3.48 (2H, s, CH2C6H3F2), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6) , 2.19 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5) , 1.92-1.76 (3H, m, 3H of BzpipH-3, H-5), 1.63 (3H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -110.5; m / z: 578 [M + H] +.
[0410] [00410] Compound 311: N - ((cis) -4- (4-fluorophenoxy) cyclohexyl) -5- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.00-6.94 (4H, m, 2H of C6H4OCH3, 2H of C6H4F), 6.87 ( 2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH -4), 3.88 (3H, s, OCH3), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.16 (2H, m, 2H of BzpipH -2, H-6), 2.07-2.02 (3H, m, 3H of cHexH-2, H-4, H-5, H-6, BzpipH-3, H-5), 1.901.75 (9H, m , 9H of cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5); 19F nmr (CDCl3) δ -123.6; m / z: 560 [M + H] +.
[0411] [00411] Compound 312: N - ((cis) -4- (4-fluorophenoxy) cyclohexyl) -5- (4- (4-fluorophenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.01-6.94 (4H, m, 2 x 2H of C6H4F), 6.89-6.84 (4H, m, 2 x 2H of C6H4F), 4.52 (1H, m, cHexH- 1 or PhOpipH-4), 4.42 (1H, m, cHexH-1 or PhOpipH-4), 4.09 (1H, m, cHexH-4)), 3.89 (2H, m, 2H of PhOpipH-2, H-6) , 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.06-1.75 (12H, m, PhOpipH-3, H-5 , cHexH-2, H-3, H-5, H-6); 19F nmr (CDCl3) δ -122.5, -123.5; m / z: 536 [M + H] + (experimental [M + H] +, 536.2416, C30H31F2N3O4 requires [M + H] + 536.2356).
[0412] [00412] Compound 313: 5- (3- (4-cyanophenoxy) azetidine-1-carbonyl) -N- (1- (3,5-difluorobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.74 (1H, m, pyH-6), 8.19 (1H, d, J 8.0 Hz, pyH-3), 8.03 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, m, NH), 7.55 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.82 (2H, d, J 6.0 Hz, C6H3F2H-2, H-6), 6.75 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.62 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 5.02 (1H, m, AzH-3), 4.61 (2H, dd, J 10.5, 6.0 Hz, 2H of AzH -2, H-4), 4.27 (2H, m, 2H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.42 (2H, s, CH2C6H3F2), 2.76 (2H, m , 2H of pipH-2, H-6), 2.15 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.95 (2H, m, 2H of pipH-3, H-5), 1.58 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ; m / z: 533 [M + H] + (experimental [M + H] +, 532.2160, C29H27F2N5O3 requires [M + H] + 532.2155).
[0413] [00413] Compound 314: 5- (3- (4-childphenyl) -5,6,7,8-tetrahydro- [1,2,4] triazole [4,3-a] pyrazine-7-carboml) -N - (1- (3,5-difluorobenzyl) piperidm-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.71 (1H, d, J 2.5 Hz, pyH-6), 8.30 (1H, d, J 8.0 Hz, pyH-3), 8.00 (1H, dd, J 8.0, 2.0 Hz, pyH- 4), 7.93 (1H, d, J 8.5 Hz, NH), 7.92 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.86 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.88 (2H, d, J 6.0 Hz, C6H3F2H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 5.07 (2H, br s, 2H triazolopyrazine), 4.27 (2H, br s , 2H triazolopyrazine), 4.14 (2H, m, 2H triazolopyrazine), 4.02 (1H, m, pipH-4), 3.49 (2H, s, CH2C6H3F2), 2.84 (2H, m, 2H of pipH-2, H -6), 2.23 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.03 (2H, m, 2H of pipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -110.5; m / z: 583 [M + H] +.
[0414] [00414] Compound 315: N - ((1s, 4s) -4- (4-cyanophenoxy) cyclohexyl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.92 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.5 Hz, 2H de C6H4OCH3), 7.61 (1H, d, J 8.0 Hz, pyH-3), 7.57 (2H, d, J 2H of C6H4CN), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.95 (2H, d , J 9.0 Hz, 2H of C6H4CN), 6.43 (1H, d, J 8.0 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.62 (1H, m, cHexH-1) , 4.12 (1H, m, cHexH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.53 (1H, m, BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.11 (2H, m, 2H of cHexH-2, H-6), 2.04-1.73 (10H, m, 2H of cHexH-2, H-6, cHexH-3, H-5, BzpipH-3, H-5); 19F nmr (CDCl3) δ -61.6, -114.9; m / z: 568 [M + H] + (experimental [M + H] +, 567.2632, C33H34N4O5 requires [M + H] + 567.2602).
[0415] [00415] Compound 316: N - ((cis) -4- (4-fluorophenoxy) cridohexyl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.65 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.00-6.94 (4H, m, 2H of C6H4OCH3, 2H of C6H4F), 6.86 (2H, dd, J 9.0, 4.5 Hz, 2H of C6H4F), 6.29 (1H, d, J 8.0 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.44 (1H, m, cHexH-1), 4.11 (1H, m , cHexH-4), 3.95 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.52 (1H, m, BzpipH-4), 3.26 (1H, ddd, J 10.5, 10.0, 3.5 Hz, 1H of BzpipH-2, H-6), 3.10 (ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.09-1.73 (12H, m, BzpipH -3, H-5, cHexH-2, H-3, H-5, H-6); 19F nmr (CDCl3) δ -123.4; m / z: 560 [M + H] + (experimental [M + H] +, 560.2511, C32H34FN3O5 requires [M + H] + 560.2555).
[0416] [00416] Compound 317: N- (1- (4-fluorobenzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.30-7.25 (2H, m, 2H of C6H4F), 7.02-6.94 (4H, m, 2H of C6H4OCH3, 2H of C6H4F), 6.32 ( 1H, d, J 8.5 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.93 (1H, m, 1H of BzpipH-2 , H-6), 3.88 (3H, s, OCH3), 3.52 (1H, m, BzpipH-4), 3.47 (2H, s, CH2C6H4F), 3.25 (1H, d, J 11.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.68-1.54 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -115.9; m / z: 560 [M + H] + (experimental [M + H] +, 559.2708, C32H35FN4O4 requires [M + H] + 538.2715).
[0417] [00417] Compound 318: 6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of COC6H4OCH3), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of CH2C6H4OCH3), 6.95 (2H, d, J 9.0 Hz, 2H of COC6H4OCH3), 6.85 ( 2H, d, J 8.5 Hz, 2H of CH2C6H4OCH3), 6.30 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH -4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1 x OCH3), 3.80 (3H, s, 1 x OCH3), 3.52 (1H, m, BzpipH -4), 3.45 (2H, s, CH2C6H4OCH3), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, ddd, J 12.0, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.92-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3 , H-5); m / z: 571 [M + H] + (experimental [M + H] +, 571.2895, C33H38N4O5 requires [M + H] + 571.2915).
[0418] [00418] Compound 319: 6- (4- (4-cyanophenoxy) piperidine-1-carboml) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH- 3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 or C6H4CN), 7.23 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 or C6H4CN), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 or C6H4CN), 6.85 (2H, d, J 8.5 Hz, 2H of C6H4OCH3 or C6H4CN), 6.43 (1H, d, J 7.5 Hz, NH), 4.69 (1H, m, PhOpipH-4), 4.01 (1H, m , pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH3), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH2C6H4OCH3), 2.88 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.03-1.93 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m / z: 554 [M + H] +.
[0419] [00419] Compound 320: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-fluorobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.86 (1H, d, J 1.5 Hz, pyH-6), 8.10 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH- 3), 7.53 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.25 (2H, m, 2H of C6H4F), 6.96 (1H, t, J 8.5 Hz, 2H of C6H4F), 6.90 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.16 (1H, m, NH), 4.63 (1H, m, PhOpipH-4), 3.99 (1H, m, pipH-4), 3.84 (2H, m, 2H of PhOpipH- 2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH2C6H4F), 3.48 (1H, m, 1H of PhOpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, m, 2H of pipH-2, H-6), 2.02-1.92 (6H, m, 2H of pipH-3, H- 5, PhOpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); m / z: 543 [M + H] +.
[0420] [00420] Compound 321: N - ((cis) -4- (4-cyanophenoxy) cidohexyl) -6- (4- (4-cyanophenoxy) piperidine-1-carboml) nicotmamide. 1H nmr (CDCl3) δ 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.5 Hz, pyH- 3), 7.58 (2H, d, J 8.5 Hz, 1 x C6H4CN 2H), 7.56 (2H, d, J 9.0 Hz, 1 x C6H4CN 2H), 6.95 (2H, d, J 8.5 Hz, 2H of 1 x C6H4CN), 6.93 (2H, d, J 9.0 Hz, 2H of 1 x C6H4CN), 6.57 (1H, d, J 8.0 Hz, NH), 4.69 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.61 (1H, m, cHexH-1), 4.10 (1H, m, cHexH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 2.11-2.04 (3H, m, 3H of PhOpipH-3, H-5, cHexH-2, H-3, H- 5, H-6), 1.98-1.73 (9H, m, 9H of PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6); m / z: 550 [M + H] +.
[0421] [00421] Compound 322: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (3,5-difluorobenzyl) piperidin-4-yl) mcotmamide. 1H nmr (CDCl3) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH- 3), 7.53 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.90 (2H, d, J 9.5 Hz, 2H of C6H4CN), 6.80 (2H, m, C6H3F2H-2, H-6), 6.62 ( 1H, tt, J 9.0, 2.0 Hz, C6H3F2H-4), 6.21 (1H, d, J 8.0 Hz, NH), 4.64 (1H, heptet, J 3.0 Hz, PhOpipH-4), 3.96 (1H, m, pipH -4), 3.85 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, ddd, J 13.0, 9.0, 3.5 Hz, 1H of PhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (2H, s, CH2C6H3F2), 2.78 (2H, m, 2H of pipH-2, H-6), 2.13 (2H, t, J 11.5 Hz, 2H pipH-2, H-6), 2.00-1.95 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.81 (1H, m, 1H of PhOpipH-3 , H-5), 1.56 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -110.5; m / z: 560 [M + H] +.
[0422] [00422] Compound 323: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of 1 x C6H4CN), 7.58 (2H, d, J 8.5 Hz, 2H of 1 x C6H4CN), 7.45 (2H, d, J 8.5 Hz, 1 x C6H4CN), 6.96 ( 2H, d, J 9.0 Hz, 2H 1 x C6H4CN), 6.94 (1H, d, J 8.0 Hz, NH), 4.70 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.01 (1H, m, pipH -4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 2.83 (2H , m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H of pipH-3, H-5 , 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m / z: 549 [M + H] +.
[0423] [00423] Compound 324: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N - ((cis) -4- (4-fluorophenoxy) cyclohexyl) nicotinamide. 1H nmr (CDCl3) δ 8.94 (1H, d, J 1.5 Hz, pyH-6), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.5 Hz, pyH- 3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.97 (4H, m, 2H of C6H4CN, 2H of C6H4F), 6.85 (2H, m, 2H of C6H4F), 6.28 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.44 (1H, br s, cHexH-1), 4.11 (1H, m, cHexH-4), 3.90 (2H, m, 2H of PhOpipH -2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.54 (1H, m, 1H of PhOpipH-2, H-6), 2.09-1.98 (5H, m, 5H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, -5), 1.90-1.73 (7H, m, 7H of cHexH-2, H-3, H-5, H- 6, PhOpipH-3, H-5); 19F nmr (CDCl3) δ -123.3; m / z: 543 [M + H] + (experimental [M + H] +, 543.2511, C31H31FN4O4 requires [M + H] + 543.2402).
[0424] [00424] Compound 325: N- (6- (4-fluorophenoxy) pyridin-3-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.57 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.47 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.32 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.42 ( 1H, d, J 8.0 Hz, pyH-3), 7.11-7.06 (4H, m, 2H of C6H4OCH3, 2H of C6H4F), 6.97-6.93 (3H, m, 2H of C6H4F, N, O-pyH-3) , 4.68 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.81 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.28-3.11 (2H, m, 2H of BzpipH-2, H-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.92-1.82 (3H, m, 3H BzpipH-3, H-5); 19F nmr (CDCl3) δ -118.6; m / z: 555 [M + H] + (experimental [M + H] +, 555.2267, C31H27FN4O5 requires [M + H] + 555.2039).
[0425] [00425] Compound 326: 6- (4- (4-cyanophenoxy) piperidine-1-carboml) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.42 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.42 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.33 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.44 ( 1H, d, J 8.0 Hz, pyH-3), 7.08 (4H, m, 2H of C6H4CN, 2H of C6H4F), 6.97-6.94 (3H, m, 2H of C6H4F, N, O-pyH-3), 4.71 (1H, m, PhOpipH-4), 3.99 (1H, m, 1H of PhOpipH-2, 6), 3.86 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.07-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.88 (1H, m , 1H of PhOpipH-3, H-5); 19F nmr (CDCl3) δ -118.3; m / z: 538 [M + H] + (experimental [M + H] +, 538.1985, C30H24FN5O4 requires [M + H] + 538.1885).
[0426] [00426] Compound 327: 6- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH- 3), 7.30-7.21 (4H, m, 2H of C6H4F, 2H of C6H4OCH3), 7.00 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.86 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.34 (1H, d, J 8.0 Hz, NH), 4.02 (1H, m, pipH-4), 3.80 (5H, m, 2H of piz, OCH3), 3.52 (2H, m, 2H of piz), 3.50 ( 2H, s, CH2C6H4F or CH2C6H4OCH3), 3.49 (2H, s, CH2C6H4F or CH2C6H4OCH3), 2.89 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, t, J 5.0 Hz, 2H of piz ), 2.41 (2H, m, t, J 5.0 Hz, 2H of piz), 2.19 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH- 3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -115.5; m / z: 546 [M + H] +.
[0427] [00427] Compound 328: 6- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (1- (4-fluorobenzyl) piperidin-4-yl) nicotmamide. 1H nmr (CDCl3) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.36 -7.25 (4H, m, 2 x 2H of C6H4F), 7.06-6.97 (4H, m, 2 x 2H of C6H4.F), 6.60 (1H, d, J 7.0 Hz, NH), 4.06 (1H, m, pipH-4), 3.80 (2H, t, J 5.0 Hz, 2H of piz), 3.63 (2H, s, 1 x CH2C6H4F), 3.51 (4H, m, 2H of piz, 1 x CH2C6H4F), 2.99 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, t, J 5.0 Hz, 2H of piz), 2.41 (2H, t, J 5.0 Hz, 2H of piz), 2.33 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.06 (2H, m, 2H of pipH-3, H-5), 1.75 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ - 114.5, -115.4; m / z: 534 [M + H] +.
[0428] [00428] Compound 329: 5- (4- (3,4-difluorobenzoyl) piperidmo-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.52 (1H, m, pyH-6), 8.16 (1H, d, J 8.0 Hz, pyH-3), 7.84 (1H, d, J 7.0 Hz, NH), 7.79 (2H, m , pyH-4, 1H of C6H3F2), 7.87 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.93 (1H, m, 1H of C6H3F2), 6.85 (1H, m, 1H of C6H3F2), 6.79 (2H , d, J 8.5 Hz, 2H of C6H4OCH3), 4.57 (1H, m, BzpipH-4), 3.93 (1H, m, pipH-4), 3.73 (3H, s, OCH3), 3.65 (1H, m, 1H of BzpipH-2, H-6), 3.42 (2H, s, CH2C6H4OCH3), 3.34 (1H, m, BzpipH-4), 3.06 (2H, m, 2H of BzpipH-2, H-6), 2.79 (2H , m, 2H of pipH-2, H-6), 2.13 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.97-1.80 (4H, m, 2H of pipH-3 , H-5, 2H of BzpipH-3, H-5), 1.75-1.52 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.2, -106.6; m / z: 577 [M + H] +.
[0429] [00429] Compound 330: 5- (4- (3,4-difluorobenzoyl) piperidmo-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 8.77 (1H, m, 1 x ArH), 8.51 (1H, d, J 2.5 Hz, 1 x ArH), 8.45 (2H, dd, J 5.0, 3.5 Hz, 2 x ArH), 8.42 (1H, s, 1 x ArH), 8.05 (1H, dd, J 8.0, 2.0 Hz, 1 x ArH), 7.99 (1H, m, 1 x ArH), 7.22-7.18 (4H, m, 4 x ArH) , 7.15-6.56 (3H, m, 3 x ArH), 4.75 (1H, m, 1H of BzpipH-2, H-6), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.53 ( 1H, m, BzpipH-4), 3.33-3.22 (2H, m, 2H of BzpipH-2, H-6), 2.07-2.02 (2H, m, 2H of BzpipH-3, H-5), 1.86 (2H , m, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.1, -106.5, -118.6; m / z: 561 [M + H] +.
