Mitotic kinesin inhibitors and methods of use thereof

THE REPUBLIC OF POLAND (12) TRANSLATION OF THE EUROPEAN PATENT (19) PL (11) PL / EP 1809280

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Patent Office of the Republic of Poland (96) Date and number of the European patent application:

October 18, 2005 05819172.7 (97) The grant of the European patent was announced: September 7, 2011 European Patent Bulletin 2011/36 EP 1809280 B1 (13) T3 (51) Int.CI.

A61K 31/4245 (2006.01)

C07D 417/00 (2006.01)

C07D 413/00 (2006.01) (54) Title of the invention:

Lactotic kinesin inhibitors and methods of their use (30)

Priority:

2004-10-19 US 620048 P

17.10.2005 US 252232 (43) Application announced:

On July 25, 2007 in the European Patent Bulletin No. 2007/30 (45) The following was announced about the submission of the translation of the patent:

30.12.2011 News of the Patent Office 2011/12 (73) Authorized by the patent:

Array Biopharma, Inc., Boulder, US (72) Inventor (s):

JEREMY HANS, Boulder, US ELI M. WALLACE, Lyons, US QIAN ZHAO, Superior, US JOSEPH P. LYSSIKATOS, Superior, US TOM AICHER, Superior, US ELLEN LAIRD, Longmont, US

JOHN ROBINSON, Commerce City, US £ 2 SHELLEY ALLEN, Loveland, US

ABOUT

CM (74) Representative:

θ thing, pat. Sebastian Walkiewicz

CO LDS

Τ 'ŁAZEWSKI DEPO I WSPÓLNICY SP.K.

ABOUT.

III ul. Mysłowicka 15

2j 01-612 Warsaw

Attention:

Within nine months of the publication of the information on the grant of the European patent, any person may file an objection to the European Patent Office against the European patent granted. The objection must be made in the form of a written statement of reasons. It is considered brought only when the opposition fee has been paid (Art. 99 (1) of the Convention on the Grant of European Patents).

Ζ-8773/11

EP 1 809 280 Β1

Mitotic kinesin inhibitors and methods of their use

Background of the invention

[0001] Field of the Invention

The invention relates to novel inhibitors of mitotic kinesins, in particular the mitotic kinesin KSP, pharmaceutical compositions containing these inhibitors and methods for the preparation of these inhibitors. The compounds of the present invention are useful in treating diseases that can be treated by inhibiting mitosis, such as cell proliferative diseases, for example cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders, fungal infections and inflammations.

[0003] Description of the known art

[0004] Among the therapeutic agents used to treat cancer are the taxanes and vinca alkaloids, which act on microtubules. Microtubules are the essential structural elements of the mitotic spindle that are responsible for distributing replicated copies of the genome to each of the two daughter cells that result from cell division. It is believed that the disruption of the mitotic spindle by these drugs inhibits cancer cell division and causes cancer cell death. However, microtubules form other types of cellular structures that involve intracellular transport routes in nervous processes. Since drugs such as taxanes and vinca-alkaloids do not specifically target mitotic spindles, they have side effects that limit their applicability.

[0005] The improvement of the specificity of agents used to treat cancer is of particular interest, in part because of the improved therapeutic benefit that could be obtained if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in cancer treatment have been associated with the identification of therapeutic agents acting through novel mechanisms. Examples include not only the taxanes, but also the camptothecin class of topoisomerase I inhibitors. From both of these perspectives, mitotic kinesins are attractive targets for new anti-cancer agents.

[0006] Mitotic kinesins are enzymes essential for the assembly and function of the mitotic spindle, but are generally not part of other microtubule structures such as nerve processes. Mitotic kinesins play an important role during all phases of mitosis. These enzymes are "molecular motors" that convert the energy released by ATP hydrolysis into a mechanical force that directs movement in a specific direction of cellular charges along the microtubules. A catalytic domain sufficient for this task is a compact structure of about 340 amino acids. During mitosis, kinesins organize microtubules into bipolar structures, i.e. mitotic spindles. Kinesins mediate the movement of chromosomes along the spindle microtubules as well as structural changes in the mitotic spindle associated with specific phases of mitosis. Experimental disruption of mitotic kinesin function causes malformation or dysfunction of the mitotic spindle, often resulting in cell cycle arrest and cell death.

[0007] Among the identified mitotic kinesins is the kinesin spindle protein (KSP). KSP belongs to the evolutionarily conserved subfamily of kinesins directed to the plus-end of microtubule motors that assemble into bipolar homotetramers consisting of anti-parallel homodimers. During mitosis, KSP binds to the microtubules of the mitotic spindle. Microinjection of anti-KSP antibodies in human cells prevents separation of the spindle pole during prometaphase, resulting in an increase in monopolar spindles and causing mitosis to arrest and induce programmed cell death. KSP and the corresponding kinesins in other non-human organisms bind antiparallel microtubules and move them relative to each other, thereby forcing the spindle poles to burst. KSP may also mediate anaphase B in spindle extension and microtubule aggregation at the spindle pole.

[0008] Human KSP (also called HsEg5) has been described (Blangy, et al., Cell, 83: 1159-69 (1995); Whitehead, et al., Arthritis Rheum., 39: 1635-42 (1996); Galtio , et al., J. Cell BioL, 135: 339-414 (1996); Blangy, et al., J. Bio. Chem., 272: 19418-24 (1997); Blangy, et al., Cell Motil Cytoskeleton , 40: 174-82 (1998); Whitehead and Rattner, J. Cell Sci., 111: 2551-61 (1998); Kaiser, et al., JBC, 274: 18925-31 (1999); GenBank accession numbers: 85137, NM004523 and U37426), and a fragment of the KP gene (TRIP5) has been described (Lee, et al., Mol. Endocrinol., 9: 243-54 (1995); GenBank. Accession number L40372). Xenopus KSP (Eg5) homologues as well as Drosophilia K-LP61 F / KRP 130 have been described. Recently, small molecule inhibitors of KSP have been described: Mayer, et al., Science, 286: 971-4 (1999); Maliga, et al., Chemistry and Biology, 9: 989-96 (2002) Sakowicz, et al., Cancer Research 64: 3276-80 (2004); Yan, et al., J. Mol. Biol. 335: 547-554 (2004); Coleman, et al., Expert Opin. Ther. Patents 14 (12): 165,967 (2004); Cox, et al., Bioorg. Med Chem. Lett. 15: 2041-5 (2005); Gartner, et al., ChemBioChem 6: 1173-7 (2005); Bergnes, et al., Current Topics in Medicinal Chemistry 5: 127-45 (2005); and PCT Publication Nos. WO 00 / 130,768, WO 01/30768, WO 01/98278, WO 03 / 050,064, WO 03 / 050,122, WO 03 / 049,527, WO 03 / 049,679, WO 03 / 049,678, WO 03/051854, WO 03/39460 WO 03 / 079,973, WO 03 / 088,903, WO 03 / 094,839, WO 03 / 097,053, WO 03 / 099,211, WO 03 / 099,286, WO 03 / 103,575, WO 03 / 105,855, WO 03 / 106,426, WO 04 / 032,840, WO 04 / 034,879, WO 04 / 037,171, WO 04 / 039,774, WO 04 / 055.008, WO 04 / 058,148, WO 04 / 058,700, WO 04 / 064,741, WO 04/092147, WO 04/111023, WO 04/111024, WO ops / 035512, WO 05/017190, WO 05/018547 and WO 05/019206.

[0009] Mitotic kinesins are attractive targets for the discovery and development of new mitotic chemotherapeutic agents. Accordingly, it is an object of the present invention to provide compounds, methods and compositions capable of inhibiting the mitotic kinesin KSP.

Summary of the invention

[0010] The present invention relates to compounds that are useful in the treatment of diseases that can be treated by inhibiting mitosis. In particular, one aspect of the present invention relates to compounds and pharmaceutical compositions thereof that inhibit mitotic kinesins, in particular the mitotic kinesin KSP. Such compounds find use as therapeutic agents for diseases that can be treated by inhibiting the assembly and / or function of microtubule structures, including the mitotic spindle. In general, the invention relates to compounds as claimed in claim 1. 1.

<img file="PL1809280T3_D0002.tif" />

[0011] Thus, one aspect of the invention pertains to a compound of formula III

III

[0012] and solvates, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof, wherein R, R¹, Ar¹ and Ar² have the meaning defined here.

[0013] Another aspect of the invention pertains to a compound of formula IV

R

<img file="PL1809280T3_D0003.tif" />

IV

[0014] and solvates, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts and prodrugs thereof, wherein R, R^and, Ar¹, Ar² and R.^and, R^x and r^y have the meaning described in claim 9.

[0015] Methods for preparing the compounds of the formulas III-IV are also described.

[0016] In a further aspect the present invention relates to compounds that modulate mitotic spindle formation, including compounds of formulas III-IV and solvates thereof, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts and in vivo cleavable prodrugs.

In a further aspect, the present invention describes a method of treating diseases that can be treated by blocking or inhibiting mitosis in humans and animals which comprises administering to a warm blooded organism an effective amount of a compound of formula III-IV, or a solvate thereof, resolved enantiomer , a diastereomer, a racemic mixture, or a pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition containing such a compound. Examples of diseases that can be treated by administering the compounds of the present invention include, but are not limited to, abnormal or undesirable conditions of cell growth such as, but not limited to, cell proliferative diseases, e.g., cancer, hyperplasia, restenosis, hyperplasia, heart disease, immune disorders, infectious diseases, fungal or other eukaryotic infections, inflammatory diseases, arthritis, transplant rejection, inflammatory bowel disease, proliferation caused by medical procedures, including, but not limited to, surgery, angioplasty, and the like.

[0018] In a further aspect, there is described a method of inhibiting abnormal or undesired cell growth which comprises administering to said abnormal or undesired cells an effective amount of a compound of formula II-IV, or a solvate, resolved enantiomer, diastereomer, racemic or pharmaceutically acceptable mixture thereof. an acceptable salt or prodrug.

[0019] In a further aspect, the present document describes a method of inducing an inhibitory effect on mitotic kinesins which comprises administering to warm blooded organisms an effective amount of a compound of formula III-IV, or a solvate, resolved enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or prodrug thereof.

[0020] The invention also relates to pharmaceutical compositions comprising a compound of formula III-IV or a solvate, resolved enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or prodrug thereof.

[0021] The compounds of the invention can be advantageously used in combination with other known therapeutic agents. Accordingly, the present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I-IV or a solvate, resolved enantiomer, diastereomer, racemic mixture, or pharmaceutically acceptable salt or prodrug thereof, in combination with a second therapeutic agent.

[0022] In a further aspect, the present invention relates to the use of the compounds of the invention as a medicament for the treatment of diseases or conditions in mammals which can be treated by blocking or inhibiting mitosis. For example, in some aspects, the present invention relates to a use for treating a hyperproliferative disorder in mammals, comprising administering to said mammals one or more compounds of Formula III-IV, or solvates, resolved enantiomers, diastereomers, racemic mixtures, or pharmaceutically acceptable salts or prodrugs thereof, in an amount. effective for treating these diseases or disorders. In other aspects, the present invention relates to use for treating fungal or other eukaryotic infections in mammals, comprising administering to said mammals one or more compounds of Formula III-IV, or solvates, resolved enantiomers, diastereomers, racemic mixtures, or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat said infection.

An additional aspect of the invention is the use of a compound of Formulas III-IV for the manufacture of a medicament for treating or preventing diseases or conditions in mammals that can be treated by blocking or inhibiting mitosis.

[0024] The invention further relates to kits comprising one or more compounds of formula IIIIV. The kit can further comprise a second compound or a composition comprising a second pharmaceutical agent for treating a disease that can be treated by inhibiting mitosis. In some embodiments, the second agent is a compound having, for example, anti-hyperproliferative or antifungal activity.

[0025] Additional advantages and novel features of the invention are set forth later in the description and in part will become apparent to those skilled in the art from examination of the following description, or may be learned by practicing the invention. The advantages of the invention can be realized and achieved by the means, combinations, compositions and methods mentioned in particular in the appended claims. Detailed description of the invention

[0026] The compounds of the invention are useful in inhibiting mitotic kinesins and microtubule mediated processes such as mitotic spindle formation. Such compounds are useful as therapeutics for diseases that can be treated by the inhibition of mitosis. In general, one aspect of the invention pertains to compounds having the general formula III

R

<img file="PL1809280T3_D0004.tif" />

III

[0028] and its solvates, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof, wherein R, R¹, Ar¹ and Ar² have the meanings given below.

[0029] In some embodiments of compounds of formula III, Ar¹ is substituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. In special solutions, Ar¹ is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR^and, NO^andR^b, NO2, CN, C (= O) OR^and, alkyl and CF3.

[0030] In some embodiments of compounds of formula III, Ar² is substituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. In special embodiments, this Ar² is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR^and, NO^andR^b, NO₂, CN, C (= O) OH, alkyl and CF₃.

[0031] In some embodiments of compounds of formula III, R is Z-NR²R³ or Z-OH. In some embodiments, R.² and r³ are independently selected from the group consisting of H, alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C (= O) alkyl, amino acid, and dipeptide, these alkyl and cycloalkyl portions being optionally substituted. In some embodiments of compounds of Formula III, Z is substituted or unsubstituted alkylene. In some embodiments, Z is substituted or unsubstituted propylene.

[0032] In some embodiments, R.¹ is alkyl, cycloalkyl, heterocycloalkyl, O-alkyl, OR^and, aryl, heteroaryl, CR^b(= NOR^c) or C (= O) R^andwherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from OR^and, NO^andR^b, halogen, cycloalkyl, alkyl, aryl and CF3. In some embodiments, R.^and is alkyl, cycloalkyl, aryl, heteroaryl or CF3, said alkyl, cycloalkyl, aryl and heteroaryl being optionally substituted with one or more groups selected from OR^C., C (= O) R^C., alkyl or aryl.

[0033] In some embodiments, R.¹ stands for NO⁴R⁵. In some embodiments, R.⁴ and r⁵ are independently selected from H, alkyl, saturated or partially unsaturated cycloalkyl, and heteroaryl.

[0034] Another aspect of the present invention pertains to a compound of formula IV

R

<img file="PL1809280T3_D0005.tif" />

IV

[0035] and solvates, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof, wherein R, Ar¹ and Ar² have the meaning given above, a

[0036] R^x and r^y are independently of each other H, alkyl, saturated or partially unsaturated cycloalkyl or aryl, said alkyl, cycloalkyl and aryl being optionally substituted with one or more groups independently selected from oxo (with the proviso that the group is not substituted on said aryl radical) ), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -O (C = O) OR^d, -NR^bSO2R^d, -SO2NR^andR^b, -C (= O) R^and, C (= O) OR^and, -OC (= O) R^and, -OCH₂C (= O) OR^and, -NR^bC (= O) OR^d, -NR^bC (= O) R^and, -C (= O) NR^andR^b, -NR^andR^b, NR ° C (= O) NR^andR^b, -NR^cC (NCN) NO^andR^b, -OR^and, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclic substituent, and heterocyclylalkyl,

[0037] or R.^x and r^y together with the atom to which they are bonded form a saturated or partially unsaturated carbocyclic ring or a heterocyclic ring containing one or more heteroatoms independently selected from N, O and S, said carbocyclic and heterocyclic rings being optionally substituted with one or more groups independently selected among oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -O (C = O) OR^d, -NR^bSO2R^d, -SO2NR^andR^b, -C (= O) R^and, C (= O) OR^and, -OC (= O) R^and, -NR^bC (= O) OR^d, -NR^bC (= O) R^and, -C (= O) NR^andR^b, -NR^andR^b, -NR^cC (= O) NO⁸R^b, NO^cC (NCN) NO^andR^b, -OR^and, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, heterocycloalkyl, and heterocyclylalkyl;

[0038] and R.^and, R^b, R^c and r^d have the meaning given above,

[0039] or R.^and and r^x together with the atoms to which they are bonded form a saturated or partially unsaturated heterocyclic ring which may contain 1 to 3 further heteroatoms in addition to the oxygen to which this R^and is bonded selected from N, O and S, said heterocyclic ring being optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, - O (C = O) OR^h, -NR^fSO2R^h, -SO2NR^cR^f, C (= O) R °, -C (= O) OR °, -OC (= O) R °, -NR^fC (= O) OR^h, -NR^fC (= O) R^c, -C (= O) NR^cR^f, -NR ° R^f, NO^sC (= O) NO^cR^f, -NR^cC (NCN) NO^cR^f, -OR^C., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, and heterocyclylalkyl, wherein R^c, R^f, R^s and r^h have the meaning given above.

[0040] In some embodiments of the compound of Formula IV, at least one of the symbols R^x and r^y is not H. In some embodiments, R.^and is H or alkyl. In some embodiments, R.^xand r^and are alkyl.

[0041] In some embodiments of the compound of Formula IV, Ar¹ is a substituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. In some implementations, Ar¹ is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR^and, NO^andR^b, NO2, CN, C (= O) OR^and, alkyl and CF3.

[0042] In some embodiments of the compound of Formula IV, Ar² is a substituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. In some embodiments, this Ar² is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR^and, NO^andR^b, NO₂, CN, C (= O) OH, alkyl and CF₃.

[0043] In some embodiments of a compound of Formula IV, R is Z-NR R or Z-OH. In some embodiments, R.² and r³ are independently selected from the group consisting of H, alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C (= O) alkyl, amino acid, and dipeptide, said alkyl and cycloalkyl portions being optionally substituted. In some embodiments of the compound of Formula IV, Z is substituted or unsubstituted alkylene. In some embodiments, Z is substituted or unsubstituted propylene.

[0044] The term "alkyl" as used herein, means a saturated linear or branched chain monovalent hydrocarbon radical containing one to ten carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. Examples of alkyl radicals include C1-C12 hydrocarbyl groups such as methyl (Me, -CH₃), ethyl (Et, -CH₂CH₃), 1-propyl (n-Pr, n-propyl, -CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, CH (CH₃)₂), 1-butyl (n-Bu, n-butyl, -CH₂CH2CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, -CH₂CH (CH₃)₂), 2-butyl (s-Bu, s-butyl, -CH (CH₃) CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH₃)₃), 1-pentyl (n-pentyl, -CH2CH₂CH2CH₂CH₃), 2-pentyl (-CH (CH₃) CH₂CH₂CH₃), 3-pentyl (-CH (CH₂CH₃)₂), 2-methyl-2-butyl (C (CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH (CH₃) CH (CH₃)₂), 3-methyl-1-butyl (-CH₂CH₂CH (CH₃)₂), 2-methyl-1-butyl (-CH₂CH (CH₃) CH₂CH₃), 1-hexyl (-CH₂CH2CH2CH2CH₂CH₃), 2-hexyl (CH (CH₃) CH₂CH₂CH₂CH₃), 3-hexyl (-CH (CH₂CH₃) (CH₂CH₂CH₃)), 2-methyl-2-pentyl (C (CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH (CH₃) CH (CH₃) CH₂CH₃), 4-methyl-2-pentyl (CH (CH₃) CH₂CH (CH₃)₂), 3-methyl-3-pentyl (-C (CH₃) (CH₂CH₃)₂), 2-methyl-3-pentyl (CH (CH₂CH₃) CH (CH₃)₂), 2,3-dimethyl-2-butyl (-C (CH₃)₂CH (CH₃)₂), 3,3-dimethyl-2-butyl (CH (CH₃) C (CH₃)₃, 1-heptyl and 1-octyl.

[0045] The term "alkylene" as used herein denotes a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms, eg, methylene (-CH₂-), 1,2-ethylene (CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-) and the like, optionally independently substituted with one or more substituents described herein.

[0046] The term alkenyl means a linear or branched chain monovalent hydrocarbon radical containing two to 10 carbon atoms and at least one double bond and includes, but is not limited to, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3 -enyl, 1-hex-5-enyl and the like, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals exhibiting cis and trans orientation, or alternatively the E and Z orientations. The term alkenyl includes allyl.

[0047] The term allyl means a radical having the formula RC = CHCHR wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which allyl may be optionally substituted with one or more substituents described herein.

[0048] The term alkenylene means a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one double bond, wherein the alkenylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethenylene (-CH = CH), propenylene (-CH = CHCH)₂-) and the like.

[0049] The term alkynyl denotes a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyn-2-yl and the like, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.

[0050] The term alkynylene denotes a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein the alkynylene radical may be optionally substituted independently with one or more substituents described herein. Alkynylene radicals include, but are not limited to, acetylene (-ChC-), propargyl (-CH₂ChC-) and 4-pentynyl (-ΟΗ₂ΟΗ₂ΟΗ₂ΟξΟ-).

[0051] The terms cycloalkyl, carbocycle and carbocyclyl are used interchangeably herein and mean a saturated or partially unsaturated (ie containing one or more double and / or triple bonds within a carbocycle) cyclic hydrocarbon radical containing from three to twelve carbon atoms. The term cycloalkyl includes monocyclic and polycyclic (e.g. bicyclic and tricyclic) cycloalkyl systems, the polycyclic systems optionally comprising a saturated or partially unsaturated cycloalkyl fused with a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Bicyclic carbocycles contain 7 to 12 ring atoms, e.g., bicyclo [4.5], [5.5], [5.6] or [6.6] systems, or bridge systems such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. Cycloalkyl may be optionally substituted independently at one or more substitutable positions with one or more substituents described herein. Such cycloalkyl groups may be optionally substituted with, for example, one or more groups independently selected from the group consisting of C._rC.₆ alkyl, C._rC.₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- (C._rC.₆) -alkylamino, di- (C_rC.₆) -alkylamino, C.₂-C₆ alkenyl, C.₂-C₆ alkynyl, C._rC.₆ haloalkyl, C._rC.₆ haloalkoxy, aminoTCr C₆) -alkyl, monoTCrCi-alkylaminoTCrCe-alkyl and di- (C.₁-C₆) -alkylamino- (C₁-C₆) -alkyl.

[0052] The term heteroalkyl denotes a saturated linear or branched chain monovalent hydrocarbon radical of one to twelve carbon atoms wherein at least one of the carbon atoms is replaced by a heteroatom selected from N, O or S, and the radical may be a radical a carbon or heteroatom radical (ie, the heteroatom may be in the middle or at the end of the radical). The heteroalkyl radical may be optionally substituted independently with one or more substituents described herein. The term heteroalkyl includes alkoxy and heteroalkoxy groups.