[0430] [00430] Compound 331: 5- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.59 (1H, d, J 1.5 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.92-7.84 (3H, m, NH, pyH-4, 1H of C6H3F2), 7.24 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.00 (1H, m, 1H of C6H3F2), 6.88 (1H, m, 1H of C6H3F2), 6.86 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.64 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H ,, m pipH-4), 3.80 (3H, s, OCH3), 3.74 (1H, m, BzpipH-2, H-6), 3.48 (2H, s, CH2C6H4OCH3), 3.41 (1H, m, BzpipH-4), 3.13 (2H, m, 2H of BzpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, dd, J 11.0, 8.5 Hz, 2H of pipH-2, H-6), 1.99 (4H, m, 2H of pipH-3, H- 5, 2H of BzpipH-3, H-5), 1.76-1.63 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.3, -11.6.5; m / z: 577 [M + H] +.
[0431] [00431] Compound 332: N - ((cis) -4- (4-cyanophenoxy) cyclohexyl) -6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH- 3), 7.58 (2H, d, J 9.0 Hz, C6H4CN), 7.28 (2H, m, 2H of C6H4F), 7.00 (2H, t, J 9.0 Hz, 2H of C6H4F), 6.95 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.19 (1H, d, J 8.0 Hz, NH), 4.62 (1H, m, cHexH-1), 4.12 (1H, m, cHexH-4), 3.82 (2H, m, 2H of piz), 3.51 (4H, m, 2H of piz, CH2C6H4F), 2.55 (2H, m, 2H of piz), 2.42 (2H, m, 2H of piz), 2.10 (2H, m, 2H of cHexH-2, H-6), 1.94 (2H, m, 2H of cHexH-2, H-6 or 2H of cHexH-3, H-5), 1.84-1.71 (4H, 2H of cHexH-3, H-5, 2H of cHexH-2, H-6 or cHexH-3, H-5); 19F nmr (CDCl3) δ -115.5; m / z: 542 [M + H] +.
[0432] [00432] Compound 333: tert-butyl 4- (6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) nicotinamido) piperidine-1-carboxylate. 1H nmr (CDCl3) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.5 Hz, 2H de C6H4CN), 7.51 (1H, d, J 8.5 Hz, pyH-3), 7.21 (1H, d, J 8.0 Hz, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4CN), 4.68 (1H, m, PhOpipH-4), 4.09 (3H, m, 3H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.94-3.80 (2H, m, 2H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.07-3.62 (1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.44 ( 1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 2.85 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.10- 1.80 (8H, m, PhOpipH-3, H-5, pipH-3, H-5), 1.45 (9H, s, C (CH3) 3); m / z: 534 [M + H] +, 478 [M + H-C4H8] +.
[0433] [00433] Compound 334: 6- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (6- (4-fluorophenoxy) pyridm-3-yl) nicotmamide. 1H nmr (CDCl3) δ 9.56 (1H, s, NH), 8.83 (1H, d, J 2.0 Hz, N, O-pyH-6), 8.38 (1H, d, J 2.5 Hz, pyH-6), 8.27 (1H, dd, J 8.5, 2.5 Hz, pyH-4), 8.00 (1H, dd, J 8.5, 2.0 Hz, N, O-pyH-4), 7.31 (1H, d, J 8.0 Hz, N, O -pyH-3), 7.20 (2H, m, 2H of 1 x C6H4F), 7.03 (4H, m, 4H of 1 x C6H4F), 6.94 (2H, t, J 9.0 Hz, 2H of 1 x C6H4F), 6.88 (1H, d, J 9.0 Hz, pyH-3), 3.76 (2H, m, 2H of piz), 3.44 (2H, s, CH2C6H4F), 3.36 (2H, m, 2H of piz), 2.47 (2H, m , 2H piz), 2.33 (2H, m, 2H piz); 19F nmr (CDCl3) δ -115.3, -118.5; m / z: 530 [M + H] +.
[0434] [00434] Compound 335: 6- (4- (4-cyanophenoxy) piperidine-1-carboml) -N- (piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (3H, m, 2H of C6H4CN, NH) , 6.95 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.68 (1H, d, J 8.0 Hz, pyH-3), 4.69 (1H, m, PhOpipH-4), 4.07 (1H, m, pipH- 4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H -6), 3.12 (2H, m, 2H of pipH-2, H-6), 2.74 (2H, m, 2H of pipH-2, H-6), 2.10-1.81 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.48 (2H, m, 2H of pipH-3, H-5); m / z: 434 [M + H] +.
[0435] [00435] Compound 336: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4- (pyrrolidin-1-yl) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.95 (1H, d, J 1.5 Hz, pyH-6), 8.19 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH- 3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.20 (2H, d, J 9.0 Hz, 2H of C6H4N), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.72 ( 1H, d, J 7.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.69 (1H, m, PhOpipH-4), 4.08 (1H, m, pipJ-4), 3.93- 3.86 (2H, m, 2h of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (2H, s, CH2C6H4N), 3.50 (1H, m, PhOpipH -2, H-6), 3.28 (4H, m, pyrrolidineH-2, H-5), 3.09 (2H, m, 2H of pipH-2, H-6), 2.35 (6H, m, 2H of pipH- 2, H-6, pyrrolidineH-3, H-4), 2.08-1.86 (8H, m, pipH-3, H-5, PhOpipH-3, H-5); m / z: 594 [M + H] +.
[0436] [00436] Compound 337: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-morpholinobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.25 (2H, m, 2H of C6H4N), 6.96 (2H, d, J 9.5 Hz, 2H of C6H4CN), 6.88 (2H, d, J 9.0 Hz, 2H of C6H4N), 6.29 (1H, d, J 7.0 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhOpipH- 2, H-6), 3.87, 3.85 (4H, d AB system, J 5.0 Hz, 2 x morpholineH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.55 (3H, m, CH2C6H4N, 1H of PhOpipH-2, H-6), 3.17, 3.15 (4H, d AB system, J 4.5 Hz, 2 x morpholineH-3, H-5), 2.96 (2H, m, 2H pipH-2, H-6), 2.24 (2H, dd, J 12.0, 10.5 Hz, 2H of pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5, 2H PhOpipH-3, H-5), 1.81-1.69 (4H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5); m / z: 610 [M + H] +.
[0437] [00437] Compound 338: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.16 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH- 3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.38 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.18 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 6.96 ( 2H, d, J 9.0 Hz, 2H of C6H4CN), 6.22 (1H, m, NH), 4.70 (1H, m, PhOpipH-4), 4.06 (1H, m, pipH-4), 3.94-3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (2H, s, CH2C6H4OCF3), 3.50 (1H, m, PhOpipH-2, H -6), 2.93 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H- 6), 2.05 (4H, m, pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.84-1.67 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5); 19F nmr (CDCl3) δ -57.9; m / z: 609 [M + H] +.
[0438] [00438] Compound 339: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (trifluoromethyl) phenyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.63 (1H, m, pyH-6), 8.27 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, m, NH), 7.92 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4CF3), 7.51 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4CF3), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4CF3), 6.94 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4CF3), 4.00 (3H, m, pipH-4, 2H of piz), 3.57 (4H, m, CH2C6H4CN, 2H of piz), 3.31 (4H, m, 4H of piz), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -61.6; m / z: 577 [M + H] +.
[0439] [00439] Compound 340: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-cyanophenyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.63 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.90 (2H, m, NH, pyH-4), 7.60 (2H, d , J 8.5 Hz, 1 x C6H4CN 2H), 7.52 (2H, d, J 9.0 Hz, 1 x C6H4CN 2H), 7.45 (2H, d, J 8.5 Hz, 1 x C6H4CN 2H), 6.87 (2H, d, J 9.5 Hz, 2H of 1 x C6H4CN), 4.03-3.90 (3H, m, pipH-4, 2H of piz), 3.60 (2H, m, 2H of piz), 3.56 (2H, s, CH2C6H4CN), 3.36 (4H, m, 4H of piz), 2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6) , 2.01 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 534 [M + H] +.
[0440] [00440] Compound 341: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4-fluorophenyl) piperazine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.63 (1H, m, pyH-6), 8.26 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.93 (1H, d, J 8.0 Hz, NH), 7.91 (1H , dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.99 (2H, m, 2H of C6H4F), 6.89 (2H, m, 2H of C6H4F), 3.99 (3H, m, pipH-4, 2H of piz), 3.57 (3H, m, CH2C6H4CN, 2H of piz), 3.18 (2H, m, 2H of piz), 3.07 (2H, m, 2H of piz), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, mdd, J 11.0, 10.0 Hz, 2H of pipH-2 , H-6), 2.03 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -122.6; m / z: 527 [M + H] +.
[0441] [00441] Compound 342: 5- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.90 (1H, s, NH), 8.67 (1H, m, 1 x pyH-6), 8.41 (1H, d, J 2.0 Hz, 1 x pyH-6), 8.36-8.33 (2H , m, 2 x pyH), 7.95 (1H, dd, J 8.0, 2.0 Hz, 1 x pyH-4), 7.89 (1H, m, 1H of C6H3F2), 7.13-7.08 (4H, m, 4H of C6H4F) , 7.00 (1H, m, 1H of C6H3F2), 6.97 (1H, d, J 9.0 Hz, 1 x pyH-3), 6.90 (1H, ddd, J 11.5, 9.0, 2.5 Hz, 1H of C6H3F2), 4.64 ( 1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.43 (1H, m, BzpipH-4), 3.19 (1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, m, 1H of BzpipH-2, H-6), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.90 (1H, m, 1H of BzpipH-3, H-5), 1.78 (2H, m, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.1, -116.5, -118.6; m / z: 562 [M + H] + (experimental [M + H] +, 561.1844, C32H35N5O3 requires [M + H] + 561.1744).
[0442] [00442] Compound 343: 6- (4- (2,4-difluorophenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.79 (1H, s, NH), 8.92 (1H, m, pyH-6), 8.47 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.08 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.36 (1H, d, J 8.0 Hz, pyH-3), 7.11- 7.01 (4H, m, C6H4F), 6.99-6.92 (2H, m, N, O-pyH-3, 1H of C6H3F2), 6.90-6.76 (2H, m, 2H of C6H3F2), 4.47 (1H, m, PhOpipH -4), 3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 1.98 (2H, m, 2H of PhOpipH-3, H-5), 1.93-1.80 (2H, m, 2H of PhOpipH-3, H-5); 19F nmr (CDCl3) δ -117.4, -118.5, -127.3; m / z: 549 [M + H] +.
[0443] [00443] Compound 344: 6- (4- (2,4-difluorophenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.21 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.57 (1H, d, J 8.0 Hz, pyH-3), 7.25 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.97 (1H, td, J 9.0, 5.5 Hz, 1H of C6H3F2), 6.89-6.75 (4H, m, 2H of C6H4OCH3, 2H of C6H3F2), 4.45 ( 1H, m, PhOpipH-4), 4.03 (1H, m, 1H of pipH-4), 3.92-3.85 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH3), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH2C6H4OCH3), 3.44-3.37 (1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m , 2H of pipH-2, H-6), 2.27 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H-6), 2.04-1.90 (5H, m, 2H of pipH-3, H -5.3H of PhOpipH-3, H-5), 1.83 (1H, m, 1H of PhOpipH-3, H-5), 1.72 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -117.7, -127.3; m / z: 565 [M + H] +.
[0444] [00444] Compound 345: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (2,4-difluorophenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.65 (1H, d, J 8.5 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.98 (1H, dt, J 5.0, 9.0 Hz, 1H of C6H3F2H-5 or H-6 ), 6.86 (1H, m, 1H of C6H3F2H-3), 6.79 (1H, m, 1H of C6H3F2H-5 or H-6), 6.24 (1H, d, J 8.0 Hz, NH), 4.47 (1H, m , PhOpipH-4), 4.03 (1H, m, pipH-4), 3.95-3.87 (2H, m, 2Hof PhOpipH-2, H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6 ), 3.57 (2H, s, CH2C6H4CN), 3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd , J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.06-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H , m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ - 117.6, -127.3; m / z: 560 [M + H] +.
[0445] [00445] Compound 346: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (2,4-difluorobenzofl) piperidmo-1-carboml) mcotmamide. 1H nmr (CDCl3) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, 1H of C6H3F2) , 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.58 (1H, m, pyH-3), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.99 (1H, ddd, J 9.5 , 9.0, 2.5 Hz, 1H of C6H3F2), 6.89 (1H, m, 1H of C6H3F2), 6.50 (1H, d, J 8.0 Hz, NH), 4.67 (1H, m, 1H of BzpipH-2, H-6 ), 4.02 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.56 (3H, s, CH2C6H4CN), 3.40 (1H, m, BzpipH-4), 3.21 (1H, m, BzpipH-2, H-6), 3.08 (1H, ddd, J 11.5, 10.5, 3.0 Hz, 1H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH- 2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.08-2.01 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.89-1.72 (3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -101.5, -106.5; m / z: 572 [M + H] +.
[0446] [00446] Compound 347: 6- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, dt, J 6.5, 8.5 Hz, 1H of C6H3F2), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.98 (1H, m, 1H of C6H3F2), 6.92-6.84 ( 3H, m, 2H of C6H4OCH3, 1H of C6H3F2), 6.39 (1H, d, J 7.5 Hz, NH), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH -4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.80 (3H, s, OCH3), 3.51 (2H, s, CH2C6H4OCH3), 3.39 (1H, m, BzpipH- 4), 3.21 (1H, ddd, J 10.5, 9.0, 3.0 Hz, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.90 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.89-1.76 (2H, m, 2H of BzpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -101.6, -106.5; m / z: 577 [M + H] +.