[0053] The terms heterocycloalkyl, heterocycle and heterocyclic substituent are used interchangeably herein and mean a saturated or partially unsaturated (i.e. containing one or more double and / or triple bonds within the carbocycle) carbocyclic radical of 3 to 8 ring atoms in which at least one ring atom is selected from nitrogen, oxygen and sulfur and the remaining ring atoms are C, wherein one or more ring atoms may be optionally substituted independently with one or more substituents described below. This radical may be a carbon radical or a heteroatom radical. The term heterocycle includes a heterocycloalkoxy group. Heterocycloalkyl also includes radicals in which heterocyclic radicals are fused with a carbocyclic, heterocyclic, aromatic or heteroaromatic ring. Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholino, thiomorpholino, thioxanyl, piperazinyl, ocetyl-thienyl, homopethynylpethynylpethynylpethynylpthienyl, , thiazepinyl, 2-pyrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithanyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3Hinridinyl, and N-chin-indolyl and N-chinidylomyl Spiro moieties are also included within this definition. The heterocycle can be C-linked or N-linked where possible. For example, a group derived from pyrrole may be pyr-1-yl (N-linked) or pyr-3-yl (C-linked). Further, the group derived from imidazole may be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked). An example of a heterocyclic group in which the 2 ring carbon atoms are substituted with oxo (= O) groups is 1,1-dioxothiomorpholinyl. Heterocyclic groups herein are unsubstituted or substituted at one or more appropriate positions with different groups.

[0054] By way of example and not limitation, carbon-bonded heterocycles are bonded to the 2, 3, 4, 5 or 6 position of the pyridine, to the 3, 4, 5 or 6 position of the pyridazines, to the 2, 4, 5 or 6 position of the pyrimidine, at position 2, 3, 5 or 6 of pyrazine, at position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, at position 2, 4 or 5 of oxazole, imidazole or thiazole, at position 3, 4 or 5 isoxazole, pyrazole or isothiazole at position 2 or 3 of aziridine at position 2, 3 or 4 of azetidines, at the 2, 3, 4, 5, 6, 7 or 8 position of the quinoline or at the 1, 3, 4, 5, 6, 7 or 8 position of the isoquinoline. Further examples of carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, -pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

[0055] By way of example and not limitation, nitrogen bonded heterocycles are bonded at the 1-position of aziridines, azetidines, pyrroles, pyrrolidines, 2-pyrrolines, 3-pyrrolines, imidazoles, imidazolidines, 2-imidazolines, 3-imidazolines, pyrazole, pyrazolines, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position isoindole or isoindoline, 4-position of morpholine and 9-position of carbazole or β-carboline. Still more typically nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrryl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0056] The term aryl denotes a monovalent aromatic carbocyclic radical having one ring (e.g. phenyl) or several fused rings wherein at least one is aromatic (e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl etc.) which is optionally substituted independently with one or more substituents described herein.

[0057] The term heteroaryl denotes a monovalent aromatic radical of 5-, 6- or 7-membered rings and includes fused ring systems (at least one of them is aromatic) of 5-10 atoms containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyridinyl, quinolinyl, isoquinolyl, indolylinyl, indolylinyl, indolylinyl, indolylinyl, indolylinyl phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Spiro moieties also fall within this definition. Heteroaryl groups are optionally substituted independently with one or more substituents described herein.

[0058] The term "halogen" denotes fluorine, bromine, chlorine and iodine.

[0059] The term "arylalkyl" means an alkyl group (as defined above) substituted with one or more aryl groups (also as defined above). Examples include, but are not limited to, aryl C 1-6 alkyl groups such as benzyl, phenylethyl and the like. The aralkyl may be optionally substituted independently with one or more substituents described herein.

[0060] The term heteroarylalkyl means an alkyl group (as defined above) substituted with a heteroaryl group (also as defined above). Examples include, but are not limited to, 5- or 6-membered heteroaryl C 1-6 alkyl groups such as oxazolylmethyl, pyridylethyl and the like. Heteroarylalkyl may be optionally substituted independently with one or more substituents described herein.

[0061] The term heterocyclylalkyl means an alkyl group (as defined above) substituted with a heterocyclic substituent (also as defined above). Examples include, but are not limited to, 5- or 6-membered heterocyclyl C1-4alkyl groups such as tetrahydropyranylmethyl. Heterocyclylalkyl may be optionally substituted independently with one or more substituents described herein.

[0062] The term cycloalkylalkyl means an alkyl group (as defined above) substituted with a cycloalkyl group (also as defined above). Examples include 5- or 6-membered cycloalkyl-C 1-6 alkyl groups such as cyclopropylmethyl. The cycloalkylalkyl may be optionally substituted independently with one or more substituents described herein.

[0063] The term "amino acid" includes natural amino acid moieties (eg. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val) in D or L form, as well as unnatural amino acids (such as, but not limited to, phosphoserine, phosphotreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydro-isoquinohydro -3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, betaalanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, parabenzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine, sulfone and tertbutylglycine). The amino acid may be linked to the rest of the compound of formula III-IV via the carboxyl terminus, the amino terminus, or any other preferred point of attachment such as, for example, via the sulfur of cysteine. In a preferred embodiment, the amino acid is linked to the remainder of the compound of Formula II-IV via the carboxyl terminus.

[0064] In general, the various moieties or functional groups of the compounds of formula III-IV may be optionally and independently substituted with one or more substituents. Examples of suitable substituents for the purposes of the present invention include, but are not limited to, oxo, halogen, cyano, nitro, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NRSO₂R ', SO₂NR'R, -C (= O) R ', -C (= O) OR', -OC (= O) R ', -NRC (= O) OR', -NRC (= O) R ', - C (= O) NR'R, -NR'R, NR'C (= O) N'R, -OR ', alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl and heterocyclylalkyl wherein R ', R and R' are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl.

[0065] It is understood that when two or more radicals are used in sequence to define a substituent attached to a structure, the first radical mentioned is considered to be the final radical and the last named radical is considered to be bound to the given structure. Thus, for example, an arylalkyl radical is bonded to a given structure via an alkyl group.

[0066] The compounds of the present invention may contain one or more asymmetric centers; such compounds can therefore be prepared as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, mixtures of diastereomers, racemic mixtures or other of these compounds. Accordingly, the present invention includes all such isomers, including diastereomeric mixtures, pure diastereomers, and pure enantiomers of the compounds of formulas III-IV.

[0067] The term "enantiomer" means two stereoisomers of a compound that are non-superimposable mirror images of one another. The term diastereomer denotes a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, optical properties, and reactivities.

[0068] Compounds of the present invention may also exist in various tautomeric forms and all such forms are included within the scope of the invention. The term tautomer or tautomeric form denotes structural isomers of different energies that are internally convertible due to a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions due to proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions due to the reorganization of some binding electrons.

[0069] In structures depicted herein, when the stereochemistry of a given chiral atom is not specified, any stereoisomers are contemplated and are considered to be included in the compounds of the invention. When the stereochemistry is defined by a solid wedge or a distribution line defining a given configuration, then the stereoisomertene is so specified and defined.

In addition to the compounds of formulas III-IV, the invention also includes solvates, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts of such compounds. The term "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients contained in the formulation and / or with the mammals being treated.

[0071] The term "solvate" means an assembly of a molecule with one or more solvent molecules.

[0072] "Pharmaceutically acceptable prodrug" means a compound that can be converted under physiological conditions or by solvolysis into the specified compound or into a pharmaceutically acceptable salt of such compound. Prodrugs include compounds in which the amino acid moiety or polypeptide chain of two or more (e.g. two, three, or four) amino acid moieties are covalently linked via an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of the present invention. The amino acid moieties include, but are not limited to, the 20 naturally occurring amino acids commonly denoted by three-letter symbols, and also include phosphoserine, phosphotreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid. statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gammaaminobutyric acid, cyrtulin, homocysteine, homoserine, methylalanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine, sulfone and tert-butylglycine. Preferred examples of prodrugs of the present invention include a compound of formula III-IV covalently linked to a phosphate moiety or to a valine moiety.

[0073] Further types of prodrugs are also within the scope. For example, free carboxyl groups can be derivatized as amides or alkyl esters. As another example, compounds of the present invention containing free hydroxyl groups can be derivatized as prodrugs by converting the hydroxyl group into groups such as, but not limited to, phosphate ester, hemisuccinate, dimethylaminoacetate or phosphoryloxymethyloxycarbonyl groups, as reported in Advanced Drug Delivery Reviews, 1996 19, 115. Also included are hydroxyl and amino carbamate prodrugs, and carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxyl groups. Also included are derivatives of hydroxyl groups in the form of (acyloxy) methyl and (acyloxy) ethyl ethers, in which the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amino, and carboxylic acid functions, or acyl is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. More specific examples relate to the replacement of a hydrogen atom of an alcohol group with a group such as (C._rC.₆) -alkanoyloxymethyl, 1 ((C1 -C6-alkanoyloxy-ethyl, 1-methyl-1-4C8-alkanoyloxy-ethyl, (C1 -C6-alkoxycarbonyloxymethyl, N- (C_rC.₆) -alkoxycarbonylaminomethyl, succinoyl, (C_rC.₆) -alkanoyl, α-amino- (C_rC.₄) -alkanoyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P (O) (OH)₂, -Ρ (Ο) (Ο (Ο_ΓC.₆) alkyl)₂ or a glycosyl group (moiety obtained by removing the hydroxyl group from the hemiacetal form of the carbohydrate).

[0074] Free amines of the compounds of the present invention can also be derivatized as amides, sulfonamides, or phosphonamides. All of these prodrug moieties can include groups including, but not limited to, ether, amine, and carboxylic acid functions. For example, a prodrug can be obtained by replacing a hydrogen atom in an amino group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl, where R and R 'are each independently (Ci-Cio) -alkyl,₃-C₇) -cycloalkyl, benzyl, or R-carbonyl is natural α-aminoacyl or natural α-aminoacyl natural α-aminoacyl, -C (OH) C (O) OY, where Y is H, (C1-CJ-alkyl or benzyl, - CiOYojY ^ where Y_about is (C1-C6-alkyl and Y₁ means (Ci-C₆) alkyl, carboxy- (C._rC.₆) -alkyl, amino- (C_rC.₄) -alkyl or mono-N- or di-N, N- (C._rC.₆) -alkylaminoalkyl, C (Y₂) Y₃where Y₂ is H or methyl and Y₃ is mono-N- or di-N, N- (C._rC.₆) -alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

For further examples of prodrug derivatives see for example a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. . (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 Design and Application of Prodrugs, by H. Bundgaard pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and e) N. Kakey, et al., Chem. Pharm. Bull., 32: 692 (1984), each of which is specifically incorporated herein by reference. Prodrugs of the compounds can be identified using routine techniques known in the art.

[0076] The term "pharmaceutically acceptable salt", unless otherwise indicated, means salts which retain the biological effectiveness of the free acids and bases of the specific compound and which are not biologically or otherwise undesirable. The compound of the invention may possess sufficiently acidic, sufficient basic, or both functional groups and thus reacts with a variety of inorganic or organic bases or acids to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates (VI), metabisulfates, bisulfates (VI), sulfates (IV), bisulfates (IV), phosphates, monohydrophosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrate, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberans, sebacates, fumarates, maleates, butyno-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, sulfates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrate, citrates, lactates, γ-hydroxybutyrate, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. Since a single compound of the present invention may contain more than one acidic or basic group, the compounds of the present invention may contain mono, di or tri-salts in a single compound.

[0077] When the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example by treating the free base with an acidic compound, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid or the like.

[0078] When the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method available, for example, by treating the free acid with an inorganic or organic base. Examples of suitable inorganic salts include those formed with alkali metals and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Examples of salts with suitable organic bases include, for example, ammonium, dibenzyl ammonium, benzyl ammonium, 2-hydroxyethyl ammonium, bis- (2-hydroxyethyl) ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like salts. Other salts of the acidic moieties may include, for example, those formed with procaine, quinine, and N-methylglucosamine, as well as salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine, and arginine.

[0079] The present invention also includes isotopically-labeled compounds of the present invention which are identical to the compounds described herein, but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. All isotopes of a given atom or element as set forth are contemplated within the scope of the compounds of the invention and their uses. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H. ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵ABOUT, ¹⁷ABOUT, ¹⁸ABOUT, ³²P, ³³P, ³³S, ¹⁸F. ³⁶CI, ¹²³li ¹²⁵l. Certain isotopically-labeled compounds of the present invention (eg, H and C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. Tritylated (i.e., H) and carbon-14 (i.e. C) labeled isotopes are particularly preferred for their ease of preparation and detection. In addition, substitution by heavier isotopes such as deuterium (ie, H) may confer certain therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and thus may be beneficial in some circumstances. Positron emitting isotopes such as¹⁵ABOUT, ¹³N, ¹¹C i ¹⁸F are suitable for use in positron emission tomography (PET) studies to study the area of ​​substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by the following procedures analogous to those shown in the Schemes and / or Examples below, replacing the isotopically labeled reagent with the non-isotopically labeled reagent.

Also within the scope of the present invention are metabolites of compounds of formulas III-IV. A "metabolite" is a pharmacologically active product produced by metabolism in the body from a specific compound or its salt. Metabolites can be obtained, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of compounds of Formulas III-IV, including those produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain its metabolic product.

[0081] Metabolites are typically identified by generating radiolabeled (e.g., C or H) isotopes of a compound of the invention, parenterally administering them at a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as a rat, mouse, guinea pig. , a monkey, or a human, allowing sufficient time for metabolism to occur (usually about 30 seconds to 30 hours) and isolating the conversion products from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies capable of binding epitopes that persist in the metabolite). Structure of metabolites is determined by conventional means, e.g. by MS, LC / MS or NMR analysis. In general, analyzes of metabolites are performed in the same manner as conventional drug metabolism studies known to those skilled in the art. Metabolites, as long as they are not otherwise found in vivo, lend themselves to diagnostic assays for therapeutic dosing of the compounds of the invention.

[0082] The compounds of the invention can be prepared using the reaction routes and synthesis schemes as described below, using techniques available in the art, using starting materials that are readily available or can be prepared using methods known in the art. An explanation of the preparation of some compounds is provided in the following Schemes I-III.

NH₂NHBoc *

Ąr¹COOH

ABOUT_v

Ar¹ --------- BocHNHN

1-2

ABOUT_xAr¹

H.₂NHN

1-3

<img file="PL1809280T3_D0006.tif" />

Scheme I

[0083] Scheme I illustrates the preparation of compounds of formula 1-6. Acid 1-1 can be coupled to tert-butyl carbazate using standard coupling methods including, but not limited to, EDCI / HOBt, PyBOP, or DIC, to afford intermediate I-2. Removal of the tert-butoxycarbonyl (Boc) group from I-2 can be accomplished by treatment with a variety of acids including, but not limited to, TFA and HCl / dioxane to afford the acid hydrazide I-3. I-3 can then be condensed with ketone I-4 to give intermediate I-5 using various acid catalysts. In one embodiment, compounds I-3 and I-4 are combined in ethanol with acetic acid and heated to an elevated temperature (95 ° C) to provide compound I-5. Oxadiazolines I-6 can be prepared by combining I-5 with the appropriate anhydride or acid chloride or carboxylic acid in the presence of a standard coupling agent. For example, oxadiazoline I-6 can be prepared by treatment with an excess of anhydride at elevated temperature in a suitable organic solvent such as DCE. Alternatively, by treatment of I-5 with an acid chloride and a suitable base such as pyridine or Et₃N, in various organic solvents such as DCM or DCE at room temperature gives oxadiazoline I-6. Alternatively, I-6 can be prepared by coupling with anhydrides, or by treating I-5 with the appropriate carboxylic acid and AC2O in DCE at elevated temperature (80 ° C). Oxadiazoline I-6 can be obtained by treatment of I-5 with a carboxylic acid and an amide-coupling reagent, including but not limited to EDCI / HOBT or diethyl cyanophosphonate, and a suitable base, Et₃N or DIEA, in a suitable organic solvent such as DCM, DCE, DMF, THF, or a mixture of solvents at room temperature or above. In some embodiments, this coupling is performed with diethyl cyanophosphonate and TEA in DCE at elevated temperature (80 ° C) to afford I-6.

<img file="PL1809280T3_D0007.tif" />

11-1

<img file="PL1809280T3_D0008.tif" />

Scheme II

[0084] Scheme II illustrates the preparation of the thiodiazolines of formulas 11-3, 11-4, 11-5, 11-6 and 11-7. The thiohydrazide 11-1 (Takasugi, JJ; Buckwalter, BL, EP Patent No. 1004241) can be condensed with a ketone II-2 in a suitable organic solvent such as ethanol to provide the thiodiazoline II-3. In some embodiments, the condensation may be catalyzed with acetic acid. Thiodiazoline II-3 can be functionalized to II-4 by standard coupling methods including, but not limited to, EDCI / HOBt, PyBOP, HATU or DIC and the appropriate carboxylic acid. Alternatively, compound II-4 can be prepared by treating II-3 with the appropriate acid chloride and amine base in a suitable organic solvent such as THF. A compound of formula II-5 can be prepared by reacting a compound II-3 with the appropriate carbamyl chloride in the presence of an amine base. Alternatively, a compound of formula II-5 can be prepared by treating a compound of formula II-3 with an appropriate isocyanate in a suitable organic solvent such as THF. Another method for producing compound II-5 is that the appropriate amine is carbonylated with a reagent such as, but not limited to, triphosgene, diphosgene, phosgene, or carbonyldiimidazole, followed by treatment with II-3. In some embodiments, the amine can be treated with triphosgene, Et₃N and a catalytic amount of DMAP followed by II-3 to give II-5. Similarly, compounds of formula II-6 can be prepared by treating II-3 with a chloroformate in the presence of an amine base. Chloroformates can be prepared by reacting alcohols with a carbonylating agent as described above. Alternatively, compounds of formulas II-5, II-6 and II-7 can be prepared by treating II-3 with carbonyldiimidazole followed by addition of MeI to obtain a stable methylimidazolium iodide salt. By adding an amine, alcohol, hydroxylamine or alkoxylamine in the presence of Et₃N to methylimidazolium iodide gives the analogs of formulas II-5, II-6 and II-7, respectively. Derivatives of formulas II-5, II-6 and II-7 can be prepared from the intermediate 4-nitrophenyl carboxylate. Thiadiazoline

11-3 can be treated with 4-nitrophenyl chloroformate in the presence of a suitable base such as DIEA or Et₃N in a suitable organic solvent such as DCE or DCM at room temperature. By adding an amine, alcohol, hydroxylamine or alkoxylamine in the presence of a suitable base such as DIEA or Et₃N, to 4-nitrophenyl carboxylate in a suitable organic solvent such as DCE or THF at elevated temperature gives the analogs of formulas 11-5, 11-6 and 11-7, respectively.

[0085] In the above schemes, R, R¹, Ar¹, Ar² may contain functional groups that require protection in the described reaction sequences. The choice of protecting group and the conditions for deprotection depend on the particular functional group and are known to those skilled in the art. Examples of the use of protecting groups are described in Scheme III. These examples are representative only and do not limit the scope of the invention in any way.

<img file="PL1809280T3_D0009.tif" />

R¹

2NHBOC

<img file="PL1809280T3_D0010.tif" />

R 'llt-2

<img file="PL1809280T3_D0011.tif" />

111-5 and h-6

Scheme III

[0086] Scheme III shows how to prepare compounds of formulas 111-4, 111-5 and 111-6. Compounds 111-1 and III-2 can be prepared as described in Schemes I and II using the appropriate ketone containing an amino group either blocked as an azide or protected as a t-butyl carbamate. Amine III-3 can be prepared from azide 111-1 by a variety of methods including, but not limited to, the Staudinger reaction using Ph₃P / water and hydrogenation in the presence of Pd / C under a pressure of 1 atm H₂. Amine III-3 can also be prepared from t-butyl carbamate III-2 by standard acidic deprotection conditions including, but not limited to, TFA in DCM, HCl in a suitable organic solvent such as dioxane or diethyl ether, and neat formic acid . The unblocked amine III-3 can then be functionalized. Derivatives III-4 in which R.² and r³ are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl, can be prepared using standard reductive amination conditions. Such conditions include, but are not limited to, treating amine III-3 with an appropriate aldehyde or ketone in the presence of a dehydrating agent such as MgSO₄, and then reduction with NaBH₄, Na (OA_c) 3BH or NaCNBH₃ in a suitable organic solvent such as DCM, DCE, acetonitrile, or THF. Alternatively, amine 111-3 can be treated with an appropriate aldehyde or ketone in the presence of acetic acid and a reducing agent such as Na (OAC)₃BH or NaCNBH₃ in a suitable organic solvent such as DCM, DCE, acetonitrile, or THF. In some embodiments, 111-3 and the appropriate aldehyde or ketone are combined in acetonitrile and stirred for 1 hour. Then acetic acid and Na (OAc) are added₃BH and the reaction mixture is heated to elevated temperature (45 ° C) to afford III-4. III4 analogs in which R.² or R³ is -C (= O) R⁶, -SO2R⁶, - C (= O) NR⁴R⁵, -SO2NR⁴R⁵, amino acid or polypeptide can be produced by standard methods known to those skilled in the art. These methods include, but are not limited to, treating amine III-3 with acid chloride, sulfamoyl chloride, sulfonyl chloride, or an isocyanate in the presence or absence of a tertiary amine base, and treatment of III-3 with a carboxylic acid, amino acid, or polypeptide in the presence of standard coupling agents including, but not limited to throttling, EDCI / HOBt, PyBOP, HATU or DIC. Derivatives of formula III-5 can also be prepared by treating III-2 with a base such as NaH, KH, LiHMDS, NaHMDS, KHMDS or other suitable bases and a suitable alkylating agent which may include, but is not limited to, alkyl halides (not ) substituted benzyl halides, (un) substituted allyl halides, (un) substituted propargyl halides, sulfonate esters and sulfate esters in a suitable solvent such as DMF or THF to afford III-5. III-6 can be prepared from III-5 by standard acidic deprotection conditions including, but not limited to, TFA in DCM, HCl in a suitable organic solvent such as dioxane or diethyl ether, and neat formic acid. In some embodiments, III-2 is treated with NaH in DMF followed by iodomethane to afford III-5 where R is methyl. Removal of BOC groups can be performed, for example, with TFA in DCM to afford III-6. Alternatively, 111-6 can be prepared from III-3 by treatment with a suitable alkylating agent and a suitable base which may include, but is not limited to, a tertiary amine, K₂WHAT₃, Na₂WHAT₃, Cs₂WHAT₃ or CsOH in a suitable solvent such as acetonitrile, DMF or THF to afford III-6.

[0087] In the synthetic methods for preparing compounds of Formula III-IV, it may be advantageous to separate the reaction products from one another and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of uniformity by known techniques. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography can involve a variety of methods such as, for example, reverse phase and normal phase; size (grain) shutdown; ion exchange; methods and instrumentation for high, medium and low pressure liquid chromatography; small-scale analysis; simulated moving bed (SMB) and preparative thin or thick layer chromatography as well as small scale thin layer and flash chromatography techniques.