[0447] [00447] Compound 348: 6- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.81 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.48 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd , J 8.5, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 8.5, 6.5 Hz, 1H of C6H3F2), 7.35 (1H, d, J 8.0 Hz, pyH-3), 7.10-6.85 (3H, m, N, O-pyH-3, 2H of C6H3F2), 4.65 (1H, m, 1H of BzpipH-2, H- 6), 3.78-3.73 (1H, m, 1H of BzpipH-2, H-6), 3.40 (1H, m, BzpipH-4), 3.23-3.07 (2H, m, 2H of BzpipH-2, H-6 ), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.74 (3H, m, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.3, - 106.5, -118.6; m / z: 561 [M + H] +. Synthesis of Compounds 349 and 350 Coupling of 1-tert-Butyloxycarbonyl-3-Fluoro-4-aminopiperidine
[0448] [00448] To a mixture of crude pyridine carboxylic acid (2.15 g of approximately 66% purity, 3.86 mmol, 1.0 eq) and 1-tert-butyl-3-fluoro-4-aminopiperidine (0, 84 g, 3.86 mmol, 1.0 eq) dimethylformamide (40 ml) was added, followed by triethylamine (1.31 ml, 9.64 mmol, 2.5 eq). After adding HATU (1.47 g, 3.86 mmol, 1.0 eq), the reaction was stirred at room temperature for 4 hours before being partitioned between EtoAc (300 mL) and water-NaHCO3 (1: 1, 300 ml). The organics were additionally washed with saline (250 ml), water (300 ml) and saline solution (250 ml) before drying (Na2SO4) and concentration under reduced pressure. MPLC (0 → 10% MeOH-CH2Cl2) provided the coupled material (1.41 g, 64%) as a light yellow oil; 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.11 (1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.56 (1H, d, J 6.0 Hz, NH), 7.50 (1H, dd, J 8.0, 2.0 Hz, pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.47 (0.5H, m, 0.5H of pipH-3), 4.31 (2.5H, m, 0.5H of pipH-3, pipH-4, 1H of pipH-2) , 4.00 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH3), 3.84 (1H, m, 1H of pipH-6), 3.53 (1H, m, BzpipH-4) , 3.23 (1H, m, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.90 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H -6), 2,081.92 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91-1.80 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.47 (9H, s, C (CH 3) 3); 19F nmr (CDCl3) δ -189.3 (d, J 47.5 Hz); m / z: 569 [M + H] +. Deprotection of the tert-Butyloxycarbonyl group
[0449] [00449] To a solution of tert-butyloxycarbonylpiperidine (1.41 g, 2.48 mmol, 1.0 eq) in dichloromethane (25 mL) was added hydrogen chloride (2.5 mL of a 4.0 M solution in dioxane, 9.93 mmol, 4.0 eq). The reaction was stirred at room temperature for 6 hours. A residue was formed during the reaction. Et2O (100 mL) was added, resulting in a precipitate after sonication, which was isolated by filtration. The resulting solid was dried in vacuo, providing fluoropiperidine dihydrochloride as a light orange solid (1.32 g, quantitative), which was used without further purification; 1H nmr (D6-DMSO) δ 8.96 (2H, m, CONH, pyH-6), 8.30 (1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.62 (1H, dd, J 8.0 Hz, pyH-3), 6.99 (2H, d, J 9.5 Hz, 2H of C6H4OCH3), 4.93, 4.75 (1H, 2m, pipH-3), 4.46 (1H, m, 1H of BzpipH-2, H-6), 4.32 (1H, m, pipH-4), 3.78 (3H, s, OCH3), 3.69 (1H, m, BzpipH-4), 3.57-3.50 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.28-3.10 (3H, m, 1H of pipH-2, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.08-2.94 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 2.02 (1H, m, 1H of pipH-5), 1.82 (2H, m, 1H of pipH-5, 1H of BzpipH-3, H-5), 1.63 (1H, m, 1H of BzpipH-3, H-5), 1.55-1.47 (2H, m, 2H of BzpipH-3, H-5); 19F nmr (D6-DMSO) δ -188.6 (d, J 50.0 Hz); m / z: 469 [M + H] +. 349
[0450] [00450] To a suspension of fluoropiperidine dihydrochloride (0.250 g, 0.462 mmol, 1.0 eq) in dichloromethane (5.0 ml) was added diisopropylethylamine (0.28 ml, 1.617 mmol, 3.5 eq), forming a clear solution. 4-Cyanobenzyl bromide (0.100 g, 0.508 mmol, 1.1 eq) was added and the reaction was stirred at room temperature for 5 hours before being poured into NaHCO3 (40 ml). The organics were extracted with CH2Cl2 (3 x 40 mL), combined, dried (Na2SO4) and concentrated under reduced pressure. MPLC (3 → 5% MeOH-CH2Cl2) provided cyanobenzylpiperidine (0.162 g, 60%) as a white foam; IR (film) 3313, 2953, 1662, 1622, 1599, 1544, 1448, 1259, 1170, 1027, 971, 912, 848, 731 cm -1; 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H de C6H4OCH3), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.48 (1H, d, J 8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.33 ( 1H, m, NH), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.70, 4.53 (1H, m, pipH-3 ), 4.15 (1H, m, pipH-4), 3.88 (3H, s, OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH2C6H4CN), 3.54 ( 1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-6), 2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H, m, 1H of pipH-6, 1H of pipH-5, 1H of pipH-2), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H BzpipH-3, H-5), 1.67 (1H, m, 1H of pipH-5); 13C nmr (CDCl3) δ 199.9, 167.2, 165.3, 163.7, 155.8, 147.5, 143.8, 136.1, 132.2, 130.8, 130.6, 129.2, 128.5, 122.6, 118.8, 114.0, 111.1, 89.5 (90.7, 88.4, d, J 178.5 Hz), 61.7, 56.5 (56.7, 56.3, J 25.0 Hz), 55.5, 52.3 (52.4, 52.1, J 17.5 Hz), 51.7, 46.7, 42.6, 41.9, 29.9 (29.9, 29.8 J 6.5 Hz), 28.6 (28.8 , 28.4, J 28.0 Hz); 19F nmr (CDCl3) δ -188.5 (d, J = 55 Hz); m / z: 584 [M + H] + (experimental [M + H] +, 584.2711, C33H34FN5O4 requires [M + H] + 584.2668). 350
[0451] [00451] To a suspension of fluoropiperidine dihydrochloride (0.100 g, 0.185 mmol, 1.0 eq) in dichloromethane (2.0 ml) was added diisopropylethylamine (0.112 ml, 0.647 mmol, 3.5 eq), forming a clear solution . Trifluoromethoxybenzyl bromide (0.035 mL, 0.218 mmol, 1.2 eq) was added and the reaction was stirred at room temperature for 4 hours before pouring into NaHCO3 (50 mL). The organics were extracted with CH2Cl2 (3 x 45 mL), combined, dried (Na2SO4), and concentrated under reduced pressure. MPLC (0 → 10% MeOH-CH2Cl2) provided trifluoromethoxypiperidine (0.076 g, 64%) as a white foam; IR (film) 3314, 3074, 2953, 1665, 1623, 1600, 1509, 1449, 1260, 1221, 1169, 1028, 971, 732 cm -1; 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H de C6H4OCH3), 7.48 (1H, d, J 8.5 H, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.15 (2H, d, J 8.0 Hz, 2H of C6H4OCF3), 6.95 ( 2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m, pipH-3), 4.15 (1H, m, pipH -4), 3.87 (3H, s, OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.58-3.50 (3H, m, CH2C6H4OCF3, BzpipH-4), 3.28-3.08 (3H , m, 2H of BzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H of pipH-2 or H-6), 2.26-2.14 (3H, m, 1H pipH-5, 2H pipH-2, H-6), 2.01 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5 ), 1.66 (1H, m, 1H of pipH-5); 13C nmr (CDCl3) δ 200.0, 167.2, 165.3, 163.7, 155.8, 148.4, 147.4, 136.7, 136.1, 130.8, 130.0, 128.5, 122.7, 120.9, 114.0, 89.7 (90.9, 88.6 J 178.5 Hz), 61.4, 56.3 ( 56.5, 56.2 J 25.4 Hz), 55.5, 52.4 (52.5, 52.3 J 18.2 Hz), 51.6, 46.7, 42.6, 41.9, 29.9 (30.0, 29.9 J 6.6 Hz), 28.6 (28.8, 28.4 J 17.7 Hz); 19F nmr (CDCl3) δ -57.9, -188.4; m / z: 644 [M + H] + (experimental [M + H] +, 643.2534, C33H34F4N4O5 requires [M + H] + 643.2538).
[0452] [00452] Compound 349: N - ((trans) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-4), 8.07 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H de C6H4OCH3), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.48 (1H, d, J 8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.33 ( 1H, m, NH), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.70, 4.53 (1H, m, pipH-3 ), 4.15 (1H, m, pipH-4), 3.88 (3H, s, OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH2C6H4CN), 3.54 ( 1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-6), 2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H, m, 1H of pipH-6, 1H of pipH-5, 1H of pipH-2), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H BzpipH-3, H-5), 1.67 (1H, m, 1H of pipH-5); 19F nmr (CDCl3) δ -188.5; m / z: 584 [M + H] +.
[0453] [00453] Compound 350: N - ((trans) -3-fluoro-1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H de C6H4OCH3), 7.48 (1H, d, J 8.5 H, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.15 (2H, d, J 8.0 Hz, 2H of C6H4OCF3), 6.95 ( 2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m, pipH-3), 4.15 (1H, m, pipH -4), 3.87 (3H, s, OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.58-3.50 (3H, m, CH2C6H4OCF3, BzpipH-4), 3.28-3.08 (3H , m, 2H of BzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H of pipH-2 or H-6), 2.26-2.14 (3H, m, 1H pipH-5, 2H pipH-2, H-6), 2.01 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5 ), 1.66 (1H, m, 1H of pipH-5); 19F nmr (CDCl3) δ -57.9, -188.4; m / z: 644 [M + H] +.]
[0454] [00454] Compound 351: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-cyanophenoxy) piperidin-1-yl) pyridazine-3-carboxamide. 1H nmr (CDCl3) δ 8.01 (1H, d, J 9.0 Hz, pzH-4 or H-5), 7.86 (1H, d, J 8.5 Hz, NH), 7.62 (2H, d, J 8.0 Hz, 2H of OC6H4CN), 7.61 (2H, d, J 9.0 Hz, 2H of CH2C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of CH2C6H4CN), 7.02 (1H, d, J 10.0 Hz, pzH-4 or H-5 ), 6.97 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.72 (1H, m, PhOpipH-4), 3.98 (3H, m, 2H of PhOpipH-2, H-6, pipH-4), 3.86 -3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (dd, J 11.0 , 9.0 Hz, 2H of pipH-2, H-6), 2.13-1.93 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.61 (1H, m, pipH- 5); m / z: 522 [M + H] +.
[0455] [00455] Compound 352: N - ((trans) -3-fluoro-1- (4- (pyrrolidin-1-yl) benzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine- 1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.52 (1H, d, J 8.0 Hz, pyH-3), 7.13 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.03 (1H, d, J 8.0 Hz, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.51 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.65, 4.48 (1H, m, pipH-3 ), 4.13 (1H, m, pipH-4), 3.87 (4H, m, OCH3, BzpipH-2, H-6), 3.54-3.47 (3H, m, NCH2C6H4N, BzpipH-4), 3.26 (6H , m, 4H pyrrolidine, 1H BzpipH-2, H-6, 1H pipH-6), 3.11 (1H, m, 1H BzpipH-2, H-6), 2.84 (1H, d, J 11.5 Hz , 1H of pipH-2), 2.19-2.12 (3H, m, 1H of pipH-2, H-5, H-6), 2.08-1.97 (5H, m, 4H of pyrrolodine, 1H of BzpipH-3, H -5), 2.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, 1H of pipH-5); 19F nmr (CDCl3) δ -188.4; m / z: 528 [M + H] +.
[0456] [00456] Compound 353: N - ((trans) -3-fluoro-1- (4-isopropoxybenzyl) piperidm-4-yl) -6- (4- (4-methoxybenzoyl) piperidmo-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.50 (1H, d, J 8.0 Hz, pyH-3), 7.18 (2H, d, J 8.5 Hz, 2H of C6H4OiPr), 7.15 (1H, m, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.83 (2H, d, J 8.5 Hz, 2H of C6H4OiPr), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.67, 4.50 (1H, m, pipH-3), 4.52 ( 1H, m, OCH (CH3) 2), 4.03 (1H, m, pipH-4), 3.87 (3H, s, OCH3), 3.83 (1H, m, 1H of BzpipH-2, H-6), 3.54, 3.47 (2H, d AB system, J 13.0 Hz, CH2C6H4O), 3.52 (1H, m, BzpipH-4), 3.22 (2H, m, 1H of BzpipH-2, H-6, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.83 (1H, d, J 11.0 Hz, 1H of pipH-2), 2.21-2.10 (3H, 1H of pipH-2, H-5, H -6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.76 (3H, m, 3H of BzpipH-3, H-5), 1.63 (1H, m, 1H of pipH- 5); 19F nmr (CDCl3) δ -188.4; m / z: 617 [M + H] +.
[0457] [00457] Compound 354: N - ((trans) -1- (4-cyano-3-fluorobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.57 (1H, dd, J 7.5, 6.5 Hz, 1H of C6H3FCN), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.30 (1H, d, J 7.0 Hz, NH), 7.23 (2H, m, 2H of C6H3FCN), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.71, 4.54 (1H, m, pipH-3), 4.17 (1H, m, pipH-4), 3.88 (3H, s, OCH3), 3.83 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH2C6H3FCN), 3.54 (1H, m, BzpipH-4), 3.28-3.09 (3H, 2H of BzpipH-2, H-6, 1H of pipH-2, H-6), 2.80 (1H, m, 1H of pipH-2, H-6) , 2.33-2.17 (3H, m, pipH-2, H-3, H-6), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1. 93-1.81 (3H, m, 3H from BzpipH-3, H-5), 1.68 (1H, m, pipH-5); 19F nmr (CDCl3) δ -106.6, -188.5; m / z: 602 [M + H] + (experimental [M + H] +, 602.2589, C33H33F2N5O4 requires [M + H] + 602.2813).
[0458] [00458] Compound 355: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (oxazol-4-ylmethyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, d, J 1.0 Hz, 1H of oxazole), 7.61 -7.26 (3H, m, 2H of C6H4CN, 1H of oxazole), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.18 (1H, d, J 7.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.53 (2H, s, CH2oxazole), 3.50 (1H, m, 1H of PhOpipH-2, H-6), 2.96 (2H, m, 2H of pipH-2, H-6), 2.26 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.07-1.99 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.88 (1H, m , 1H of PhOpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); m / z: 516 [M + H] +.
[0459] [00459] Compound 356: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (thiazol-2-ylmethyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.71 (1H, dd, J 6.5, 2.0 Hz, 1H of thiophene) , 7.58 (3H, m, pyH-3, 2H of C6H4CN), 7.27 (1H, dd, J 6.5, 3.5 Hz, 1H of thiophene), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.56 ( 1H, d, J 7.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.05-3.91 (3H, m, pipH-4, 2H of PhOpipH-2, H-6), 3.89 (2H, s , CH2thiophene), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m, 2H of pipH-2, H-6), 2.37 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.04 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H- 5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m / z: 531 [M + H] +.
[0460] [00460] Compound 357: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (dimethylcarbamoyl) phenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN 2H), 7.47 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.40 (2H, d, J 9.0 Hz, 2H of C6H4CON (CH3) 2), 6.91 (2H, d, J 9.0 Hz, 2H of C6H4CON (CH3) 2), 4.66 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH -4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH2C6H4CN), 3.38 (1H , m, 1H of PhOpipH-2, H-6), 3.05 (6H, s, N (CH3) 2), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 10.5, 10.0 Hz, 2H of pipH-2, H-6), 2.20 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.87 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 595 [M + H] +.
[0461] [00461] Compound 358: 5- (4- (4-acetylphenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) picolinamide. 1H nmr (CDCl3) δ 8.61 (1H, d, J 2.0 Hz, pyH-6), 8.25 (1H, d, J 8.5 Hz, pyH-3), 7.94 (2H, d, J 9.5 Hz, 2H of C6H4COCH3) , 7.90 (1H, m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.95 (2H, d, J 8.5 Hz, 2H of C6H4COCH3), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 4.00-76 (2H, m, 2H of PhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH2C6H4CN), 3.40 (1H, m, 1H of PhOpipH-2 , H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.55 (3H, s, COCH3), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.91 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 566 [M + H] +.
[0462] [00462] Compound 359: 5- (4- (4-acetylphenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 9.89 (1H, s, NH), 8.68 (1H, d, J 2.0 Hz, pyH-6), 8.41 (1H, 2.5 Hz, N, O-pyH-6), 8.34 (2H, m, pyH-3, N, O-pyH-4), 7.96 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4COCH3), 7.09 (4H , m, C6H4F), 6.95 (3H, m, 2H of C6H4COCH3, N, O-pyH-3), 4.75 (1H, m, PhOpipH-4), 3.98 (1H, m, 1H of PhOpipH-2, H- 6), 3.87 (1H, m, 1H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (1H, m, 1H of PhOpipH-2, H -6), 2.56 (3H, s, COCH3), 2.04-1.93 (4H, m, PhOpipH-3, H-5); m / z: 555 [M + H] +.
[0463] [00463] Compound 360: 5- (4- (4- (dimethylcarbamoyl) phenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) picolinamide. 1H nmr (CDCl3) δ 8.90 (1H, s, NH), 8.69 (1H, m, pyH-6), 8.41 (1H, d, J 3.0 Hz, N, O-pyH-6), 8.35 (2H, m , pyH-3, N, O-pyH-4), 7.96 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.40 (2H, d, J 9.0 Hz, 2H of C6H4CON (CH3) 2), 7.10 (4H, m, C6H4F), 6.97 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.92 (2H, d, J 9.0 Hz, 2H of C6H4CON (CH3) 2), 4.68 (1H , m, PhOpipH-4), 3.95 (1H, m, 2H of PhOpipH-2, H-6), 3.89 (1H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 2H of PhOpipH-2, H-6), 3.41 (1H, m, 2H of PhOpipH-2, H-6), 3.06 (6H, s, N (CH3) 2), 2.02 (2H, m, 2H of PhOpipH-3 , H-5), 1.91 (2H, m, 2H of PhOpipH-3, H-5; 19F nmr (CDCl3) δ -118.5; m / z: 584 [M + H] +.
[0464] [00464] Compound 361: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (trifluoromethyl) phenoxy) piperidin-1-yl) pyridazine-3-carboxamide. 1H nmr (CDCl3) δ 8.00 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.87 (1H, d, J 8.0 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.56 (2H, d, J 9.0 Hz, 2H of C6H4CF3), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.01 (2H, d, J 8.5 Hz, pyH-4 or H-5 ), 7.00 (2H, d, J 9.0 Hz, 2H of C6H4CF3), 4.71 (1H, m, PhOpipH-4), 4.03-3.94 (3H, m, pipH-4, 2H of PhOpipH-2, H-6) , 3.86-3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 2.79 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.12-1.93 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -61.6; m / z: 565 [M + H] + (experimental [M + H] +, 565.2567, C30H31F3N6O2 requires [M + H] + 565.2533).
[0465] [00465] Compound 362: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidin-1-yl) pyridazine-3-carboxamide. 1H nmr (CDCl3) δ 7.99 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.87 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.00 (1H, m, pyH-4 or H-5), 6.97 ( 2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.52 (2H, m, 2H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (3H, s, OCH3), 3.58 (1H, m, BzpipH-4), 3.55 (2H, s, CH2C6H4CN), 3.28 (2H, m, 2H of BzpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H -6), 2.23 (2H, dd, J 11.0, 9.0 Hz, 2H of pipH-2, H-6), 2.03- 1.87 (6H, m, 2H of pipH-3, H-5, BzpipH-3, H -5) 1.63 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -61.6, -114.9; m / z: 539 [M + H] + (experimental [M + H] +, 539.2782, C31H34N6O3 requires [M + H] + 539.2765).
[0466] [00466] Compound 363: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-nitrophenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.20 (2H, d, J 9.0 Hz, 2H of C6H4NO2), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.44 (2H, d, J 8.0 Hz, 2H of C6H4CN), 6.97 (2H, d, J 9.5 Hz, 2H of C6H4NO2), 6.44 (1H, d, J 8.0 Hz, NH), 4.75 (1H, heptet, J 3.0 Hz, PhOpipH-3), 4.00 (1H, m, pipH-4), 3.92 ( 2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.51 (1H, m, 1H of PhOpipH -2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.12-2.00 ( 5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.90 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m / z: 569 [M + H] +.
[0467] [00467] Compound 364: 6- (4- (4-aminophenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CD3OD) δ 8.90 (1H, m, pyH-6), 8.33 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.80 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.70 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.67 (1H, d, J 9.0 Hz, pyH-3), 6.84 (4H, s, C6H4NH2), 4.53 (1H, m, PhOpipH-4), 4.15 (2H, s, CH2C6H4NH2), 4.10 (1H, m, 1H of PhOpipH-2, H-6), 3.97 (1H, m, 1H of PhOpipH-2, H-6), 3.77 (1H, m, 1H of PhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.37 (2H, m, 2H of pipH-2, H-6), 2.86 (2H, dd, J 11.5, 12.0 Hz, 2H of pipH-2, H-6), 2.13 (2H, m, 2H of PhOpipH-3, H-5 or pipH-3, H-5), 2.04-1.73 (6H, m, 2H or 4H of pipH-3, H-5, 2H or 4H of PhOpipH-3, H-5); m / z: 539 [M + H] +.
[0468] [00468] Compound 365: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidino-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.86 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, C6H4CN), 6.53 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.73 ( 1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.51 (1H, m, BzpipH-4), 3.37 (4H, m, 4H of pyrrolidine), 3.21-3.13 ( 2H, m, 2H of BzpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 9.5 Hz, pipH-2, H- 6), 2.06-2.00 (7H, m, 4H of pyrrolidine, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 605 [M + H] +.
[0469] [00469] Compound 366: 6- (4- (4-acetamidophenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.5 Hz, pyH-4), 7.63 (1H, m, pyH-3), 7.60 (2H, d , J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.39 (2H, d, J 9.0 Hz, 2H of C6H4NHAc), 7.15 (1H, s, NHAc), 6.88 (2H, d, J 9.0 Hz, 2H of C6H4NHAc), 6.31 (1H, d, J 8.5 Hz, NHCO), 4.56 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (2H, s, CH2C6H4CN), 3.48 - 3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 9.0 Hz, 2H of pipH-2, H-6) , 2.15 (3H, s, COCH3), 2.08-1.92 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H -5); m / z: 581 [M + H] +.
[0470] [00470] Compound 367: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (methylsulfonamido) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.20 (2H, d, J 9.0 Hz, 2H of C6H4NHMs), 6.90 (2H, d, J 9.0 Hz, C6H4NHMs), 6.31 (1H, d, J 8.5 Hz, NHCO), 4.78 (1H, m, PhOpipH- 4), 4.03 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.46 (1H, m, 1H of PhOpipH-2, H-6 ), 2.96 (3H, s, SO2CH3), 2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.06 -1.94 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.85 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m , 2H of pipH-3, H-5); m / z: 617 [M + H] +.
[0471] [00471] Compound 412: 6- (4- (3-acetamidophenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH- 3), 7.35 (2H, m, NHAc, C6H4NHAcH-2), 7.22 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.19 (1H, t, J 8.0 Hz, C6H4NHAcH-5), 6.89 (1H, m, C6H4NHAcH-4 or H-6), 6.85 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.66 (1H, dd, J 8.0, 1.5 Hz, C6H4NHAcH-4 or H-6), 6.29 (1H , d, J 8.0 Hz, NH), 4.60 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH3), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH2C6H4OCH3), 3.41 (1H, m, 1H of PhOpipH-2, H-6) , 2.86 (2H, m, 2H of pipH-2, H-6), 2.15 (5H, m, NHCOCH3, 2H of pipH-2, H-6), 2.03-1.92 (5H, m, 2H of pipH-3 , H-5, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); m / z: 587 [M + H] +.
[0472] [00472] Compound 413: 6- (4- (3-acetamidophenoxy) piperidine-1-carbonyl) -N- (1- (4-fluorobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.56 (1H, d, J 8.0 Hz, pyH-3), 7.54 (1H, br s, C6H4NHAcH-2), 7.36 (1H, s, NHAc), 7.29-7.25 (2H, m, 2H of C6H4F), 7.18 (1H, t, J 8.5 Hz, C6H4NHAcH-5), 6.99 ( 2H, t, J 8.5 Hz, 2H of C6H4F), 6.90 (1H, d, J 8.5 Hz, C6H4NHAcH-4 or H-6), 6.65 (1H, dd, J 8.5, 2.0 Hz, C6H4NHAcH-4 or H- 6), 6.58 (1H, d, J 7.5 Hz, NH), 4.59 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.47 (1H, s, CH2C6H4F), 3.43 (1H, m, 1H of PhOpipH-2, H-6), 2.85 ( 2H, m, 2H of pipH-2, H-6), 2.14 (5H, m, NHCOCH3, 2H of pipH-2, H-6), 2.02-1.90 (5H, m, 2H of pipH-3, H- 5, 3H of PhOpipH-3, H-5), 1.83 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDQ3) δ -115.8; m / z: 574 [M + H] +.
[0473] [00473] Compound 414: 6- (4- (3-acetamidophenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.85 (1H, s, NH), 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.45 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.30 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4) 7.66 (1H, s, NHAc), 7.39 (1H, d , J 8.5 Hz, pyH-3), 7.34 (1H, br s, C6H4NHAcH-2), 7.17 (1H, t, J 8.0 Hz, C6H4NHAcH-5), 7.09-7.06 (4H, m, C6H4F), 6.90 ( 2H, m, C6H4NHAcH-4 or H-6, N, O-pyH-3), 6.64 (1H, d, J 8.0 Hz, C6H4NHAcH-4 or H-6), 4.56 (1H, m, PhOpipH-4) , 3.93-3.77 (2H, m, 2H of PhOpipH-2, H-6), 3.59 (1H, m, 1H of PhOpipH-2, H-6), 3.33 (1H, m, 1H of PhOpipH-2, H -6), 2.13 (3H, s, NHCOCH3), 1.95-1.89 (3H, m, 3H of PhOpipH-3, H-5), 1.82 (1H, m, 1H of PhOpipH-3, H-5); 19F nmr (CDCl3) δ -118.5; m / z: 570 [M + H] +.
[0474] [00474] Compound 415: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (4- (trifluoromethylsulfonyl) phenoxy) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.87 (1H, s, pyH-4 or pyH-6), 8.08 (1H, s, pyH-4 or pyH-6), 7.93 (2H, d, 9.0 Hz, 2H of C6H4OCH3), 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.64 (1H, m , 1 x NH), 4.94 (1H, m, 1 x NH), 7.72 (1H, m, 1H of BzpipH-2, H-6), 4.05 (1H, m, pipH-4), 3.88 (3H, s , OCH3), 3.56 (2H, s, CH2C6H4CN), 3.56-3.41 (3H, m, BzpipH-4, 1H of BzpipH-2, H-6), 3.13 (4H, m, 2H of BzpipH-2, H- 6, CH2CH2CH2NHCO), 2.83 (2H, m, 2H of pipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CH2CH2CH2NHCO), 2.20 (2H, dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.89 (2H, m, CH2CH2CH2NHCO), 1.76 (2H, m, 2H of BzpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.46 (9H, s, C (CH3) 3); 19F nmr (CDCl3) δ -78.7; m / z: 656 [M + H] +.
[0475] [00475] Compound 416: 3- (5- (1- (4-cyanobenzyl) piperidin-4-ylcarbamoyl) -2- (4- (4-methoxybenzoyl) piperidmo-1-carboml) pyridm-3-yl) propylcarbamate tert-butyl. 1H nmr (CDCl3) δ 8.87 (1H, s, pyH-4 or H-6), 8.08 (1H, s, pyH-4 or H-6), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3) , 7.60 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.64 (1H, m, NH), 4.94 (1H, m, NHCOOC (CH3) 3), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4), 3.88 (3H, s, OCH3), 3.56 (2H, s, CH2C6H4CN), 3.52-3.41 (2H, m, BzpipH-4, BzpipH-2, H-6), 3.17-3.08 (4H, m, 2H of BzpipH-2 , H-6, CH2CH2CH2NHCO), 2.83 (2H, m, 2H of pipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CH2CH2CH2NHCO), 2.20 (2H, dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.94-1.82 (3H, m, 1H of BzpipH-3, H-5, CH2CH2CH2NHCO), 1.76 (2H, m, 2H of BzpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.46 (9H, s , C (CH3) 3); m / z: 724 [M + H] +, 624 [M + H-CO2-C6H4] +.
[0476] [00476] Compound 417: N- (1- (4-cyanophenyl) piperidin-4-yl) -6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.86 (1H, d, J 2.0 Hz, pyH-6), 8.05 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.49 (1H, d, J 8.0 Hz, pyH- 3), 7.57 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.29-7.24 (2H, m, 2H of C6H4F), 7.00 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.87 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.85 (1H, m, NH), 4.23 (1H, m, pipH-4), 3.99 (2H, m, 2H of pipH-2, H-6), 3.75, 3.73 (2H, 2d, AB system, J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH2C6H4F), 3.46 (2H, m, 2H of piz), 3.07 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.49, 2.48 (2H, 2d AB system, J 5.0 Hz, 2H piz), 2.38, 2.37 (2H, 2d AB system, J 5.0 Hz, 2H piz), 2.13 (2H , m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -115.4; m / z: 527 [M + H] +.
[0477] [00477] Compound 418: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanophenyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of 1 x C6H4CN) , 7.54 (1H, d, J 8.0 Hz, pyH-3), 7.47 (2H, d, J 9.0 Hz, 1 x C6H4CN 2H), 6.95 (2H, d, J 9.0 Hz, 1 x C6H4CN), 6.88 (2H, d, J 9.0 Hz, 2 x 1 x C6H4CN), 6.79 (1H, d, J 7.5 Hz, NH), 4.68 (1H, m, PhOpipH-4), 4.25 (1H, m, pipH-4 ), 3.92-3.81 (4H, m, 2H of pipH-2, H-6, 2H of PhOpipH-2, H-6), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.46 ( 1H, m, 1H of PhOpipH-2, H-6), 3.07 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.14 (2H, m, 2H of pipH- 3, H- 5), 2.03-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.85 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3 , H-5); m / z: 535 [M + H] +.
[0478] [00478] Compound 419: N- (1- (4-cyanobenzyl) piperidin-4-yl) -5- (4- (thiophene-2-carbonyl) piperidine-1-carbonyl) picolinamide. 1H nmr (CDCl3) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd , J 8.0, 2.0 Hz, pyH-4), 7.75 (1H, dd, J 3.5, 1.0 Hz, thiopheneH-3 or H-5), 7.68 (1H, dd, J 5.0, 1.0 Hz, thiopheneH-3 or H -5), 7.61 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.16 (1H, dd, J 5.0, 3.5 Hz, thiopheneH-4) , 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.41 (1H, m, BzpipH-4), 3.18 (2H, m, 2H of BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.87 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 542 [M + H] +.
[0479] [00479] Compound 420: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4- (methylsulfonyl) phenyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H de C6H4CN or C6H4SO2CH3), 7.57 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4SO2CH3), 7.46 (1H, d, J 8.0 Hz, pyH-3), 7.09 (1H, d, J 8.0 Hz, NH), 6.95 (2H, d, J 8.5 Hz, 2H of C6H4CN or C6H4SO2CH3), 6.93 (2H, d, J 9.0 Hz, 2H of C6H4CN or C6H4SO2CH3), 4.67 (1H, m, PhOpipH-4), 4.26 (1H, m , pipH-4), 3.93 (2H, m, 2H of pipH-2, H-6), 3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH- 2, H-6), 3.45-3.37 (1H, m, 1H of PhOpipH-2, H-6), 3.09 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 3.00 (3H , s, SO2CH3), 2.10 (2H, m, 2H of pipH-3, H-5), 1.98-1.90 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m / z: 588 [M + H] +.
[0480] [00480] Compound 421: 6- (4- (4-fluorobenzyl) piperazine-1-carboml) -N- (1- (4- (methylsulfonyl) phenyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H de C6H4SO2CH3), 7.46 (1H, d, J 8.0 Hz, pyH-3), 7.25 (2H, m, 2H of C6H4F), 6.99 (3H, m, NH, 2H of C6H4F), 6.93 (2H, d, J 9.0 Hz, 2H of C6H4SO2CH3), 4.24 (1H, m, pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6), 3.74, 3.73 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH2C6H4F), 3.46 (2H, m, 2H of piz), 3.08 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 3.00 (3H, s , SO2CH3), 2.50, 2.48 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.38, 2.36 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.11 (2H, m, 2H of pipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -115.4; m / z: 581 [M + H] +.
[0481] [00481] Compound 422: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-fluorophenyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.63 (1H, m, pyH-6), 7.85 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.89 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.55 (2H, m, 2H of C6H4F), 4.70 (1H, m, PhOpipH-4), 4.58 (1H, m, pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6 ), 3.78-3.71 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.57-3.47 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2 , H-6), 3.17 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 2.21-1.94 (7H, 7H of pipH-3, H-5, PhOpipH-3 , H-5), 1.88 (1H, m, 1H of pipH-3, H-5, PhOpipH-3, H-5); 19F nmr (CDCl3) δ -127.1; m / z: 528 [M + H] +.
[0482] [00482] Compound 423: 6- (4- (4-cyanophenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxyphenyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.92 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.92 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.84 (2H, d, J 9.5 Hz, 2H of C6H4OCH3), 6.45 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, PhOpipH-4), 4.12 (1H, m, pipH-4), 3.93-3.84 (2H, m, 2H of pipH-2, H-6, PhOpipH-2, H-6), 3.77 (3H, s, OCH3), 3.71 (1H, m, 1H of pipH-2, H-6, PhOpipH-2, H-6), 3.53-3.49 (3H, m, 3H of pipH-2, H-6, PhOpipH-3, H-6), 2.85 (2H, t, J 11.5 z, 2H of pipH2, H-6) , 2.15 (2H, m, 2H of pipH-3, H-5), 2.06-1.98 (3H, m, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H -5), 1.74 (2H, m, 2H of pipH-3, H-5); m / z: 540 [M + H] +.
[0483] [00483] Compound 424: 6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (1- (3- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.65 (1H, d, J 8.0 Hz, pyH-3), 7.33 (1H, t, J 8.0 Hz, C6H4OCF3H-5), 7.24 (2H, m, C6H4OCF3H-2 and H-4 or H-6), 7.10 ( 1H, d, J 8.5 Hz, C6H4OCF3H-4 or H-6), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.22 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m , 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.94 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.54 (3H, m, CH2C6H4OCF3, BzpipH-4), 3.26 (1H, m, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.04 (3H, m, 2H of pipH-3, H- 5. 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.7; m / z: 625 [M + H] +.
[0484] [00484] Compound 425: 6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (1- (3-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 8.5 Hz, 2H of COC6H4OCH3), 7.57 (1H, d, J 7.5 Hz, pyH-3), 7.22 (1H, t, J 8.0 Hz, C6H4OCH3H-5), 6.95 (2H, d, J 9.0 Hz, 2H of COC6H4OCH3), 6.89 (2H, m, C6H4OCH3H-2 and H-4 or H-6), 6.80 (1H, dd, J 8.5, 2.0 Hz, C6H4OCH3H-4 or H-6), 6.59 (1H, d, J 8.0 Hz, NH), 4.68 (1H , m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1 x OCH3), 3.80 (3H, s, 1 x OCH3), 3.53 (2H, s, CH2C6H4OCH3), 3.51 (1H, m, BzpipH- 4), 3.24 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H de BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.91 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.04-2.00 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.91-1.79 (3H , m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m / z: 571 [M + H] +.
[0485] [00485] Compound 426: N - (((3S, 4R) -3-fluoro-1 - (((5-methylisoxazol-3-yl) methyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H de C6H4OCH3), 7.53 (1H, d, J 8.0 Hz, pyH-3), 7.09 (1H, d, J 7.5 Hz, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 5.97 (1H, d, J 1.0 Hz, isoxazoleH-4), 4.70-4.62 (1.5H, m, 1H of BzpipH-2, H-6, 0.5H of pipH-3), 4.49 (0.5H, dt, J 5.0, 9.5 Hz , 0.5H of pipH-3), 4.12 (1H, m, pipH-4), 3.87 (3H, s, OCH3), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.64 (2H, s, CH2isoxazole), 3.53 (1H, m, BzpipH-4), 3.26-20 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.11 (1H, t, J 11.0 Hz , 1H of BzpipH-2, H-6), 2.84 (m, 1H of pipH-2), 2.41 (3H, d, J 1.0 Hz, isoxazolCH3), 2.32 (1H, m, 1H of pipH-6), 2.27 -2.18 (2H, m, 1H of pipH-2, 1H of pipH-5), 2.02 (1H, m, BzpipH-3, H-5), 1.92-1.80 (3H, m, 3H of BzpipH-3, H -5) 1.63 (1H, m, 1H of pipH-5); 19F nmr (CDCl3) δ -188.6; m / z: 565 [M + H] +.