[0088] Another class of separation methods involves treating the reaction mixture with a reagent selected to bind or otherwise separate a desired product, unreacted starting material, reaction by-products, or the like. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents may be acids for basic substances, bases for acid substances, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction (LIX) reagents or the like.

[0089] The choice of suitable separation methods depends on the nature of the substance in question. For example, the boiling point and molecular weight in the case of distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of substances in acidic and basic media in multiphase extraction, and the like. One skilled in the art can select the most appropriate techniques to obtain the desired separation.

[0090] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g. a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. by hydrolysis) the individual diastereomers into the corresponding pure enantiomers. Also, certain compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered part of the invention. Enantiomers can also be separated using a chiral HPLC column.

[0091] A particular stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer, may be obtained by resolving a racemic mixture using a method such as obtaining diastereomers with optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds, John Wiley &amp; Sons, Inc., New York, 1994; Lochmuller, CH, J. Chromatogr., (1975), 113 (3): 283-302). Racemic mixtures of chiral compounds of the invention may be separated and isolated by any suitable method, such as: (1) formation of ionic, diastereomeric salts with chiral compounds and resolution by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatization reagents, separation of diastereomers and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993). [0092] In method (1), diastereomeric salts can be prepared by reacting enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine) and the like with asymmetric compounds containing an acid functional group such as carboxylic acid and sulfonic acid. Diastereomeric salts can be introduced into separation by either fractionated crystallization or ion chromatography. The addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid, is used to separate the optical isomers of the amine compounds to give diastereomeric salts.

Alternatively, using method (2), the substrate to be separated is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. Stereochemistry of Organic Compounds, John Wiley &amp; Sons, Inc., 1994, p. 322). Diastereomeric compounds can be obtained by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents such as menthyl derivatives followed by diastereomer separation and hydrolysis to provide the pure or enriched enantiomer. Optical purity is determined by the formation of chiral esters such as the menthyl ester, e.g. (-) - menthyl chloroformate, in the presence of a base, or Mosher's ester, α-methoxy-α (trifluoromethyl) -phenyl acetate (Jacob III. J. Org. Chem., (1982) 47: 4165), racemic mixture and spectral analysis ¹H NMR for the presence of two atropisomeric enantiomers or diastereomers. The stable diastereomers of the atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography according to the separation methods of atropisomeric naphthyl isoquinolines (WO 96/15111). By method (3), the racemic mixture of the two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) WJ Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513: 375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0094] The compounds of the invention find use in various fields of use. According to certain embodiments, the present invention relates to methods of blocking or inhibiting mitosis by administering an effective amount of a compound of Formula III-IV. It is known to those skilled in the art that mitosis can be modified in various ways; and thus, mitosis can be influenced by increasing or decreasing the activity of a component in the mitotic pathway. In other words, mitosis can be attacked (e.g. disrupted) by disturbing the balance by inhibiting or activating certain components using the compounds of the present invention, for example by modulating spindle function or blocking mitotic kinesins. Similar suggestions can be used to modify meiosis.

[0095] In certain embodiments, compounds of the invention can be used to modulate mitotic spindle formation, resulting in prolonged mitotic cell cycle arrest. By "modulating" is meant a change in mitotic spindle formation by increasing and decreasing spindle formation. By the term "mitotic spindle formation" is meant here the organization of microtubules into bipolar structures by means of mitotic kinesins. By the term "mitotic spindle dysfunction" herein is meant mitotic arrest and formation of a monopolar spindle.

[0096] In certain embodiments, the compounds of the invention can be used to bind and / or modulate the activity of mitotic kinesins. In one embodiment, the mitotic kinesin is a member of the bimC subfamily of the mitotic kinesins as described in US Patent No. 6,284,480, incorporated herein by reference. In another embodiment, the mitotic kinesin is human KSP, although the activity of mitotic kinesins from other organisms can also be modulated with the compounds of the invention. In this context, modulating means increasing or decreasing the separation of the spindle pole, causing distortion, i.e. flattening, of the mitotic spindle pole, or otherwise causing morphological disturbance of the mitotic spindle. Also included within the definition of KSP for this purpose are variants and / or fragments of KSP. Furthermore, other mitotic kinesins can be inhibited with the compounds of the present invention.

[0097] In some embodiments, the compounds of the invention can be used to treat abnormal or undesirable conditions of cell growth such as, but not limited to, cell proliferative diseases, e.g., cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders, infectious diseases, infections fungal or other eukaryotic diseases, inflammatory diseases, arthritis, transplant rejection, inflammatory bowel disease, proliferation caused by medical procedures, including, but not limited to, surgery, angioplasty and the like, by administering a therapeutically effective amount of a compound of formula III-IV, or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

[0098] The terms "abnormal cell growth" and "hyperproliferative disorders" are used interchangeably in this application and, unless otherwise stated, mean cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Examples of disease states associated with abnormal cell growth include, but are not limited to, cancer, autoimmune diseases, arthritis, transplant rejection, inflammatory bowel disease, or medical treatment induced proliferation.

[0099] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a given disease, condition, or disorder, (ii) reduces, ameliorates or removes one or more of the symptoms of the disease, condition, or disorder. or disorder, or (iii) prevents or delays the occurrence of one or more symptoms of a given disease, disease state, or disorder described herein. In cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow to some extent the development and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow to some extent the development and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or relieve to some extent one or more symptoms associated with cancer. Since the drug may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by estimating disease development time (TTP) and / or determining the magnitude of response (RR).

[0100] It is believed that in some cases the cells are not in a hyper- or hypoproliferative (abnormal) state, but still require treatment. For example, during wound healing, cells may proliferate "normally" but it is desirable to increase proliferation. Similarly, as discussed above, in the agricultural field, cells may be in a "normal" state, but modulating proliferation may be desirable to increase yield by directly increasing crop growth, or by inhibiting plant or organism growth that adversely affects the crop. Thus, in certain embodiments, the present invention relates to the use of cells or organisms which are affected by, or may be optionally affected by, one of these disorders or disease states.

[0101] The invention also relates to a pharmaceutical composition for treating hyperproliferative disorders in mammals which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof, and a pharmaceutically acceptable carrier. In some embodiments, the invention relates to a pharmaceutical composition for the treatment of solid tumors such as cancers of the skin, breast, brain, cervix, testicular cancers, etc. More preferably, cancers can be treated with the compositions and methods of the invention which include, but are not limited to: Cardiac: sarcomas (hemangioma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lungs: bronchogenic carcinoma (squamous epithelial cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrocytoma, mesothelioma; Gastrointestinal: cancer of the esophagus (cancer of the epithelial cells, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell adenoma, glucagonoma, tumor, gastrointestinal cancer, gastric cancer , lymphoma, carcinoid neoplasms, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, fibroadenoma, fibroma), colon (adenocarcinoma, tubular adenoma, papillary adenoma, hamartoma, leiomyoma); Urogenital tract: kidneys (adenocarcinoma, Wilms tumor [immature nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous epithelial cancer, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, cancer embryonic, malignant teratoma, malignant chorionic epithelioma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), bile duct cancer, hepatoma, hemangioma, hepatocellular adenoma, hemangioma; Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chord, osteochronoma, chondrosarcoma, chondrosarcoma, chondrosarcoma, chondrosarcoma , osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, jaundice, deforming osteitis), meninges (meningioma, meningioma, glioblastoma), brain (astrocytoma, medulloblastoma, glioblastoma, ependymoma, glioblastoma, glioblastoma, neuroblastoma , retinal glioma, congenital neoplasms), spinal cord (fibroadenoma, meningioma, glioma, sarcoma); Gynecological system: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovaries (ovarian cancer [serous cystic adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinomas], neoplasms of the granulomatous layer, post-cell carcinoma malignant), vulva (squamous cell carcinoma, endothelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, angina sarcoma [rhabdomyosarcoma], (cancer) of the fallopian tubes; Hematology: blood (lymphocytic leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous epithelial carcinoma, Kaposi's sarcoma, polypoid dysplastic nevus, lipoma, hemangioma, skin fibroma, keloids, psoriasis; and Endocrine glands: neuroblastoma. The term "cancer cells" as used herein includes cells affected by any of the above-mentioned disease states.

[0102] The invention also includes a method of treating a hyperproliferative disorder in mammals which comprises administering to said mammals a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or solvate thereof. In some embodiments, the method relates to the treatment of cancers encompassing the above-mentioned disease states.

The invention also relates to compositions for treating hyperproliferative disorders in mammals comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof, in combination with an antineoplastic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalator antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinal-like receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors and prenyl-protein transferase inhibitors .

The invention also relates to a method of treating hyperproliferative disorders in mammals which comprises administering to said mammals a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or solvate thereof, in combination with an anti-neoplastic agent selected from the group consisting of mitotic inhibitors. alkylating agents, anti-metabolites, antisense DNA or RNA, intercalating antibiotics (intercalators), growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinal-like receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, antiandrogens, targeted antibodies, HMG-CoA reductase inhibitors and prenyl transferase inhibitors .

[0105] The invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof, in combination with an amount of a chemotherapeutic agent, the amount of the compound, salt, solvate and or a prodrug and a chemotherapeutic agent are effective together to inhibit abnormal cell growth. Numerous chemotherapeutic agents are known in the art. In some embodiments, the chemotherapeutic agents are selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, intercalator antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinal-like receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, anti-androgens, targeting antibodies, HMG-CoA reductase inhibitors and / or prenyl-protein transferase inhibitors.

The invention further relates to a method of inhibiting abnormal cell growth in a mammal or treating a hyperproliferative disorder, the method comprising administering to mammals an amount of a compound of the invention, or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof, in combination with radiation therapy, the amount of the compound being administered to a mammal. , salt, The solvate or prodrug in combination with radiation therapy are effective in inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of a compound of the invention in this combination therapy can be determined as described herein.

[0107] It is contemplated that the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation to kill and / or inhibit growth of such cells. Accordingly, the present invention further relates to a method of sensitizing abnormal cells in mammals to radiation treatment which comprises administering to mammals an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof, the amount being effective. in sensitizing abnormal cells to radiation treatment. The amount of a compound, salt, solvate, metabolite or prodrug to be used in this method can be determined according to the means for determining the effective amount of such compounds as described herein or by methods known to those skilled in the art.

The invention also relates to pharmaceutical compositions and a method of using them for inhibiting abnormal cell growth in mammals comprising administering to mammals in need of such treatment an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof, and the amount of one or more substances. selected from the group consisting of anti-angiogenesis agents, signal transduction inhibitors and antiproliferative agents, in an amount effective to inhibit abnormal cell growth.

[0109] For example, anti-angiogenesis agents such as MMP-2 inhibitors (matrix metalloproteinase 2), MMP-9 inhibitors (matrix metalloproteinase 9) and COX-II (cyclooxygenase II) inhibitors may be used in conjunction with the compound or pharmaceutical compositions of invention. Examples of suitable COX-II inhibitors include CELEBREX ™ (alecoxib), BEXTRA® (valdecoxib), Arcoxia ™ (etoricoxib), Prexige® (lumiracoxib) and Vioxx (rofecoxib). Examples of MMP-2 and MMP-3 inhibitors are those that have little or no MMP-1 inhibitory activity and include compounds that selectively inhibit MMP-2 and / or MMP-9 over other matrix metalloproteinases (i.e., MMP-1, MMP -3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

[0110] The invention also relates to a composition for treating undesired cell growth, for example a fungal infection, in a mammal, comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or solvate thereof. In certain embodiments, the compositions of the present invention modulate the activity of fungal members of the bimC kinesin subgroup, as described in US Patent No. 6,284,480.