[0486] [00486] Compound 427: N - (((3S, 4R) -3-fluoro-1 - (((2-methylthiazol-4-yl) methyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.94 (1H, m, pyH-6), 8.16 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.59 (1H, d, J 8.0 Hz, pyH-3), 6.96 (2H, J 9.0 Hz, 2H of C6H4OCH3), 6.95 (1H, s, thiazolH-4), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, ddt, J 50.0, 5.0, 9.5 Hz, pipH-3), 4.15 (1H, m, pipH-4), 3.92 (1H, m, 1H of BzpipH-2, H-6 ), 3.87 (3H, s, OCH3), 3.71, 3.64 (2H, 2d AB system, J 13.0 Hz, CH2thiazole), 3.51 (1H, m, BzpipH-4), 3.29-3.20 (2H, m, 1H of pipH -6, 1H of BzpipH-2, H-6), 3.10 (1H, dd, J 12.5, 11.0 Hz, 1H BzpipH-2, H-6), 2.89 (1H, m, 1H of pipH-2), 2.71 (3H, s, thiazolCH3), 2.27-2.12 (3H, m, 1H of pipH-2, 1H of pipH-5, 1H of pipH-6), 2.02 (1H, m, 1H of BzpipH-3, H-5 ), 1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, m, 1H of pipH-5); 19F nmr (CDCl3) δ -188.6; m / z: 581 [M + H] +.
[0487] [00487] Compound 428: 6- (4- (4-acetamidophenoxy) piperidino-1-carbonyl) -N- (1- (3- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.58 (1H, d, J 8.5 Hz, pyH-3), 7.38 (2H, d, J 9.0 Hz, 2H of C6H4NHAc), 7.32 (1H, t, J 8.0 Hz, C6H4OCF3H-5), 7.31 (1H, m, 1 x NH), 7.23 (2H, m, C6H4OCF3H-2, H-4 or H-6), 7.09 (1H, d, J 8.0 Hz, C6H4OCF3H-4 or H-6), 6.86 (2H, d, J 9.0 Hz, 2H of C6H4NHAc), 6.49 (1H, m, 1 x NH), 4.54 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H PhOpipH-2, H-6), 3.52 (2H, s, CH2C6H4OCF3), 3.47-3.40 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.14 (3H, s, NHCOCH3), 2.04-1.90 (5H, m, 2H of pipH-3, H -5.3H of PhOpipH-3, H-5), 1.80 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.7; m / z: 640 [M + H] +.
[0488] [00488] Compound 429: 6- (4- (3-acetamidophenoxy) piperidine-1-carbonyl) -N- (1- (3- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.89 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.48 (1H, s, 1 x NH), 7.36 (1H, s, C6H4NHAcH-2), 7.32 (1H, m, C6H4NHAcH-5), 7.24-7.16 (3H, m, C6H4OCF3H-2, H-4 or H- 6, C6H4NHAcH-5), 7.10 (1H, d, J 8.5 Hz, C6H4OCF3H-4 or H-6), 6.90 (1H, d, J 8.0 Hz, C6H4NHAcH-4 or H-6), 6.65 (1H, d , J 8.0 Hz, C6H4NHAcH-4 or H-6), 6.50 (1H, d, J 8.0 Hz, NH), 4.59 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH- 4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (2H, s, CH2C6H4OCF3), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.15 (3H , s, NHCOCH3), 2.08-1.91 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.81 (1H, m, 1H of PhOpipH-3, H-5 ), 1.62 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.7; m / z: 641 [M + H] +.
[0489] [00489] Compound 430: 6- (4- (4-methoxybenzoyl) piperidmo-1-carboml) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.81 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.34 (2H, d, J 9.0 Hz, 2H of C6H4OCF3), 7.15 (2H, d, J 8.0 Hz, 2H of C6H4OCF3), 6.96 (2H, d, J 9.5 Hz, 2H of C6H4OCH3), 6.26 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.02 (1H, m, pipH-4), 3.94 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.53 (1H, m, BzpipH-4), 3.51 (2H, s, CH2C6H4OCF3), 3.25 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.93-1.73 (4H , m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.9; m / z: 626 [M + H] +.
[0490] [00490] Compound 431: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.56-7.52 (3H, m, 2H of C6H4CN, pyH-3) , 7.39-3.37 (4H, m, 2H of C6H4CN, 1 x NH, C6H4NH-2), 7.13 (1H, t, J 8.0 Hz, C6H4NH-5), 6.79 (1H, dd, J 8.0, 1.5 Hz, C6H4NH -4 or H-6), 6.58 (1H, dd, J 8.0, 2.0 Hz, C6H4NH-4 or H-6), 6.26 (1H, d, J 7.5 Hz, 1 x NH), 4.55 (1H, m, PhOpipH-4), 3.96 (1H, m, pipH-4), 3.82 (2H, m, 2H of PhOpipH-2, H-6), 3.61 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH2C6H4CN), 3.42-3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.76 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd , J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.99-1.82 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.78 (1H , m, 1H of PhOpipH-3, H-5), 1.54 (2H, m, 2H of pipH-3, H-5), 1.43 (1H ,, m cPrH-1), 1.01 (2H, m, 2H of cPrH-2, H-3), 0.79 (2H, m, 2H of cPrH-2, H-3); m / z: 608 [M + H] +.
[0491] [00491] Compound 432: 6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carbonyl) -N- (1- (4-fluorobenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.81 (1H, m, pyH-6), 8.03 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, s, 1 x NH), 7.50 (1H, d , J 8.5 Hz, pyH-3), 7.36 (1H, s, C6H4NH-2), 7.23-7.18 (2H, m, 2H of C6H4F), 7.11 (1H, t, J 8.0 Hz, C6H4NH-5), 6.92 (2H, t, J 9.0 Hz, 2H of C6H4F), 6.82 (1H, dd, J 8.0, 1.0 Hz, C6H4NH-4 or H-6), 6.57 (1H, dd, J 8.0, 1.5 Hz, C6H4NH-4 or H-6), 6.45 (1H, d, J 8.0 Hz, 1 x NH), 4.52 (1H, m, PhOpipH-4), 3.94 (1H, m, pipH-4), 3.80 (2H, m, 2H PhOpipH-2, H-6), 3.58 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (2H, s, CH2C6H4F), 3.34 (1H, m, 1H of PhOpipH-2, H- 6), 2.77 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.95-1.80 (5H, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.75 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H -5), 1.45 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H, m, 2H of cPrH-2, H-3); 19F nmr (CDCl3) δ -115.9; m / z: 601 [M + H] +.
[0492] [00492] Compound 433: 6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.56 (1H, s, 1 x NH), 8.85 (1H, m, pyH-6), 8.38 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.24 (1H , dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.04 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.56 (1H, s, 1 x NH), 7.36 (1H, s, C6H4NH-2), 7.34 (1H, d, J 8.5 Hz, pyH-3), 7.11 (1H, t, J 8.0 Hz, C6H4NH-5), 7.03-6.99 (4H, m, C6H4F), 6.86 ( 1H, d, J 8.5 Hz, N, O-pyH-3), 6.78 (1H, dd, J 8.0, 1.5 Hz, C6H4NH-4 or H-6), 6.57 (1H, dd, J 8.0, 2.0 Hz, C6H4NH-4 or H-6), 4.52 (1H, m, PhOpipH-4), 3.87 (1H, m, 1H of PhOpipH-2, H-6), 3.74 (1H, m, 1H of PhOpipH-2, H -6), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 3.27 (1H, m, 1H of PhOpipH-2, H-6), 1.91-1.76 (4H, m, PhOpipH-3, H-5), 1.43 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.789 (2H, m, 2H of cPrH-2, H-3); 19F nmr (CDCl3) δ -118.5; m / z: 596 [M + H] +.
[0493] [00493] Compound 434: N - ((cis) -4- (4-cyanophenoxy) cyclohexyl) -6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.85 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (1H, s, 1 x NH), 7.48 (2H, d , J 9.0 Hz, 2H of C6H4CN), 7.40 (1H, s, C6H4NH-2), 7.11 (1H, t, J 8.0 Hz, C6H4NH-5), 6.87 (2H, d, J 9.0 Hz, 2H of C6H4CN) , 6.80 (1H, dd, J 8.0, 1.0 Hz, C6H4NH-4 or H-6), 6.64 (1H, d, J 8.0 Hz, 1 x NH), 6.57 (1H, dd, J 8.0, 2.0 Hz, C6H4NH -4 or H-6), 4.54 (2H, m, cHexH-1, PhOpipH-4), 4.04 (1H, m, cHexH-4), 3.83 (1H, m, 1H of PhOpipH-2, H-6) , 3.77 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (1H, m, 1H of PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2, H-6 ), 2.04 (2H, m, 2H of cHexH-2, H-6), 1. 94-1.80 (4H, m, 4H of cHexH-2, H-3, H-5, H-6, PhOpipH-3 , H-5), 1,801.64 (6H, m, 6H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5), 1.45 (1H, m, cPrH-1 ), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.78 (2H, m, 2H of cPrH-2, H-3); m / z: 609 [M + H] +.
[0494] [00494] Compound 435: 6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.82 (1H, m, pyH-6), 8.04 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.54 (1H, s, 1 x NH), 7.52 (1H, d , J 8.5 Hz, pyH-3), 7.36 (1H, s, C6H4NH-2), 7.15 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 7.11 (1H, t, J 8.5 Hz, C6H4NH-5) , 6.82 (1H, m, C6H4NH-4 or H-6), 6.79 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.57 (1H, dd, J 8.0, 2.0 Hz, C6H4NH-4 or H-6 ), 6.31 (1H, d, J 7.5 Hz, 1 x NH), 4.53 (1H, m, PhOpipH-4), 3.93 (1H, m, pipH-4), 3.81 (2H, m, 2H of PhOpipH-2 , H-6), 3.73 (3H, s, OCH3), 3.59 (1H, m, 1H of PhOpipH-2, H-6), 3.39 (2H, s, CH2C6H4OCH3), 3.33 (1H, m, 1H of PhOpipH -2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.96- 1.71 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.47-1.39 (1H, m, cPrH-1), 1.00 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H, m, 2H of cPrH-2, H-3); m / z: 613 [M + H] +.
[0495] [00495] Compound 436: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (trifluoromethylthio) phenoxy) piperidine-1-carbonyl) pyridazine-3-carboxamide. 1H nmr (CDCl3) δ 8.42 (1H, d, J 9.0 Hz, pyH-5 or H-6), 8.07 (1H, d, J 8.0 Hz, NH), 8.01 (1H, d, J 8.5 Hz, pyH- 5 or H-6), 7.62 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.58 (2H, d, J 8.5 Hz, 2H of C6H4SCF3), 7.46 (2H, d, J 8.0 Hz, 2H of C6H4CN ), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4SCF3), 4.71 (1H, m, PhOpipH-4), 4.10-4.03 (2H, m, pipH-4, 1H of PhOpipH-2, H-6) , 3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.82 (1H, ddd, J 13.0, 8.5, 4.5 Hz, 1H of PhOpipH-2, H-6), 3.71-3.64 (1H, m , 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH2C6H4CN), 2.84 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.15-1.97 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -43.8; m / z: 625 [M + H] +.
[0496] [00496] Compound 437: 6- (4- (4-acetylphenoxy) piperidine-1-carbonyl) -N- (1- (4-cyanobenzyl) piperidin-4-yl) pyridazine-3-carboxamide. 1H nmr (CDCl3) δ 8.43 (1H, d, J 8.5 Hz, pyH-5 or H-6), 8.07 (1H, d, J 8.0 Hz, NH), 8.01 (1H, d, J 9.0 Hz, pyH- 5 or H-6), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4Ac), 7.62 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN ), 6.96 (2H, d, J 9.5 Hz, 2H of C6H4Ac), 4.78 (1H, m, PhOpipH-4), 4.11-4.04 (2H, m, pipH-4, 1H of PhOpipH-2, H-6) , 3.89 (1H, m, 1H of PhOpipH-2, H-6), 3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.72-3.65 (1H, m, 1H of PhOpipH-2, H -6), 3.57 (2H, s, CH2C6H4CN), 2.83 (2H, m, 2H of pipH-2, H-6), 2.56 (3H, s, COCH3), 2.23 (2H, dd, J 11.0, 9.5 Hz , 2H of pipH-2, H-6), 2.16-2.02 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3 , H-5); m / z: 568 [M + H] +.
[0497] [00497] Compound 438: 6- (4- (3- (cyclopropanecarboxamido) phenoxy) piperidine-1-carboml) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.46 (2H, m, C6H4NH-2, 1 x NH), 7.34 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.19-7.14 (3H, m, 2H of C6H4OCF3, C6H4NH-5), 6.86 (1H, d, J 8.5 Hz, C6H4NH-4 or H-6), 6.65 (1H, dd, J 8.5, 2.0 Hz, C6H4NH-4 or H-6), 6.23 (1H, d, J 8.0 Hz, 1 x NH) , 4.61 (1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.95-3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH2C6H4OCF3), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6 ), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.05-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5 ), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5), 1.49 (1H, m, cPrH-1), 1.08 (2H , m, 2H cPrH-2, H-3), 0.85 (2H, m, 2H cPrH-2, H-3); 19F nmr (CDCl3) δ -57.9; m / z: 666 [M + H] + (experimental [M + H] +, 666.3879, C35H38F3N5O5 requires [M + H] + 666.2898).
[0498] [00498] Compound 439: N- (1- (4-methoxybenzyl) piperidin-4-yl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (2H, d, J 8.5 Hz, 2H of C6H4N), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.85 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.52 (2H, d, J 9.0 Hz, 2H of C6H4N), 6.32 (1H, m, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.79 (3H, s, OCH3), 3.53 (1H, m, BzpipH-4), 3.49 (2H, s, CH2C6H4OCH3), 3.38, 3.35 (4H, 2d AB system, J 6.5 Hz, 4H pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.88 (2H, m , 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.05, 2.02 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine ), 1.98 (2H, m, 2H of pipH-3, H-5), 1.91-1.78 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H- 5); m / z: 611 [M + H] +.
[0499] [00499] Compound 440: 6- (4- (4- (pyrrolidm-1-yl) benzoyl) piperidino-1-carbonyl) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide . 1H nmr (CDCl3) δ 8.92 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.56 (1H, d, J 8.5 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.14 (2H, d, J 8.0 Hz, 2H of C6H4OCF3), 6.60 (1H, d, J 7.5 Hz, NH), 6.52 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.88 (1H, m, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.50 (2H, s, CH2C6H4OCF3), 3.38, 3.35 (4H, 2d AB system, J 6.5 Hz , 4H pyrrolidine), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH- 2, H-6), 2.18 (2H, mdd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.98 (2H, m, 2H of pipH-3, H-5), 1,921.76 (4H, m, BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.9; m / z: 665 [M + H] +.
[0500] [00500] Compound 441: 6- (4- (4- (pyrrolidm-1-yl) benzoyl) piperidine-1-carbonyl) -N- (1- (3- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide . 1H nmr (CDCl3) δ 8.84 (1H, m, pyH-6), 8.05 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.80 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.25 (1H, t, J 7.5 Hz, C6H4OCF3H-5), 7.17 (2H, m, C6H4OCF3H-2, H-4 or H-6), 7.02 ( 1H, d, J 8.0 Hz, C6H4OCF3H-4 or H-6), 6.54 (1H, d, J 8.0 Hz, NH), 6.46 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.64 (1H, m , 1H of BzpipH-2, H-6), 3.95 (1H, m, pipH-4), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.46 (2H, s, CH2C6H4OCF3), 3.42 (1H, m, BzzpipH-4), 3.31, 3.29 (4H, 2d AB system, J 6.5 Hz, Pyrrolidine 4H), 3.17 (1H, m, BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 2.78 (2H, m, 2H of pipH-2, H-6), 2.12 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H- 6), 1.99-1.95 (6H, m, 4H of pyrrolidine, 2H of pipH-3, H-5), 1.86- 1.72 (4H, m, BzpipH-3, H-5), 1.57 (2H, m, 2H pipH-3, H-5); 19F nmr (CDCl3) δ -57.7; m / z: 665 [M + H] +.
[0501] [00501] Compound 442: N - ((cis) -4- (4-cyanophenoxy) cyclohexyl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.82 (1H, m, pyH-6), 7.86 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.57-7.52 (3H, m, 2H of C6H4CN, pyH-3), 6.93 (2H, d, J 9.0 Hz, 2H of C6H4CN), 6.77 (1H, d, J 8.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H of C6H4N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.61 (1H, br s, cHexH-1), 4.11 (1H, m, cHexH-4), 3.88 (1H, m, 1H of BzpipH-2, H-6), 3.48 (1H ,, m BzpipH-4), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, 4H pyrrolidine), 3.23 (1H, m, 1H BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.12-2.09 (2H, m, 2H of cHexH-2, H-3, H-5, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H pyrrolidine), 1.98-1.90 (2H, m, 2H cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.88-1.69 (8H, 8H of cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5); 19F nmr (CDCl3) δ -118.6; m / z: 607 [M + H] + (experimental [M + H] +, 606.3158, C36H39N5O4 requires [M + H] + 606.3075).
[0502] [00502] Compound 443: N- (1- (3-fluoro-4-methoxybenzyl) piperidin-4-yl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.08 (1H, dd, J 12.0, 2.0 Hz, C6H3FOCH3H-2), 6.99 (1H, d, J 8.5 Hz, C6H3FOCH3H-6), 6.89 (1H, t, J 8.5 Hz, C6H3FOCH3H-5), 6.53 (2H, d, J 9.0 Hz, 2H of C6H4N), 6.49 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2 , H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-32, H-6), 3.87 (3H, s, OCH3), 3.50 (1H, m, BzpipH -4), 3.43 (2H, s, CH2C6H3FOCH3), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, Pyrrolidine 4H), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.15 (2H, t, J 11.5 Hz, 2H of pipH-2, H -6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H pyrrolidine), 1.99 (2H, m, 2H pipH-3, H-5), 1.90-1.78 (4H, m, BzpipH- 3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -135.6; m / z: 629 [M + H] +.