[0111] The invention also relates to a method of treating undesired cell growth, for example a fungal infection, in a mammal which comprises administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or solvate thereof.

[0112] The compounds of the invention may be used alone in combination with other drugs and therapies used to treat disease states that would benefit from the inhibition of KSP kinesins. For example, a compound of the present invention may be used in combination with one or more other anti-cancer substances, including, but not limited to, mitotic inhibitors such as vinblastine; alkylating agents such as cis-platinum, carboplatin and cyclophosphamide; anti-metabolites such as 5-fluorouracil, cytosine arabinide and hydroxyurea; one of the preferred anti-methylalytes described in European Patent Application No. 239362, such as N- (5- [N (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino] acid -2-tenoyl) -L-glutamic;

antisense RNA and DNA oligonucleotides such as G3139, ODN698 and GEM231; growth factor inhibitors; MEK inhibitors, signal transduction inhibitors such as agents that can inhibit EGFR (epidermal growth factor receptor) responses such as EGRF antibodies, EGF antibodies, and molecules that are EGFR inhibitors such as ZD-1839 (AstraZeneca) and ΒΙΒΧ- 1382 (Boehringer Ingelheim); VEGF inhibitors such as SU-6668 (Sugen, Inc., South San Francisco, CA) or Avestin anti-VEGF monoclonal antibodies (Genentech, Inc., South San Francisco, CA); cell cycle inhibitors; inclusion antibiotics such as adriamycin and bleomycin; enzymes, for example interferon; retina-like receptor modulators such as bexarotene, ILX23-7553, and Ν-4-carboxyphenylretinamide; proteasome inhibitors such as lactacystin and bortezomib; topoisomerase inhibitors such as topotecan, rebutecan and teniposide; anti-hormones such as TM TM anti-estrogens such as Nolvadex (tamoxifen); anti-androgens such as Casodex (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 '- (trifluoromethyl) propionanilide); targeted monoclonal antibody therapeutic agents that contain cytotoxic agents or radioisotopes attached to cancer-cell-specific or target-specific monoclonal antibodies; HMG-CoA reductase inhibitors (3-hydroxy-3-methylglutaryl-CoA reductase) such as simvastatin (ZOCOR®) and atorvastatin (LIPITOR®); prenyl-protein tranferase inhibitors; protein kinase inhibitors that transduce cell cycle checkpoint signals (e.g., ART, ARM, Chk1 and Chk2 kinases, cdk and cdc kinases) such as 7-hydroxystaurosporin, flavopyridol, and CYC202 (Cyclacel); and inhibitors of mitotic progression associated kinases, wherein such kinases include, but are not limited to, Polo-type kinases and aurora kinases. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0113] The compounds of the present invention can also be used in combination with other known inhibitors of mitotic kinesins. Examples of inhibitors of mitotic kinesins, and in particular human mitotic KSP kinesins, are those described in POT publications WO 01/30768, WO 01/98278, WO 03/050064, WO 03/050122, WO 03/049527, WO 03/049679, WO 03 / 049678, WO 03/051854, WO 03/39460 WO 03/079973, WO 03/088903, WO 03/094839, WO

03/097053, WO 03/099211, WO 03/099286, WO 03/103575, WO 03/105855, WO 03/106426, WO

04/032840, WO 04/034879, WO 04/037171, WO 04/039774, WO 04/055008, WO 04/058148, WO

04/058700, WO 04/064741, WO 04/092147, WO 04/111023, WO 04/111024, WO 05/035512, WO

05/017190, WO 05/018547 and WO 05/019206, which are specifically incorporated herein by reference. Examples of such inhibitors are (2S) -4- (2,5-difluorophenyl) -N - [(3S, 4S) -3-fluoro-1-methylpiperidin-4-yl] -2- (hydroxymethyl) -N-methyl-2- phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; (2S) -4- (2,5-difluorophenyl) -N - [(3S, 4R) -3-fluoro-1-methylpiperidin-4-yl] -2- (hydroxymethyl) -N-methyl-2-phenyl2,5- dihydro-1H-pyrrole-1-carboxamide; (2S) -4- (2,5-difluorophenyl) -N - [(3R, 4S) -3-fluoro-1-methylpiperidin-4-yl] -2- (hydroxymethyl) -N-methyl-2-phenyl-2, 5-dihydro-1H-pyrrole-1-carboxamide, (2S) -4- (2,5-difluorophenyl) -N - [(2R, 4R) -2- (fluoromethyl) -1-methylpiperidin-4-yl] - 2- (hydroxymethyl) N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide and (2S) -4- (2,5-difluorophenyl) -N - [(3R, 4S) - 3-fluoro-1-methylpiperidin-4-yl] -N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide.

[0114] The compounds of the present invention can also be used in the treatment of cancer in combination with compounds that are not anti-cancer compounds. For example, a compound of the present invention may be used in combination with one or more substances including, but not limited to, PPAR-γ and PPAR-δ agonists such as troglitazone, gene therapy agents, and inhibitors of inherent multidrug immunity (e.g., p-glycoprotein inhibitors) .

[0115] A compound of the present invention may also be used in combination with an antiemetic to treat nausea or vomiting by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0116] A compound of the present invention may also be administered in combination with an agent useful in the treatment of anemia such as epoetin alfa by the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0117] A compound of the present invention can also be administered in combination with an agent useful in the treatment of neutropenia by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such an agent for treating neutropenia is, for example, hematopoietic growth factor which regulates the production and function of neutrophils such as human granulocyte colony stimulating factor (G-CSF). An example of G-CSF is filgrastim.

[0118] A compound of the present invention may also be administered in combination with an immune boosting drug such as levamisole, isoprinosine and Zadaxin®, by way of simultaneous, sequential or separate dosing of the individual components of treatment.

[0119] Further, a compound of formula III-IV is claimed for use as a medicament for the treatment of the diseases or conditions described above in warm-blooded organisms, such as mammals, for example man, suffering from such diseases or conditions. Also claimed is the use of a compound of formula III-IV for the preparation of a medicament for the treatment of the diseases and conditions described above in warm-blooded organisms, such as mammals, e.g. humans, suffering from such disorders.

[0120] The term "treating" as used herein, unless otherwise indicated, means reversing, ameliorating, inhibiting the development or preventing of the disorder or disease state to which the term refers, or of one or more symptoms of such disorders or conditions. . The term "treating" as used herein, unless otherwise specified, refers to the act of treating as "treating" defined immediately above. "Treatment" is intended to mean at least alleviating a disease state in a mammal, such as a human, and includes, but is not limited to, modulating and / or inhibiting the disease state and / or ameliorating the disease state.

When treating a subject, it is understood that the specific dosage level and frequency of dosing for any particular subject may vary and is dependent upon various factors such as the activity of the specific compound of Formula III-IV, type, age, weight, general condition. the health, sex, and diet of a given subject, mode and timing of administration, excretion frequency, drug combination, and the severity of a given disease state, but can nevertheless be routinely determined by one of skill in the art.

[0122] The compounds of the invention may be administered by any route appropriate to the disease state being treated. A suitable route of administration is parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, intranasal, topical (including buccal and sublingual), e.g., by bolus injection or by continuous infusion. Other suitable routes are vaginal, intraperitoneal, pulmonary, oral and intranasal. Alternatively, compounds of the invention may be administered topically (e.g. to the skin) for the treatment of a local disease condition such as a fungal skin infection. It should be noted that the preferred route of administration may vary depending, for example, on the condition of the recipient. When the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or vehicle. When the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dose form for injection, as detailed below.

When a compound of formula III-IV or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof is used for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, it is formulated in accordance with standard practice as a pharmaceutical composition. According to this aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula III-IV, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

When preparing the pharmaceutical compositions of the present invention, a therapeutically or prophylactically effective amount of a compound of Formula III-IV, or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof (alone or with an additional therapeutic agent as defined above) is thoroughly mixed, for example, with a pharmaceutically acceptable carrier according to conventional pharmaceutical technique to make up a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., orally or parenterally. Examples of suitable carriers include any and all solvents, dispersing media, excipients, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, stabilizers (to facilitate long-term storage), emulsifiers, binders, thickeners, salts, preservatives, flavorings, and mixed substances such as buffers and absorbents which may be needed when preparing certain therapeutic compositions. The use of such media and agents with pharmaceutically active substances is known in the art. If any conventional medium or agent is incompatible with a compound of Formula III-IV, its use in therapeutic compositions and formulations should be considered. Supplementary active ingredients can also be incorporated into the compositions and preparations as described herein.

[0125] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be prepared according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents which have been mentioned above. This suspension can be obtained according to the known art using suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile oils can conventionally be used as a solvent or suspending medium. For this purpose, a neutral flat oil containing synthetic mono- or diglycerides may be used.

In addition, fatty acids such as oleic acid can be used in the preparation of injectables. The injectable solutions or microemulsions can be introduced into the bloodstream of the patient by local injection of one bolus of the drug. Alternatively, it may be advantageous to introduce the solution or microemulsion in such a way as to keep the recycle concentration of the compound in question constant. A continuous intravenous drug delivery device can be used to maintain such a constant concentration. An example of such a device is the DeltecCADD-PLUS ™ model 5400 intravenous pump.

[0126] The compositions according to the invention may also be in a form suitable for oral administration (for example tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical application (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g. as fine powders or liquid aerosols), for administration by insufflation (e.g. as finely divided powders) or for parenteral administration (e.g. as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular dosing or as suppositories for rectal administration). For example, compositions for oral administration may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0127] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating or disintegrating agents such as corn starch or alginic acid; binding agents such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Tablet preparations may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract or to improve their stability and / or appearance, each time using conventional coating agents and methods known in the art.

[0128] The compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatine capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0129] Aqueous suspensions usually contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wettable agents such as lecithin or alkylene oxide fatty acid condensation products (e.g. polyoxyethylene stearate), or ethylene oxide condensation products with long chain aliphatic alcohols, e.g. heptadekaethylene oxycetanol, or ethylene oxide condensation products with partial fatty acids derived from hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame).

[0130] Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavoring agents may be added to improve the taste of the oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0131] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are already exemplified above. Additional excipients, such as sweetening, flavoring, and coloring agents, may also be present.

[0132] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as, for example, liquid paraffin, or a mixture thereof. Suitable emulsifying agents can be, for example, naturally occurring gums such as acacia or tragacanth, naturally occurring phosphatides such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monoleate) and products condensation of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preserving agents.

[0133] Syrups and elixirs may be prepared with sweetening agents such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, and may also contain an anti-irritant, preservative, flavoring and / or coloring agent.

[0134] Suppositories may be prepared by mixing the active ingredient with a suitable non-irritating base which is solid at normal temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients are, for example, cocoa butter and polyethylene glycols.

[0135] Topical preparations, such as creams, ointments, gels, and aqueous or oily solutions or suspensions, may generally be prepared by formulating the active ingredient with a conventional topically acceptable vehicle or diluent using conventional procedures known in the art.

[0136] Compositions for insufflation may be in the form of a finely divided powder having particles with an average diameter of, for example, 30 µm or substantially less, the powder either containing the active ingredient alone or diluted with one or more physiologically acceptable carriers such as like lactose. The insufflation powder is then preferably held in a capsule containing, for example, 1 to 50 mg of active ingredient for use in a turbo-inhalation device, such as that used for insufflation of the known agent of sodium cromoglycate.

[0137] Compositions for administration by inhalation may be in the form of conventional pressurized aerosols adapted to deliver the active ingredient in the form of an aerosol containing a finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used and the aerosol device is preferably adapted to deliver a measured amount of the active ingredient.

[0138] Compositions for transdermal administration may be in the form of transdermal skin patches, as are known to those skilled in the art.

[0139] For further information on formulations, see Chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

The formulations may be packaged in unit dose containers or multi-dose containers, for example sealed ampoules and vials, and may be stored under freeze-drying (freeze-drying) conditions, requiring only the addition of a sterile liquid carrier, for example water, for injection. immediately before use. Injectable solutions or suspensions prepared immediately before use are prepared from sterile powders, granules and tablets of the type described above. Preferred unit dose formulations are those containing the daily dose or daily sub-dose unit as described above or an appropriate fraction of the active ingredient.

[0141] The amount of a compound of the present invention that is combined with one or more vehicles to produce a single dose will, of course, depend on the treated subject, the seriousness of the disorder or condition, the mode of administration, the disposition of the compound and the discretion of the prescribing physician. In some embodiments, a suitable amount of a compound of Formula III-IV is administered to a mammal in need of cancer treatment. Application in some embodiments is in an amount between about 0.001 mg / kg body weight to about 60 mg / kg body weight per day. In another embodiment, application is in an amount of between 0.5 mg / kg body weight to about 40 mg / kg body weight per day. In some cases, a dosage level below the lower limit of the above range may be more appropriate, while in other cases even higher doses may be used without causing any undesirable side effects, provided that such larger doses are first divided into several small doses to be administered over a period of time. day. For further information on administration routes and dosing regimens, see Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0142] The size of the therapeutic or prophylactic dose of a compound of formula III-IV may of course be varied depending on the nature and severity of the disease state, the age and sex of the animal or patient, and the route of administration, in accordance with known medical principles.

[0143] Another embodiment of the invention is an article or "kit" comprising materials useful for the treatment of the disorders described above. In some embodiments, the kit comprises a container containing a compound of Formula III-IV. In some embodiments, the invention relates to a kit for treating a hyperproliferative disorder. In another embodiment, the invention relates to a kit for treating or preventing a fungal or other eukaryotic infection. The kit can further include a label or package insert inserted into or associated with the container. In some embodiments, labels or package inserts indicate that a composition comprising a compound of Formula III-IV can be used, for example, to treat a hyperproliferative disorder, or to treat a fungal or other eukaryotic infection. A label or package insert may also indicate that the composition can be used to treat other diseases.

[0144] In some embodiments, the kit further comprises a container. Suitable containers are, for example, bottles, vials, syringes, blister packs, etc. The container can be made of various materials such as glass or plastic. The container holds a compound of Formula 11I-IV or a pharmaceutical formulation thereof in an amount effective to treat the condition and may have a sterile access point (for example, the container may be an intravenous bag or vial having a stopper that can be pierced by a hypodermic injection needle).

[0145] Alternatively or additionally, the kit may further comprise a second container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution. In addition, it may contain other materials desirable from a commercial and user standpoint, such as other buffers, diluents, filters, needles, and syringes.

[0146] The kit can further include directions for administering a compound of Formula III-IV and, if present, a second pharmaceutical formulation. For example, where the kit comprises a first composition comprising a compound of Formula III-IV and a second pharmaceutical formulation, the kit may further include directions for the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to a patient in need of such treatment.

[0147] According to certain embodiments, the kit can include (a) a first container containing a compound of Formula III-IV; and optionally (b) a second container containing a second pharmaceutical formulation, wherein the second pharmaceutical formulation contains a compound exhibiting, for example, anti-hyperproliferative or antifungal activity. Alternatively or additionally, the kit may further comprise a third container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may also contain other materials desirable from a commercial and user standpoint, such as other buffers, diluents, filters, needles, and syringes.

[0148] In certain other embodiments where the kit comprises a pharmaceutical formulation of a compound of Formula III-IV and a second formulation containing a second therapeutic agent, the kit may include a container containing separate formulations, such as a divided bottle or a divided foil packet; however, separate compositions may also be contained in a single, undivided container. Typically, the kit includes directions for administering the separate components. The kit form is particularly advantageous when the separate components are administered in different dosage forms (e.g., orally and parenterally), are administered at different dosage intervals, or when the measurement of the individual components of the combination is desired by the prescribing physician.

[0149] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of formula III-IV, such as tablets or capsules. Such a kit comprises, for example, a number of unit doses. Such a kit may contain a dose chart for their intended use. An example of such a set is a "blister pack". Blister packs are known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, the package may be provided with a memory aid, for example in the form of numbers, letters or other markings, or with a calendar insert to indicate days in the treatment regimen during which the dose may be administered.

[0150] While compounds of formula III-IV are primarily of value as therapeutic agents for use in warm-blooded organisms (including humans), they are also useful, where desired, to inhibit the action of KSP kinesins. Thus, they are also suitable for use as pharmacological standards in the development of new biological tests and in the search for new pharmacological agents.

[0151] Representative compounds of the present invention that are included in the present invention include, but are not limited to, the compounds of the examples and pharmaceutically acceptable salts, solvates, metabolites, and prodrugs thereof. The following examples are intended to explain particular embodiments of the invention and are not intended to limit the scope of the description and the claims in any way.

Examples

[0152] The following examples are provided to illustrate the invention. However, it is to be understood that these examples do not limit the invention and are only intended to suggest a method of practicing the invention. It is known to those skilled in the art that the chemical reactions described herein are readily adaptable to the production of a number of other KSP inhibitors of the invention, and alternative methods for preparing compounds of the present invention are recognized within the scope of this invention. For example, the syntheses of compounds of the invention not exemplified in the examples can be successfully accomplished by modifications apparent to the skilled person, e.g. by adequately protecting the interfering groups, by using other suitable reagents known in the art other than those described, and / or by routine modification of the reaction conditions. . Alternatively, other reactions disclosed herein or known in the art may be considered as being applicable to the preparation of other compounds of the invention.

[0153] In the following examples, unless otherwise indicated, all temperatures are set forth in degrees Celsius. The reagents are obtained from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and are used without further purification, unless otherwise stated. Tetrahydrofuran (THF), Ν, Ν-dimethylformamide (DMF), dichloromethane (DCM), toluene, dioxane, and 1,2-dichloroethane (DCE) were purchased from Aldrich in securely sealed bottles and used as received.

[0154] The following reactions are performed essentially under nitrogen or argon pressure in a blast system or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks are usually closed with rubber stoppers to introduce the reactants and reagents with a syringe. . The glassware is dried in an oven and / or by heating.

[0155] Column chromatography is performed with a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or SepPak silica gel cartridge (Waters).

[0156] Spectra ¹H-NMR is recorded on Varian instruments operating at 400 MHz. Specters¹HNMR is obtained in CDCI solutions₃, d₆-DMSO, CD₃OD or CDCI₃: CD₃OD (reported in ppm), using trimethylsilane as standard control (0.00 ppm). When multiple peak multiples are recorded, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (extended), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are recorded in hertz (Hz).

Example 1 (not according to the invention)

[0157]

<img file="PL1809280T3_D0012.tif" />

Preparation of 1- [2- (3-aminoDroovlo) -5- (2,5-difluorophenyl) -2-phenyl- [1,3,41 oxadiazol-3-yl-2-methylpropan-1-one

Step A: Preparation of (4-Oxo-4-phenylbutyl) -carbamic acid tert-butyl ester: To a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7.03 g, 38 mmol) in THF ( 130 ml), phenylmagnesium bromide (1.0 M solution, 50 ml) is added at -78 ° C. After stirring for 2 hours at -78 ° C, HCl (2 M, 35 mL) was added to quench the reaction mixture which was then warmed to room temperature and the aqueous layer was extracted with EtOAc (2 x 100 mL). . The combined organic phases are washed with brine (50 ml) and dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 9.56 g (96% yield) of the desired product.

Step B: Preparation of 2.5-difluorobenzoic acid hydrazide: To a solution of 2,5-difluorobenzoic acid (3.5 g, 22 mmol) in THF / DMF (20 mL / 20 mL) is added EDCI (4.7 g, 24 mmol). ), DMAP (50 mg) and NH₂NHBoc (3.07 g, 23.2 mmol). After stirring for 16 hours, the reaction mixture was quenched with water (30 mL) and diluted with EtOAc (30 mL). The organic layer was then washed with HCl (0.5 M, 20 mL), saturated NaHCO₃ (20 ml) and brine (20 ml). The organic layer is then dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give crude Boc-protected product which was then dissolved in DCM (60 mL) at 0 ° C. TFA (50 ml) is added to the above DCM solution. After stirring for 2 hours, the reaction mixture was concentrated and the residue was dissolved in DCM (60 ml). The solution was washed with saturated NaHCO₃ (40 ml) and dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the desired crude product.

[0160] Step C: Preparation of {4 - [(2,5-difluorobenzoyl) -hydrazono] -4-phenyl-butyl-carbamic acid tert-butyl ester: For a solution of (4-oxo-4-phenyl-butyl) -carbamic acid tert-butyl ester (3 , 2 g, 12.2 mmol) and 2,5-difluorobenzoic acid hydrazide (2.1 g, 12 mmol) in EtOH (40 ml) is added HOAc (0.5 ml). The reaction mixture is then heated to reflux and stirred for 3 days. The reaction mixture was then cooled to room temperature and concentrated to give the desired product (5.1 g).

[0161] Step D: Preparation of {3- [5- (2,5-difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro- [1,3,4] oxadiazol-2-yl acid tert-butyl ester ] -propyl} -carbamic: To a solution of {4 - [(2,5-difluorobenzoyl) -hydrazono] -4-phenylbutyl} -carbamic acid tert-butyl ester (420 mg, 1.01 mmol) in DCE (2 mL) isobutyric anhydride (2 ml) is added. The reaction mixture was then sealed and heated at 110 ° C and stirred for 5 hours. The reaction mixture is then cooled and concentrated. The residue was purified by flash column chromatography (12: 1 hexanes / EtOAc) to provide the product (200 mg, 41%).

Step E: Preparation of 1- (2- (3-aminoDroovlo) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropane- 1-one: To a solution of {3- [5- (2,5-difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro- [1,3,4] oxadiazol-2-yl] acid tert-butyl ester -propyl} -carbamic acid (60 mg, 0.123 mmol) in DCM (2 ml) was added TFA (1 ml) at 0 ° C. After stirring for 10 minutes, the reaction mixture was concentrated and the residue was purified by preparative thin layer chromatography (10: 1: 0.2 EtOAc / MeOH / 30% NH₄OH) to give the desired product (25 mg, 53%). MS ESI (+) m / z 388 (M + 1) detected;¹1 H NMR (400 MHz, CDCl₃) δ 7.59 (m, 2H), 7.50 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 3.17 (m, 1H, J = 7Hz ), 3.02 (m, 1H), 2.8 (br, 2H), 2.56 (m, 1H), 1.8 (br, 2H), 1.6 (m, 2H), 1.2 (d, 3H, J = 7Hz). 1.13 (d, 3H, J = 7Hz).

[0163] The following compounds are prepared in an analogous manner using the appropriate hydrazides and anhydrides.