[0503] [00503] Compound 444: 6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) -N- (1- (4- (pyrrolidin-1-yl) benzyl) piperidin-4 -il) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of COC6H4N), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.15 (2H, d, J 9.0 Hz, 2H of CH2C6H4N), 6.53 (2H, d, J 9.0 Hz, 2H of 1 x C6H4N), 6.52 (2H, d, J 8.5 Hz, 1 x C6H4N 2H), 6.33 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH -4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.49 (1H, m, BzpipH-4), 3.43 (2H, s, CH2C6H4N), 3.38, 3.35 (4H, 2d AB system , J 6.5 Hz, 4 x 1 x pyrrolidine), 3.28, 3.26 (4H, 2d AB system, J 6.5 Hz, 4 x 1 x pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH- 2, H-6), 2.04-1.96 (10H, m, 2H of pipH-3, H-5, 4H of 2 x pyrrolidine), 1.90-1.78 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m / z: 650 [M + H] +.
[0504] [00504] Compound 445: 6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (piperidin-4-yl) nicotinamide (in the form of its dihydrochloride salt). 1H nmr (CDCl3) δ 8.99 (1H, s, pyH-6), 8.75 (3H, m, NH, NH2), 8.30 (1H, dt, J 8.5, 2.0 Hz, pyH-4), 7.98 (2H, d , J 9.0 Hz, C6H4OCH3), 7.65 (1H, d, J 8.0 Hz, pyH-3), 7.04 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 4.50 (1H, m, BzpipH-2, H- 6), 4.06 (1H, m, pipH-4), 3.83 (3H, s, OCH3), 3.73 (1H, m, BzpipH-4), 3.60 (1H, m, 1H of BzpipH-2, H-6) , 3.33-3.17 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 3.06-2.98 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 1.99-1.86 (3H, m, 3H of pipH-3, H-5, BzpipH-3, H-5), 1.77-1.65 (3H, m, 3H of pipH-3, H-5, BzpipH-3, H-5), 1.60-1.49 (2H, m, 2H of pipH-3, H-5, BzpipH-3, H-5); m / z: 452 [M + H] +.
[0505] [00505] Compound 446: N- (1- (4-isopropoxybenzyl) piperidin-4-yl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) d 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.80 (2H, d, J 9.5 Hz, 2H of C6H4N), 7.54 (1H, d, J 8.0, pyH-3), 7.13 (2H, d, J 9.0 Hz, 2H of C6H4OiPr), 6.76 (2H, d, J 9.0 Hz, 2H of C6H4OiPr), 6.46 (2H, d, J 9.0 Hz, 2H of C6H4N), 6.28 (1H, d, J 8.0 Hz, NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H, heptet, J 6.0 Hz, OCH ( CH3) 2), 3.94 (1H, m, pipH-4), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.43 (1H, m, BzpipH-4), 3.39 (2H, s, CH2C6H4OiPr), 3.31, 3.29 (4H, 2d AB system, J 6.5 Hz, Pyrrolidine 4H), 3.17 (1H, m, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2 , H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.09 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1. 98, 1.96 ( 4H, 2d AB system, J 6.5 Hz, Pyrrolidine 4H), 1.92 (2H, m, 2H of pipH-3, H-5), 1.87-1.67 (4H, m, 4H of BzpipH-3, H-5) , 1.55 (2H, m, 2H of pipH-3, H-5); m / z: 638 [M + H] +.
[0506] [00506] Compound 447: N- (1- (4-cyano-3-fluorobenzyl) piperidm-4-yl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C6H4N), 7.56 (1H, d, J 8.0 Hz, pyH-3), 7.54 (1H, dd, J 8.0, 6.5 Hz, C6H3FCNH-H-5 or H-6), 7.26 (1H, d, J 10.0 Hz, C6H3FCNH-2 ), 7.22 (1H, d, J 8.5 Hz, C6H3FCNH-5 or H-6), 6.61 (1H, d, J 7.5 Hz, NH), 6.53 (2H, d, J 8.5 Hz, 2H of C6H4N), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.55 (2H, s, CH2C6H4N), 3.51 (1H, m, BzpipH-4), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, pyrrolidine 4H), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH- 2, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H pyrrolinine), 2.00 (2H, m, 2H pipH-3, H-5), 1.95-1.78 (4H, m , BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -106.9; m / z: 624 [M + H] +.
[0507] [00507] Compound 448: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (cyclopropanesulfonamido) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.45 (1H, m, pyH-6), 8.08 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.38 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.15 (2H, d, J 9.5 Hz, 2H of C6H4NHSO2), 6.82 (2H, d, J 9.0 Hz, 2H of C6H4NHSO2), 6.10 (1H, s, NHSO2), 6.04 (1H, d, J 7.5 Hz, NH), 4.51 (1H, m, PhOpipH-4), 3.97 (1H, m, pipH- 4), 3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.46-3.38 (1H, m, 1H of PhOpipH-2 , H-6), 2.76 (2H, m, 2H of pipH-2, H-6), 2.36 (1H, m, cPrH-1), 2.15 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH- 2, H-6), 2.00-1.1.86 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.79 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.05 (2H, m, 2H of cPrH-2, H-3), 0.88 (2H, m, 2H of cPrH-2 , H-3); m / z: 644 [M + H] +.
[0508] [00508] Compound 449: 6- (4- (4- (cyclopropanesulfonamido) phenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.45 (1H, s, 1 x NH), 8.95 (1H, m, pyH-6), 8.44 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.33 (1H , dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 9.0 Hz, 2H of C6H4NHSO2), 7.20-7.08 (4H, m, C6H4F), 6.94 (1H, d, J 8.5 Hz, N, O-pyH-3), 6.89 (2H, d , J 9.0 Hz, 2H of C6H4NHSO2), 6.29 (1H, s, 1 x NH), 4.58 (1H, m, PhOpipH-4), 3.99-3.93 (1H, m, 1H of PhOpipH-2, H-6) , 3.88-3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41-3.36 (1H, m, 1H of PhOpipH-2 , H-6), 2.43 (1H, m, cPrH-1), 2.01-1.91 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H- 5), 1.12 (2H, m, 2H of cPrH-2, H-3), 0.94 (2H, m, 2H of cPrH-2, H-3); 19F nmr (CDCl3) δ -118.5; m / z: 632 [M + H] +.
[0509] [00509] Compound 450: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (trifluoromethylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 9.5 Hz, 2H de 7.70 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, pyH-3), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.11 ( 2H, d, J 9.0 Hz, 2H of C6H4SO2), 6.14 (1H, d, J 7.5 Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.94 ( 2H, m, 2H of PhOpipH-2, H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (3H, m, 1H of PhOpipH-2, H-6, CH2C6H4CN) , 2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.14-1.98 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.92 (1H, m, 1H of PhOpipH-3, H-5) 1.62 (2H, m, 2H of pipH-3, H- 5); 19F nmr (CDCl3) δ -78.8; m / z: 656 [M + H] +.
[0510] [00510] Compound 451: N - ((3S, 4R) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4- (trifluoromethylsulfonyl) phenoxy) piperidine-1-carbonyl ) nicotinamide 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C6H4SO2) , 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.62 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.44 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.11 (2H, d, J 9.0 Hz, 2H of C6H4SO2), 6.64 (1H, d, J 7.5 Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.56 (1H, dtd, J 50.5, 9.5, 4.5 Hz, pipH -3), 4.15 (1H, m, pipH-4), 3.99-3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6) , 4.14, 4.09 (2H, 2d AB system, J 7.5 Hz, CH2C6H4CN), 3.54 (1H, m, 1H of PhOpipH-2, H-6), 3.18 (1H, m, 1H of pipH-2), 2.80 ( 1H, m, 1H of pipH-6), 2.13-2.18 (3H, m, 1H of pipH2, 1H of pipH-5, 1H of pipH-6), 2.10 (1H, m, 1H of PhOpipH-3, H- 5), 2.04 (2H, m, 2H of PhOpipH-3, H-5), 1.91 (1H, m, 1H of PhOpipH-3, H-5), 1.63 (1H, m, 1H of pipH-5); 19F nmr (CDCl3) δ -78.8, -188.6; m / z: 674 [M + H] +.
[0511] [00511] Compound 452: N - (((3R, 4R) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. Compound 452 was separated from the racemic mixture of Compound 349 using chiral chromatography on a 25 cm x 10 mm (R, R) -Whelk-O 1 column (silica modified with 4- (3,5-dinitrobenzamido) covalently linked tetrahydrophenanthrene ), made available by Regis Technologies. The instrument consisted of a semi-prepared HPLC TharSFC system, and the elution was performed in an isocratic way using 50% MeOH with 0.1% diethylamine in supercritical carbon dioxide at 14 mL / minute at 30 ° C. Compound 452 was the peak that eluted last (at about 21 minutes under the conditions described above). The spectral data is in accordance with Compound 349. Compound 452 was independently synthesized in an enantioselective manner as described in the following scheme:
[0512] [00512] The first stage of the synthesis followed the method of Kwiatkowski, P .; Beeson, T. D .; Conrad, J. C .; MacMillan, D. W. C., J. Am. Chem. Soc., 2011, 133 (6), 1738-1741, which is hereby incorporated herein by reference in its entirety. 9-Epi-DHQA is (1R) - ((2R) -5-ethylquinuclidin-2-yl) (6-methoxyquinolin-4-yl) methanamine. The optical rotation [α] of the (3R, 4S) -tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate was -20.0 ° (c 0.33, CH2Cl2); the literature value for the corresponding compound (3S, 4R) is + 21.6 °. See International Patent Application Publication No. WO 2010/128425.
[0513] [00513] Compound 453: N - (((3S, 4S) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. Compound 453 was separated from the racemic mixture of Compound 349 using chiral chromatography as described above for Compound 452. Compound 452 was the peak that eluted earlier (at about 20 minutes under the conditions described above). The spectral data are in accordance with Compound 349.
[0514] [00514] Compound 454: N - ((cis) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.94 (1H, d, J 2.0 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.59 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.46 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.93 ( 1H, m, NH), 4.87 (0.5H, m, 0.5H of pipH-3), 4.68 (1.5H, m, 0.5H of pipH-3, 1H of BzpipH-2, H-6), 4.28-4.12 (1H, m, pipH-4), 3.91 (1H, m, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3), 3.64, 3.58 (2H, 2d AB system, J 14.0 Hz, CH2C6H4CN), 3.52 (1H, m, BzpipH-4), 3.28-3.16 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2 , H-6), 2.91 (1H, m, 1H of pipH-6), 2.41 (0.5H, d, J 13.0 Hz, 0.5H of pipH-2), 2.26 (1.5H, m, 0.5H of pipH- 2, 1H of pipH-6), 2.10-1.98 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91-1.80 (4H, m, 4H of pipH-5, BzpipH-3, H-5); 19F nmr (CDCl3) δ -200.8 (q, J = 63 Hz); m / z: 584 [M + H] +.
[0515] [00515] Compound 455: 6- (4- (4- (cyclopropanocarbonyl) phenoxy) piperidino-1-carbonyl) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C6H4OCF3 or C6H4COcPr) , 7.64 (1H, d, J 8.0 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C6H4OCF3 or C6H4COcPr), 7.15 (2H, d, J 8.0 Hz, 2H of C6H4OCF3 or C6H4COcPr), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCF3 or C6H4COcPr), 6.30 (1H, d, J 7.5 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4 ), 3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (3H, m, CH2C6H4OCF3, 1H of PhOpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.62 (1H, tt, J 7.5, 4.5 Hz, cPrH-1), 2.18 (2H, t, J 11.0 Hz, 2H pipH-2, H-6), 2.10-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3 , H-5), 1.60 (2H, m, 2H of pipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.00 (2H, m, 2H of cPrH- 2, H-3); 19F nmr (CDCl3) δ -57.2; m / z: 651 [M + H] +.
[0516] [00516] Compound 456: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4- (cyclopropanocarbonyl) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C6H4COcPr), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.5 Hz, 2H of C6H4CN), 6.97 ( 2H, d, J 9.0 Hz, 2H of C6H4COcPr), 6.40 (1H, d, 8.0 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.96-3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH2C6H4CN), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.62 (tt, J 7.5, 4.5 Hz, cPrH-1), 2.20 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.05-1.94 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); m / z: 593 [M + H] +.
[0517] [00517] Compound 457: 6- (4- (4- (cyclopropanocarbonyl) phenoxy) piperidine-1-carbonyl) -N- (6- (4-fluorophenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.63 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.46 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd , J 8.5, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C6H4COcPr), 7.41 ( 1H, d, J 8.0 Hz, pyH-3), 7.10-7.07 (4H, m, C6H4F), 6.96 (2H, d, J 8.5 Hz, 2H of C6H4COcPr), 6.95 (1H, d, J 8.5 Hz, N , O-pyH-3), 4.74 (1H, m, PhOpipH-4), 4.01 (1H, m, 1H of PhOpipH-2, H-6), 3.86 (1H, m, 1H of PhOpipH-2, H- 6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH -1), 2.11-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m, 2H of cPrH- 2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); 19F nmr (CDCl3) δ -118.5; m / z: 581 [M + H] +.
[0518] [00518] Compound 458: 6- (4- (4- (cyclopropanocarbonyl) phenoxy) piperidine-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C6H4COcPr), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4COcPr), 6.85 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 6.38 (1H, d, J 7.5 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.95-3.86 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH3), 3.71 (1H, m, PhOpipH-2, H-6), 3.50 (3H, m, CH2C6H4OCH3, 1H of PhOpipH-2 , H-6), 2.90 (2H, m, 2H of pipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH-1), 2.20 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); m / z: 597 [M + H] +.
[0519] [00519] Compound 459: N- (6- (4-cyanophenoxy) pyridm-3-yl) -6- (4- (4- (methylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.64 (1H, s, NH), 8.96 (1H, m, pyH-6), 8.52 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C6H4SO2CH3), 7.68 ( 2H, d, J 9.0 Hz, 2H of C6H4CN), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.5 Hz, 2H of C6H4CN), 7.06 (1H, m, N , O-pyH-3), 7.03 (2H, d, J 9.0 Hz, 2H of C6H4SO2CH3), 4.75 (1H, m, PhOpipH-4), 4.02 (1H, m, 1H of PhOpipH-2, H-6) , 3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.45 (1H, m, 1H of PhOpipH-2, H-6 ), 3.04 (3H, s, SO2CH3), 2.18-1.96 (3H, m, 3H of PhOpipH-3, H-5), 1.90 (1H, m, 1H of PhOpipH-3, H-5); m / z: 598 [M + H] +.
[0520] [00520] Compound 460: N- (6- (4-cyanophenoxy) pyridin-3-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.95 (1H, s, NH), 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.57 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.09 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 ), 7.67 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.38 (1H, d, J 8.5 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.06 (1H , d, J 8.5 Hz, N, O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.70 (1H, m, 1H of BzpipH-2, H-6), 3.88 ( 3H, s, OCH3), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.24 (1H, m, 1H of BzpipH-2, H-6 ), 3.16 (1H, m, 1H of BzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H of BzpipH-3, H-5); m / z: 562 [M + H] +.
[0521] [00521] Compound 461: N - ((cis) -3-fluoro-1- (4- (trifluoromethoxy) benzyl) piperidm-4-yl) -6- (4- (4-methoxybenzoyl) piperidmo-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.96 (1H, m, pyH-6), 8.17 (1H, dd, J 8.0, 2.0m Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.68 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.36 (2H, d, J 9.0 Hz, 2H of C6H4OCF3), 7.17 (2H, d, J 8.0 Hz, 2H of C6H4OCF3), 6.95 (2H , d, J 9.0 Hz, 2H of C6H4OCH3), 6.57 (1H, d, J 9.0 Hz, NH), 4.86 (0.5H, m, 0.5H of pipH-3), 4.68 (1.5H, m, 1H of BzpipH -2, H-6, 0.5H of pipH-3), 4.33-4.15 (1H, m, pipH-4), 3.96 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s , OCH3), 3.60, 3.55 (2H, 2d AB system, J 14.0 Hz, CH2C6H4OCF3), 3.52 (1H, m, BzpipH-4), 3.31-3.22 (2H, m, 1H of pipH-2, 1H of BzpipH- 2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.95 (1H, m, 1H of pipH-6), 2.39 (0.5H, d, J 12.5 Hz, 0.5H of pipH-2), 2.24 (1.5 Hz, 0.5H of pipH-2, 1H of pipH-6), 2.05-1.97 (2H, m, 1H of pipH-5, 1H of BzpipH-3, H-5), 1.93-1.81 (4H, m, 1H of pipH-5, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -57.9, -200.8; m / z: 644 [M + H] +.
[0522] [00522] Compound 462: N- (6- (4-acetylphenoxy) pyridin-3-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.98 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.56 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.42 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.99 (2H, d, J 9.0 Hz, 2H of C6H4COCH3), 7.93 ( 2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.38 (1H, d, J 8.0 Hz, pyH-3), 7.18 (2H, d, J 8.5 Hz, 2H of C6H4COCH3), 7.03 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.68 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH3), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.15 ( 1H, m, 1H of BzpipH-2, H-6), 2.59 (3H, s, COCH3), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.92-1.81 (3H, m, 3H BzpipH-3, H-5); m / z: 579 [M + H] +.
[0523] [00523] Compound 463: N- (6- (4-cyanophenoxy) pyridin-3-yl) -6- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.99 (1H, s, NH), 8.90 (1H, m, pyH-6), 8.57 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, C6H3F2H-6), 7.68 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.34 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.05 (1H, d , J 9.0 Hz, N, O-pyH-3), 7.00 (1H, m, C6H3F2H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5, 2.5 Hz, C6H3F2H-3 or H-5 ), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.24-3.09 (2H, m, 2H of BzpipH-2, H-6), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91- 1.72 (3H, m, 3H of BzpipH-3, H-5 ); 19F nmr (CDCl3) δ -101.1, -106.5; m / z: 568 [M + H] +.
[0524] [00524] Compound 464: N- (6- (4-acetylphenoxy) pyridin-3-yl) -6- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.62 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.41 (1H, dd, J 8.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H , dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C6H4COCH3), 7.87 (1H, dt, J 6.5, 8.5 Hz, C6H3F2H-6), 7.42 (1H, d, J 8.0 Hz, pyH-3), 7.19 (2H, d, J 9.0 Hz, 2H of C6H4COCH3), 7.04 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.99 (1H, m , C6H3F2H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.4, 2.0 Hz, C6H3F2H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.41 (1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6), 2.60 (3H , s, COCH3), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.74 (3H, m, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.3, -106.5; m / z: 585 [M + H] +.
[0525] [00525] Compound 465: 6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) -N- (6- (4- (methylsulfonyl) phenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 9.92 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.59 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.45 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (2H, d, J 8.5 Hz, 2H of C6H4OCH3 or C6H4SO2CH3), 7.93 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 or C6H4SO2CH3), 7.39 (1H, d, J 8.0 Hz, pyH-3), 7.30 (2H, d, J 9.0 Hz, 2H of C6H4SO2CH3), 7.07 (1H , d, J 9.0 Hz, N, O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.69 (1H, m, 1H of BzpipH-2, H- 6), 3.88 ( 3H, s, OCH3), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.29-3.13 (2H, m, 2H of BzpipH-2, H -6), 3.07 (3H, s, SO2CH3), 2.03 (1H, m, 1H, m, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H- 5); m / z: 615 [M + H] +.
[0526] [00526] Compound 466: 6- (4- (2,4-difluorobenzofl) piperidmo-1-carbonyl) -N- (6- (4- (methylsulfonyl) phenoxy) pyridin-3-yl) nicotinamide. 1H nmr (CDCl3) δ 10.00 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.60 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd , J 8.5, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C6H4SO2CH3), 7.87 ( 1H, dt, J 6.5, 9.0 Hz, C6H3F2H-6), 7.35 (1H, d, J 8.0 Hz, pyH-3), 7.30 (2H, d, J 8.5 Hz, 2H of C6H4SO2CH3), 7.07 (1H, d , J 8.5 Hz, N, O-pyH-3), 6.99 (1H, m, C6H3F2H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5, 2.0 Hz, C6H3F2H-3 or H-5 ), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.09 (2H, m, 2H of BzpipH-2, H-6), 3.07 (3H, s, SO2CH3), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.75 (3H, m, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -101.2, -106.5; m / z: 621 [M + H] +.
[0527] [00527] Compound 467: N- (6- (4-fluorophenylsulfonyl) pyridin-3-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 10.11 (1H, s, NH), 8.98 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.90 (1H, m, pyH-6), 8.63 (1H, dd , J 8.5, 2.5 Hz, N, O-pyH-4), 8.20 (1H, d, J 8.5 Hz, N, O-pyH-3), 8.10-8.06 (3H, m, pyH-4, 2H of C6H4F ), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.39 (1H, d, J 8.5 Hz, pyH-3), 7.20 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.97 (2H , d, J 9.0 Hz, 2H of C6H4OCH3), 4.69 (1H, m, 1H of BzpipH-2, H-6), 3.89 (3H, s, OCH3), 3.76 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.21 (2H, m, 2H of BzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.76 (3H, m, 3H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -103.6; m / z: 603 [M + H] + (experimental [M + H] +, 603.1692, C31H27FN4O6S requires [M + H] + 603.1708).
[0528] [00528] Compound 468: N- (5- (4-cyanophenoxy) pyridin-2-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.32 (1H, s, NH), 8.97 (1H, d, J 2.0 Hz, pyH-6), 8.50 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.41 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3 ), 7.68 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.50 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.07 (1H , d, J 9.0 Hz, N, O-pyH-3), 6.96 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 4.69 (1H, m, 1H of BzpipH-2, H-6), 3.89 ( 3H, s, OCH3), 3.85 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.22-3.10 (2H, m, 2H of BzpipH-2, H -6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.80 (3H, m, 3H of BzpipH-3, H-5); m / z: 562 [M + H] +.
[0529] [00529] Compound 469: N- (5- (4-cyanophenoxy) pyridin-2-yl) -6- (4- (2,4-difluorobenzoyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.72 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.54 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd , J 9.0, 3.0 Hz, N, O-pyH-4), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.88 (1H, dt, J 6.5, 9.0 Hz, C6H3F2H-6), 7.68 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.40 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.06 (1H, d , J 9.0 Hz, N, O-pyH-3), 7.00 (1H, m, C6H3F2H-3 or H-5), 6.90 (1H, ddd, J 11.0, 8.5, 2.0 Hz, C6H3F2H-3 or H-5 ), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.911.75 (3H, m, 3H of BzpipH-3, H-5 ); 19F nmr (CDCl3) δ -101.2, -106.5; m / z: 568 [M + H] +.
[0530] [00530] Compound 470: 6- (4- (4-fluorophenylsulfonyl) piperidine-1-carbonyl) -N- (1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F) , 7.63 (1H, d, J 7.5 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C6H4OCF3), 7.26 (2H, t, J 8.5 Hz, 2H of C6H4F), 7.16 (2H, d, J 7.5 Hz, 2H of C6H4OCF3), 6.31 (1H, d, J 8.0 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H of BzpipH -2, H-6), 4.01 (1H, m, pipH-4), 3.52 (2H, s, CH2C6H4OCF3), 3.16 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.04 (1H, m , 1H of BzpipH-2, H-6), 2.87-2.75 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.17 (2H, t, J 11.5 Hz , 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.79 (2H, qd, J 12.5, 4.0 Hz , 2H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -57.9, -102.6; m / z: 649 [M + H] +.
[0531] [00531] Compound 471: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-fluorophenylsulfonyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.89 (dd, J 9.0, 5.0 Hz, 2H of C6H4F), 7.63 (1H, m, pyH-3), 7.61 (2H, d, J 8.0 Hz, C6H4CN 2H), 7.45 (2H, d, J 8.0 Hz, C6H4CN 2H), 7.27 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.36 (1H, d, J 7.5 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H of BzpipH-2 , H-6), 4.01 (1H, m, pipH-4), 3.56 (2H, s, CH2C6H4CN), 3.17 (1H, tt, J 12.0, 4.0 Hz, BzpipH-4), 3.04 (1H, t, J 12.0 Hz, 1H of BzpipH-2, H-6), 2.85-2.74 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.20 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.11-1.95 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.80 (qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -102.6; m / z: 590 [M + H] +.
[0532] [00532] Compound 472: N- (6- (4-cyanophenoxy) pyridin-3-yl) -6- (4- (4-fluorophenylsulfonyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.61 (1H, s, NH), 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.49 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.42 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F), 7.69 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.27 (2H, m, 2H of C6H4F), 7.23 (2H, d , J 8.5 Hz, 2H of C6H4CN), 7.06 (1H, d, J 8.5 Hz, N, O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2, H-6), 3.96 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.84 (1H, m, 1H of BzpipH -2, H-6), 2.10 (1H, d, J 12.0 Hz, 1H of BzpipH-3, H-5), 1.99 (1H, d, J 11.5 Hz, 1H of BzpipH-3, H-5), 1.82 (2H, m, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -102.2; m / z: 586 [M + H] +.
[0533] [00533] Compound 473: N- (6- (4-acetylphenoxy) pyridin-3-yl) -6- (4- (4-fluorophenylsulfonyl) piperidine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.31 (1H, s, NH), 8.95 (1H, m, pyH-6), 8.45 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.38 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.14 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.02 (2H, d, J 9.0 Hz, 2H of C6H4Ac), 7.89 ( 2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.27 (2H, t, J 8.5 Hz, 2H of C6H4F), 7.20 (2H, d , J 9.0 Hz, 2H of C6H4Ac), 7.05 (1H, d, J 9.0 Hz, N, O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.06 (1H, m, 1H of BzpipH-2, H-6), 2.83 (1H, m, 1H of BzpipH -2, H-6), 2.60 (3H, s, COCH3), 2.10 (1H, d, J 12.5 Hz, 1H of BzpipH-3, H-5), 2.01 (1H, d, J 12.5 Hz, 1H of BzpipH-3, H-5), 1.82 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5); 19F nmr (CDCl3) δ -102.3; m / z: 603 [M + H] + (experimental [M + H] +, 603.1689, C31H27FN4O6S requires [M + H] + 603.1708).
[0534] [00534] Compound 474: 6- (4- (4-fluorofemlsulfoml) piperidmo-1-carbonyl) -N- (1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F) , 7.66 (1H, d, J 8.0 Hz, pyH-3), 7.29 (2H, t, J 9.0 Hz, 2H of C6H4F), 7.24 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.88 (2H, d, J 8.5 Hz, 2H of C6H4OCH3), 6.31 (1H, d, J 8.0 Hz, NH), 4.85 (1H, m, 1H of BzpipH-2, H-6), 4.16 (1H, m, 1H of BzpipH -2, H-6), 4.02 (1H, m, pipH-4), 3.83 (3H, s, OCH3), 3.48 (2H, s, CH2C6H4OCH3), 3.19 (1H, tt, J 12.0, 3.5 Hz, BzpipH -4), 3.07 (1H, t, J 12.0 Hz, 1H of BzpipH-2, H-6), 2.90-2.77 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H -6), 2.17 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H -5), 1. 81 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -102.6; m / z: 595 [M + H] +.
[0535] [00535] Compound 475: 6- (4- (4-fluorofemlsulfoml) piperidine-1-carbonyl) -N- (1- (3-methoxybenzyl) piperidin-4-yl) nicotinamide. 1H nmr (CDCl3) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.88 (2H, dd, J 9.0, 5.0 Hz, 2H of C6H4F), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.29-7.20 (3H, m, 2H of C6H4F, 1H of C6H4OCH3), 6.91-6.88 (2H, m, 2H of C6H4OCH3), 6.79 (1H, m, 1H of C6H4OCH3), 6.35 (1H, d, J 7.5 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.12 (1H, m, 1H of BzpipH -2, H-6), 4.03 (1H, m, pipH-4), 3.81 (3H, s, OCH3), 3.49 (2H, s, CH2C6H4OCH3), 3.16 (1H, tt, J 12.0, 3.5 Hz, BzpipH -4), 3.04 (1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.88-2.74 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H -6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5 ), 1.78 (2H, qd, J 12.5, 4.5 Hz, 2H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); 19F nmr (CDCl3) δ -102.6; m / z: 595 [M + H] +.
[0536] [00536] Compound 476: N- (6- (4-cyanophenoxy) pyridin-3-yl) -6- (4- (4-fluorobenzyl) piperazine-1-carbonyl) nicotinamide. 1H nmr (CDCl3) δ 9.87 (1H, s, NH), 8.89 (1H, m, pyH-6), 8.54 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd , J 9.0, 2.5 Hz, N, O-pyH-4), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.68 (2H, d, J 9.0 Hz, 2H of C6H4CN), 7.35 ( 1H, d, J 7.5 Hz, pyH-3), 7.25 (2H, m, 2H of C6H4F), 7.22 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.03 (2H, t, J 8.5 Hz, 2H of C6H4F), 6.99 (1H, d, J 8.5 Hz, N, O-pyH-3), 3.83 (2H, m, 2H of piz), 3.50 (2H, s, CH2C6H4F), 3.42, 3.41 (2H, 2d AB system, J 4.5 Hz, 2H piz), 2.55, 2.53 (2H, 2d AB system, J 4.5 Hz, 2H piz), 2.40, 2.38 (2H, 2d AB system, J 4.5 Hz, 2H piz); 19F nmr (CDCl3) δ -115.2; m / z: 537 [M + H] +.
[0537] [00537] Compound 491: N- (1- (4-cyanobenzyl) piperidin-4-yl) -6- (4- (4-fluorobenzyl) piperazin-1-yl) pyridazine-3-carboxamide. Compound 491 was prepared as follows: Step 1
[0538] [00538] 6-Chloropyridazine-3-carboxylic acid (0.96 g, 6.2 mMol) was dissolved in dichloromethane (20 ml) and treated with 4-amino-1- (4-cyanobenzyl) piperidine dihydrochloride (1, 79 g, 6.2 mMol), HATU (2.37 g, 6.2 mMol) and DIEA (3.6 ml, 3.3 eq.). The reaction was stirred at RT for 3 days. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure.
[0539] [00539] The crude product was purified by means of flash chromatography on silica gel, eluting with 2% methanol in dichloromethane.
[0540] [00540] 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 10.0 Hz, 1H, NH), 7.68 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.02 (m, 1H), 3.15 (m, 2H), 2.81 (m, 2H), 2.29 (m, 2H ), 2.12 (m, 2H); m / z = 356.05 (M + H) +; m / z = 354.11 (MH) + Step 2
[0541] [00541] The product from step 1 (109 mg, 0.306 mMol) was dissolved in CH3CN (3 mL) and treated with 4-Fluorobenzylpiperazine (1.2 eq.), Tetrabutylammonium iodide (24 mg) and DBU (100 □ L ). The reaction mixture was then heated to 82 ° C for 1.5 hours. The reaction mixture was concentrated to dryness and purified by radial chromatography on silica gel, eluting with 5% methanol in dichloromethane, providing Compound 491. 1H NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 9.6, 1.4 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H, NH), 7.58 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.26-7.30 (m, 2H ), 6,927.02 (m, 3H), 3.97 (m, 1H), 3.73 (m, 4H), 3.52 (s, 2H), 3.49 (s, 2H), 3.12 (m, 2H), 2.77 (m, 2H), 2.54 (m, 4H), 2.20 (m, 2H), 1.97 (m, 2H); m / z = 514.18 (M + H) +;
[0542] [00542] For use in the synthesis of Compound 125, 1- (4-fluorobenzyl) -2,2-dimethylpiperazine was synthesized. To a solution of piperazin-2-one (0.500 g, 5.00 mmol, 1.0 eq) in dichloromethane (50 ml) was added trityl chloride (1.533 g, 5.50 mmol, 1.1 eq). The reaction was stirred at room temperature for 18 hours before diluting with CH2Cl2 (50 mL). The reaction was washed with NaHCO3 (100 ml) and saline (100 ml), dried (Na2SO4) and concentrated under reduced pressure, providing 4-tritylpiperazin-2-one as a white foam, which was used without further purification. . 1H nmr (CDCl3) 7.48 (6H, d, J 7.5 Hz, 6H of trityl), 7.28 (6H, m, 6H of trityl), 7.18 (3H, m, 3H of trityl), 5.95 (1H, m, NH) , 3.45 (2H, broad s, 2H of oxopip), 3.06 (2H, s, 2H of oxopip), 2.46 (2H, br s, 2H of oxopip). A suspension of 4-tritylpiperazin-2-one (0.405 g, 1.18 mmol, 1.0 eq) in tetrahydrofuran (11 ml) was cooled to 0 ° C and 4-fluorobenzyl bromide (0.246 g, 0 , 16 mL, 1.30 mmol, 1.1 eq), followed by sodium hydride (0.057 g of a 60% suspension in oil, 1.42 mmol, 1.2 eq). Dimethylformamide (3 ml) was added to aid dissolution. The reaction mixture was allowed to warm to room temperature with stirring for 14 hours. More 4-fluorobenzyl bromide (0.16 mL, 1.1 eq) and sodium hydride (0.057 g, 1.2 eq) were added and the reaction was stirred at room temperature for 3 hours and at 60 ° C for 15 hours. The reaction was cooled and partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was washed with saline (50 ml), water (50 ml) and saline solution (50 ml), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10 → 30% EtOAc-hexane, 0 → 15 minutes, then 30 → 70% EtOAc-hexane 15 → 25 minutes) provided 4-tritylpiperazin-2-one as a white solid (0.374 g, 70%). 1H nmr (CDCl3) 7.48 (6H, d, J 7.5 Hz, 3 x 2H of C6H5), 7.28 (6H, t, J 7.5 Hz, 3 x 2H of C6H5), 7.23-7.15 (5H, m, 3 x 1H of C6H5, 2H of C6H4F), 7.01 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.78 (2H, s, CH2C6H4F), 3.31 (2H, t, J 5.5 Hz, 2H of oxopip), 3.15 (2H , s, 2H of oxopip), 2.43 (2H, m, 2H of oxopip); m / z 451 [M + H] +. A solution of 4-tritylpiperazin-2-one (0.165 g, 0.367 mmol, 1.0 eq) and di-t-butylpyridine (0.097 mL, 0.440 mmol, 1.2 eq) in dichloromethane (3.5 mL) was cooled to -78 ° C. Trifluoromethanesulfonic acid (0.074 mL, 0.440 mmol, 1.2 eq) was added and the reaction was stirred at -78 ° C for 45 minutes before the addition of methylmagnesium bromide (0.79 mL of a 1.4 M solution in toluene, 1,100 mmol, 3.0 eq). The reaction mixture was left with stirring at -78 ° C for 2 hours and was heated to 0 ° C over 2 hours before rapid cooling with NH4Cl (3 ml). The reaction was partitioned between NH4Cl (50 ml) and CH2Cl2 (70 ml). The aqueous phase was extracted with CH2Cl2 (2 x 50 ml) and the combined organics were dried (Na2SO4) before being concentrated under reduced pressure. MPLC (10 → 30% EtOAc-hexane, 5 → 18 minutes) provided 1- (4-fluorobenzyl) -2,2-dimethyl-4-tritylpiperazine (0.126 g, 74%) as a white solid; m / z 451 [M + H] +. To a solution of 1- (4-fluorobenzyl) -2,2-dimethyl-4-tritylpiperazine (0.126 g, 0.272 mmol, 1.0 eq) in dichloromethane (3.0 mL) was added hydrogen chloride (0.27 mL of a 4 M solution in dioxane, 1.086 mmol, 4.0 eq). The reaction was stirred at room temperature for 4 hours. More hydrogen chloride (0.27 mL of a 4 M solution in dioxane, 1.086 mmol, 4.0 eq) was added and the reaction was stirred at room temperature for 1 hour before being concentrated under reduced pressure. The residue was triturated with Et2O (2 x 10 mL), providing 1- (4-fluorobenzyl) -2,2-dimethylpiperazine as a white solid, which was dried in vacuo and used without further purification. 1H nmr (CD3OD) 7.62 (2H, m, 2H of C6H4F), 7.23 (2H, t, J 8.5 Hz, 2H of C6H4F), 3.53 (2H, s, 2H of piz), 3.44 (4H, m, 4H of piz), 1.68 (6H, s, C (CH 3) 2); m / z 223 [M + H] +. The syntheses of gem-dimethyl compounds are also generically described in Xiao, KJ .; Luo, JM .; Ye, KY .; Wang, Y .; Huang, PQ. Angew. Chem. Int. Ed. 2010, 49, 3037-3040. Synthesis of 1-tert-Butyloxycarbonyl-4-N-methylaminopiperidine
[0543] [00543] To a solution of 1-tert-butyloxycarbonyl-4-oxopiperidine (0.45 g, 2.26 mmol, 1.0 eq) in dichloromethane (20 mL) was added methylamine (2.26 mL of a solution 2 M in tetrahydrofuran, 4.52 mmol, 2.0 eq). After equilibration at room temperature for 10 minutes, sodium triacetoxyborohydride (0.72 g, 3.39 mmol, 1.5 eq) was added and the reaction was stirred at room temperature for 30 minutes. Rochelle salt (20 ml) was added and the reaction was stirred for 1 hour before adding NaHCO3 (50 ml). The organics were extracted with CH2Cl2 (2 x 100 mL), combined, washed with saline (50 mL), dried (Na2SO4) and concentrated under reduced pressure, providing the title compound as a colorless oil; 1H nmr (CDCl3) δ 4.03 (2H, m), 2.79 (2H, t, J 12.0 Hz), 2.50 (1H, tt, J 12.0, 3.0 Hz), 2.43 (3H, s), 1.85 (2H, m) , 1.47 (9H, s,), 1.22 (2H, m); m / z: 215 [M + H] +. Coupling of 4-N-methylpiperidine
[0544] [00544] To a mixture of 1-tert-butyloxycarbonyl-4-N-methylaminopiperidine (0.136 g, 0.636 mmol, 1.0 eq) and pyridine carboxylic acid (0.231 g, 0.636 mmol, 1.0 eq) in dimethylformamide ( 6 ml) triethylamine (0.13 ml, 0.953 mmol, 1.5 eq) was added, followed by HATU (0.214 g, 0.636 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before being partitioned between EtOAc (100 mL) and NaHCO3-water (1: 1, 100 mL). The organics were additionally washed with saline solution (100 ml), water (100 ml) and saline solution (100 ml) before drying (Na2SO4) and concentration under reduced pressure. MPLC (0 10% MeOH-CH2Cl2) provided the coupled material (0.215 g, 61%) as a white foam; 1H nmr (CDCl3) δ 8.60 (1H, s, pyH-6), 7.92 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.80 (1H, d, J 9.0 Hz, pyH-3 or pyH-6) , 7.67 (1H, d, J 9.0 Hz, pyH-3 or pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.63 (1H, m, 1H of BzpipH-2, H-6 ), 4.23 (1H, m, pipH-4), 3.98 (1H, m, 1H of BzpipH-2, H- 6), 3.86 (3H, s, OCH3), 3.52 (1H, m, BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.97 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 2.82 (3H, br s, NCH3), 2.55 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 1. 97 (1H, m, 1H of pipH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.92-1.66 (9H, m, 9H of pipH-2, H-3, H-5 , H-6, BzpipH-3, H-5), 1.45 (9H, s, C (CH3) 3); m / z: 565 [M + H] +. Synthesis of 1-tert-Butyloxycarbonyl-3,3-difluoro-4-aminopiperidine 1 -tert-Butyloxycarbonyl-3,3-difluoro-4-benzylaminopiperidine
[0545] [00545] To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 ml) was added benzylamine (0.070 ml , 0.638 mmol, 1.5 eq), followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 ml) and CH2Cl2 (50 ml). The aqueous phase was extracted with CH2Cl2 (2 x 50 ml). The combined organics were washed with saline (50 ml), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30 → 70% EtOAc-hexane) provided the title compound (0.045 g, 32%) as a colorless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m) , 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C (CH3) 3); 19F nmr (CDCl3) δ -109.0 (dd, J 243.0, 115.5 Hz), -119.5 (d, J 251.0 Hz); m / z: 327 [M + H] +. 1-tert-Butyloxy-3,3-difluoro-4-aminopiperidine
[0546] [00546] Palladium hydroxide (approximately 0.030 g) was added to a solution of benzylaminopiperidine (0.045 g, 0.138 mmol) in ethanol (3.0 mL). The flask was purged with hydrogen and the reaction was stirred under an atmosphere of hydrogen for 2 hours. The flask was purged with nitrogen and the reaction was filtered through celite, eluting with 5% MeOH-CH2Cl2 (4 x 5 mL). The filtrate was concentrated under reduced pressure, providing the title compound as a colorless oil, which was used without purification; Coupling of 3,3-difluoro-4-aminopiperidine to pyridine carboxylic acid
[0547] [00547] To a solution of difluoroaminopiperidine (0.035 g, 0.148 mmol, 1.0 eq) and pyridine carboxylic acid (0.055 g, 0.148 mmol, 1.0 eq) in dimethylformamide (1.5 ml) was added triethylamine (0.031 mL, 0.222 mmol, 1.5 eq), followed by HATU (0.056 g, 0.148 mmol, 1.0 eq). The resulting yellow solution was stirred at room temperature for 5 hours before being partitioned between EtOAc (100 ml) and NaHCO3-water (1: 1, 100 ml). The organics were additionally washed with saline solution (100 ml), water (100 ml) and saline solution (100 ml) before drying (Na2SO4) and concentration under reduced pressure. MPLC (0 → 10% MeOH-CH2Cl2) provided the diamide (0.057 g, 67%) as a white foam; 1H nmr (CDCl3) δ 8.97 (1H, s, pyH-6), 8.17 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.5 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.5 Hz, pyH-4), 7.07 (1H, m, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, m, 1H of pipH-2), 4.42 (1H, m, 1H of pipH-2), 4.19 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH3), 3.52 (1H, m, BzpipH-4), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 3.05-2.87 (2H, m, pipH-6), 2.04-1.99 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91 -1.67 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.46 (9H, s, C (CH3) 3); m / z: 587 [M + H] +. Syntheses of (cis) -e (trans) -tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate
[0548] [00548] For use in the synthesis of the various compounds described above, (cis) - and (trans) - tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate were prepared as described in the scheme below:
[0549] [00549] The compounds were evaluated for their ability to activate AMPK using an enzyme-linked immunosorbent assay. Reagents and procedures for measuring AMPK activation are well known, and AMPK activation assay kits are available on the market. EC50 values for AMPK activation for compounds 1-498 are shown in Table 2 below, where “A” is less than 0.5 μM; "B" is 0.5-1 μM; "C" is 1-5 μM; and “D” is 5-10 μM; and “E” is> 10 μM:

权利要求:
Claims (30)
[0001]
Compound, characterized by the fact that it has the structural formula
[0002]
Compound according to claim 1, characterized by the fact that it has the structural formula
[0003]
Compound according to claim 1 or claim 2, characterized in that x is 0.
[0004]
Compound according to claim 1, characterized by the fact that the ring system designated as “B” is
[0005]
Compound according to claim 1 or claim 3, characterized by the fact that it has the structural formula
[0006]
Compound according to any one of claims 1 to 3, characterized by the fact that it has the structural formula
[0007]
Compound according to any one of claims 1 to 3, characterized by the fact that it has the structural formula
[0008]
Compound according to any one of claims 1 to 3, characterized by the fact that it has the structural formula
[0009]
Compound according to any one of claims 1 to 8, characterized by the fact that each R3 is independently selected from - (C0-C3 alkyl) -NR8R9; each R4 is independently selected from - (C1-C3 alkyl) and -halogen, or two R4 on the same carbon are optionally combined to form oxo; on what each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl ) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and each R9 is independently selected from -H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) and -C (O) O- (C1-C4 alkyl).
[0010]
Compound according to any one of claims 1 to 9, characterized by the fact that the fraction
[0011]
Compound according to any one of claims 1 to 9, characterized by the fact that the fraction
[0012]
Compound according to any one of claims 1 to 3 and 9 to 11, characterized by the fact that the fraction
[0013]
Compound according to claim 12, characterized by the fact that R17 is phenyl.
[0014]
Compound according to any one of claims 1 to 12, characterized in that each R5 is independently selected from - (C1-C3 alkyl), - (C1-C3 haloalkyl), - (C0-C3 alkyl) -L-R7 , - (C0-C3 alkyl) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10 , -halogen, -N3, -SF5, -NO2 and -CN; on what each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl ) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and each R9 is independently selected from -H, - (C1-C4 alkyl), -C (O) - (C1-C4 alkyl) and -C (O) O- (C1-C4 alkyl).
[0015]
Compound according to any one of claims 1 to 14, characterized by the fact that R17 is aryl or heteroaryl substituted with 1, 2 or 3 substituents independently selected from - (C1-C3 alkyl), - (C1-C3 alkyl), - (C0-C3 alkyl) -L-R7, - (C0-C3 alkyl ) -NR8R9, - (C0-C3 alkyl) -OR10, - (C0-C3 alkyl) -C (O) R10, - (C0-C3 alkyl) -S (O) 0-2R10, -halogen, -NO2 and -CN; and on what each R7, R8 and R10 is independently selected from H, - (C1-C2 alkyl), - (C1-C2 haloalkyl), - (C0-C2 alkyl) -NR9 (C0-C2 alkyl), - (C0-C2 alkyl ) -C (O) - (C0-C2 alkyl) and - (C0-C2 alkyl) -S (O) 0-2- (C0-C2 alkyl), and each R9 is independently selected from -H, - (C1 -C4 alkyl), -C (O) - (C1-C4 alkyl) and -C (O) O- (C1-C4 alkyl) where aryl represents a radical of 6 to 13 carbon atoms; wherein heteroaryl represents a radical being an aromatic ring system containing at least one heteroatom and containing 3 to 9 carbon atoms.
[0016]
Compound according to any one of claims 1 to 15, characterized by the fact that R1 is H.
[0017]
Compound according to any one of claims 1 to 15, characterized in that w is 0.
[0018]
Compound according to claim 1, characterized by the fact that G is -CH2-, -C (O) -, or -S (O) 2-; R17 is phenyl or monocyclic heteroaryl; w is 0 or 1; J is absent, is -C (O) -, -NH-, -NHC (O) - or -C (O) NH-; the ring system designated as “B” is
[0019]
Compound according to claim 18, characterized by the fact that R17 is phenyl and the ring system designated "A" is phenyl.
[0020]
Compound according to claim 18 or claim 19, characterized in that Q is a single bond and G is CH2-.
[0021]
Compound according to any one of claims 18 to 20, characterized in that J is -C (O) -.
[0022]
Compound according to any one of claims 1, 10 and 11, characterized in that the compound is N - ((trans) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4 - (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide or a pharmaceutically acceptable salt thereof.
[0023]
Compound, characterized by the fact that it has the structural formula
[0024]
Compound according to claim 1, characterized by the fact that the compound is N - ((trans) -1 - (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - ((trans) -3-fluoro-1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - ((trans) -1- (4-cyano-3-fluorobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - (((3S, 4R) -3-fluoro-1 - (((5-methylisoxazol-3-yl) methyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbon) nicotinamide; N - (((3S, 4R) -3-fluoro-1 - (((2-methylthiazol-4-yl) methyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbon) nicotinamide; N - ((trans) -1 - (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4- (trifluoromethylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide; N - (((3R, 4R) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - (((3S, 4S) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - ((cis) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N - ((cis) -3-fluoro-1 - (4- (trifluoromethoxy) benzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; or a pharmaceutically acceptable salt thereof.
[0025]
Compound, characterized by the fact that it is N- (cis-1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide; 5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) -N- (cis-3-fluoropiperidin-4-yl) picolinamide; N- (cis-3-fluoro-1- (pyridin-4-ylmethyl) piperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide; N- (cis-1- (4-chlorobenzyl) -3-fluoropiperidin-4-yl) -5- (4- (4-fluorobenzyl) piperazine-1-carbonyl) picolinamide; N - ((trans) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -5- (4- (4- (methylsulfonyl) benzoyl) piperidine-1-carbonyl) picolinamide; N - ((trans) -3-fluoro-1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) -5- (4- (4- (methylsulfonyl) benzoyl) piperidine-1-carbonyl) picolinamide; N - ((trans) -1- (4-cyanobenzyl) -3-fluoropiperidin-4-yl) -5- (4- (4- (methylsulfonyl) phenoxy) piperidine-1-carbonyl) picolinamide; N - ((trans) -3-fluoro-1- (4- (trifluoromethoxy) benzyl) piperidin-4-yl) -5- (4- (4- (methylsulfonyl) phenoxy) piperidine-1-carbonyl) picolinamide; N- (1- (4-cyanobenzyl) piperidin-4-yl) -5 - ((trans) -4- (4-cyanophenoxy) -3-fluoropiperidine-1-carbonyl) picolinamide; N - ((((trans) -3-fluoro-1- (4- (pyrrolidin-1-yl) benzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide ; N - ((trans) -3-fluoro-1- (4-isopropoxybenzyl) piperidin-4-yl) -6- (4- (4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide; N- (1- (3-fluoro-4-methoxybenzyl) piperidin-4-yl) -6- (4- (4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) nicotinamide; or a pharmaceutically acceptable salt thereof.
[0026]
Compound according to claim 1, characterized by the fact that it has the structural formula
[0027]
Pharmaceutical composition, characterized by the fact that it comprises: at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.
[0028]
Use of a compound as defined in any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, or of a composition as defined in claim 27, characterized in that it is for preparing a medicament to activate the AMPK pathway.
[0029]
Use of a compound as defined in any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, or of a composition as defined in claim 27, characterized in that it is for preparing a medicament to treat or ameliorate a disorder in an individual, in which the disorder is selected from the group consisting of type II diabetes, atherosclerosis, exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonic epilepsy, Kearns-Sayre syndrome, Leigh syndrome, myopathy syndrome and mitochondrial encephalopathy, lactic acidosis, stroke (MELAS), stroke-like episodes, hypoxic states, angina pectoris, coronary ischemia and damage to organs secondary to coronary vessel occlusion, intermittent claudication, multi-infarction dementia, myocardial infarction , stroke, high altitude sickness, heart failure, including congestive heart failure, dystrophy Duchenne muscle, Becker muscular dystrophy, and Freidreich's ataxia.
[0030]
Use of a compound as defined in any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, or of a composition as defined in claim 27, characterized in that it is for preparing a medicament to increase metabolic efficiency, capacity fiber oxidation, endurance, aerobic workload, improving exercise efficiency, resistance to exercise, athletic performance or any combination of these in an individual in need.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-01-28| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-02-11| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-17| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2021-02-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-04-06| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/07/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US36892810P| true| 2010-07-29|2010-07-29|

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US61/368,928|2010-07-29|

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PCT/US2011/046019|WO2012016217A1|2010-07-29|2011-07-29|Ampk-activating heterocyclic compounds and methods for using the same|

---