Example 2 (not according to the invention)

[0164]

<img file="PL1809280T3_D0013.tif" />

1- [2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl- [1,3,4] oxadiazol-3-ylol-ethanone

[0165] MS ESI (+) m / z 360 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.58 (m, 2H), 7.50 (m, 1H), 7.37 (m, 3H), 7.18 (m, 2H), 3.05 (m, 1H), 2.9 (m, 2H), 2.56 (m, 1H), 2.28 (s, 3H), 1.7 (m, 2H).

Example 3 (not according to the invention)

[0166]

<img file="PL1809280T3_D0014.tif" />

- [2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] oxadiazol-3-ylol-2-methylpropan-1-one [0167] MS ESI (+) m / z 370 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.67 (d, 1H, J = 8Hz), 7.56 (m, 1H), 7.52 (m, 2H), 7.42 (m, 1H), 7.35 (m, 3H ), 7.2 (m, 1H), 3.35 (m, 1H, J = 7Hz), 3.05 (m, 1H), 2.85 (t, 2H, J = 7Hz), 2, 52 (m, 1H), 1.62 (m, 2H), 1.17 (d, 3H, J = 7Hz), 1.11 (d, 3H, J = 7Hz) Example 4 (not according to the invention)

[0168]

<img file="PL1809280T3_D0015.tif" />

1- [2- (3-Aminopropyl) -5- (3-chlorophenyl) -2-phenyl- [1,3,4loxadiazol-3-l-2-methylpropan-1-one

[0169] MS ESI (+) m / z 386 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.86 (s, H), 7.77 (d, 1H, J = 8Hz), 7.54 (m, 2H), 7.46 (d, 1H, J = 8Hz), 7, 4-7.34 (m, 4H), 3.37 (m, 1H, J = 7Hz), 3.05 (m, 1H), 2.81 (br, 2H), 2.52 (m, 1H ), 2.39 (br, 3H), 1.61 (m, 2H), 1.19 (d, 3H, J = 7Hz), 1.13 (d, 3H, J = 7Hz). Example 5

[0170]

<img file="PL1809280T3_D0016.tif" />

Preparation of 1- [2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4-thiadiazol-3-yl-2-methyl-1-one

Step A: Preparation of {3- [5- (3-fluoro-phenyl) -2-phenyl-2,3-dihvdro [1,3,4] thiadiazol-2-yl] -propyl} - acid tert-butyl ester carbamic acid: To a solution of (4-oxo-4-phenylbutyl) -carbamic acid tert-butyl ester (2.2 g, 8.5 mmol) in ethanol / DCM (30 ml / 10 ml) is added 3-fluorothiobenzoic acid hydrazide (Takasugi, JJ; Buckwalter, BL European Patent EP 1004241,2004) (1.2 g, 7.1 mmol) at room temperature. After stirring for 3 days, the reaction mixture was concentrated and purified by flash column chromatography (20: 1 hexanes / EtOAc) to provide the product (2.65 g, 90%).

Step B: Preparation of (3- [5- (3-fluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihvdro- [1,3,4-thiadiazol-2-yl-propyl-carbamic acid tert-butyl ester: To a solution of {3- [5- (3-fluorophenyl) -2-phenyl-2,3-dihydro- [1,3,4] thiadiazol-2-yl] -propyl} -carbamic acid tert-butyl ester (400 mg, 0.96 mmol) in DCM (4 ml) was added triethylamine (130 mg, 1.3 mmol) followed by isobutyryl chloride (130 mg, 1.3 mmol). After stirring for 1 hour, the reaction mixture was quenched by adding methanol (0.1 ml). The reaction mixture was concentrated and purified by flash column chromatography (15: 1 hexanes / EtOAc) to provide the product (350 mg, 75%).

[0173] Step C: Preparation of 1- [2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-yl] -2-methylpropan-1-one: HCl (1 ml, 4 M in dioxane) is introduced into {3- [5- (3-fluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro- [1,3,4] acid tert-butyl ester thiadiazol-2-yl] propyl} carbamic acid (100 mg, 0.21 mmol) at 0 ° C. After stirring for 0.5 hour, the reaction mixture was concentrated to give the desired product as the dihydrochloride salt.

MS ESI (+) m / z 386 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.51 (s, 2H), 7.55 (m, 2H), 7.4-7.2 (m, 6H), 7.15 (m, 1H), 3.43 (m, 2H) , 3.06 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.8 (br, 1H), 1.2 (d, 3H, J = 7Hz) , 1.1 (d, 3H, J = 7Hz).

Example 6

<img file="PL1809280T3_D0017.tif" />

[0174]

2- (3-Aminopropyl) -5- (3-fluoro-phenyl) -2-phenyl- [1,3,4-thiadiazole-3-carboxylic acid dimethylamide This compound is prepared by analogy to Example 5 using dimethylcarbamyl chloride instead of isobutyryl chloride. MS ESI (+) m / z 387 (M + 1) detected;¹H NMR (di-TFA salt, 400 MHz, CDCl₃) δ 7.7 (s, 3H), 7.5-7.2 (m, 8H), 7.15 (m, 1H), 6.75 (br, 3H), 3.2-2.9 ( m, 3H), 3.02 (s, 6H), 2.38 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H).

Example 7

[0176]

<img file="PL1809280T3_D0018.tif" />

Preparation of [2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4-thiadiazol-3-yl-pyridin-2-ylmethanone

[0177] To a solution of {3- [5- (3-fluorophenyl) -2-phenyl-2,3-dihydro [1,3,4] thiadiazol-2-yl] -propyl} -carbamic acid tert-butyl ester ( 300 mg, 0.72 mmol) in DMF / THF (2 mL / 2 mL) at room temperature are added picolinic acid (100 mg, 0.9 mmol), EDCI (170 mg, 0.87 mmol), HOBT monohydrate ( 130 mg, 0.87 mmol), triethylamine (88 mg, 0.87 mmol) and DMAP (2 mg). After stirring for 1 hour, EtOAc (20 mL) and saturated NaHCO were added to the reaction solution.₃ (10 ml). The phases are separated and the aqueous layer is extracted with EtOAc (2 x 10 mL). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (8: 1 hexanes / EtOAc) to provide the Boc-protected product (130 mg, 35%). 51 mg of this product is cooled to 0 ° C and HCl (1 ml, 4 M in dioxane) is added. After stirring for 0.5 hour, the reaction mixture was concentrated to give the desired product as the trihydrochloride salt.

MS ESI (+) m / z 421 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.6-8.2 (m, 5H), 7.85 (s, 1H), 7.7 (m, 2H), 7.4-7.2 ( m, 9H), 7.1 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 3.06 (m, 1H), 2.5 (m, 1H), 2.1 (m, 2H).

Example 8

[0178]

<img file="PL1809280T3_D0019.tif" />

[2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-ylol-pyridin-3-ylmethanone

[0179] The trihydrochloride salt of this compound is prepared in a manner analogous to that described in Example 7. MS ESI (+) m / z 421 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 9.6 (s, 1H), 8.81 (s, 2H), 8.43 (s, 3H), 7.81 (br, 1H), 7.6 (m, 2H ), 7.4-7.3 (m, 5H), 7.2 (m, 1H), 7.15 (m, 1H), 3.58 (m, 1H), 3.2 ( m, 1H), 3.0 (m, 1H), 2.4 (m, 1H), 2.15 (m, 2H).

Example 9 (not according to the invention)

[0180]

<img file="PL1809280T3_D0020.tif" />

Preparation of 1- [5- (2,5-difluorophenyl) -2- (3-methylaminopropyl) -2-phenyl- [1,3,4] oxadiazol-3-ylol-2-methylpropan-1-one

[0181] To a solution of {3- [5- (2,5-difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro- [1,3,4] oxadiazol-2-yl] - acid tert-butyl ester NaH (14 mg, 0.58 mmol, 60% dispersion in mineral oil), previously washed with hexanes, was added propyl} -methylcarbamic (13 mg, 0.027 mmol) in DMF (0.5 mL). After stirring at room temperature for 30 minutes, methyl iodide (23 mg, 0.16 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then diluted with saturated NaHCO₃ (20 ml). The mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic phases are washed with brine (20 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (8% to 20% ethyl acetate in hexanes) to provide the Boc-protected product (6.6 mg, 48%). To this product in dichloromethane (1 ml) at 0 ° C TFA (6 µΙ) is added. After 30 minutes, more TFA (100 µΙ) was added and the mixture was stirred for 1 hour. The reaction mixture is concentrated under a stream of N₂, diluted with dichloromethane (20 mL) and washed with 10% Na₂WHAT₃ (20 ml). The mixture is extracted with dichloromethane (2 × 30 mL). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (6: 2: 92 MeOH / thetylamine / ethyl acetate) to give the final product (3.8 mg, 72%) as yellow film.

MS ESI (+) m / z 402 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.16 (m, 2H), 3.37 (m, 1H), 3.03 (m, 1H), 2.68 (m, 2H), 2.54 (m, 1H), 2.42 (s, 3H), 1.66 (m, 2H), 1.20 (d, 3H, J = 6Hz), 1.14 (d, 3H, J = 7Hz).

Example 10 (not according to the invention)

<img file="PL1809280T3_D0021.tif" />

[0182]

Preparation of 1- [5- (2,5-difluorophenyl) -2- (3-dimethylaminopropyl) -2-phenyl- [1,3,4loxadiazol-3-yl-2-methylpropan-1-one

[0183] To a solution of 1- [2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl- [1,3,4] oxadiazol-3-yl] -2-methylpropan-1-one ( 9 mg, 0.023 mmol) in MeOH (0.5 mL) was added paraformaldehyde (11 mg, 0.35 mmol). The reaction mixture was heated to 70 ° C and stirred for 2 hours. After cooling to room temperature, sodium cyanoborohydride solution (0.070 mL, 0.070 mmol, 1M in THF) is added. The mixture was stirred for 20 minutes and then diluted with half saturated NaCl (50 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases are washed with saturated NaCl, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (2:40:60 triethylamine / ethyl acetate / hexanes) to provide the product (5.1 mg, 53%).

MS ESI (+) m / z 416 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.16 (m, 2H), 3.37 (m, 1H) 3.01 ( m, 1H), 2.51 (m, 1H), 2.34 (m, 2H), 2.20 (s, 6H), 1.66 (m, 2H), 1.20 (d, 3H, J = 6Hz), 1.14 (d, 3H, J = 7Hz).

Example 11 (not according to the invention)

[0184]

<img file="PL1809280T3_D0022.tif" />

Preparation of 1- [5- (2,5-difluorophenyl) -2- (3-isopropylaminopropyl) -2-phenyl- [1,3,4] oxadiazol-3-ylol-2-methylpropan-1-one

[0185] To a solution of 1- [2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl- [1,3,4] oxadiazol-3-yl] -2-methylpropan-1-one ( 12 mg, 0.031 mmol) in acetonitrile (0.5 mL), acetone (60 µL, 0.082 mmol) and sodium triacetoxyborohydride (10 mg, 0.045 mmol) are added. After stirring at room temperature for 45 minutes, more sodium triacetoxyborohydride (10 mg, 0.045 mmol) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture is diluted with Na 10%₂WHAT₃ (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with brine (45 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes with 2% triethylamine) to give the final product (3.3 mg, 25%).

MS ESI (+) m / z 430 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.56 (m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.15 (m, 2H), 3.36 (m, 1H), 3.01 (m, 1H), 2.78 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 1.66 (m, 2H), 1.20 (d, 3H, J = 7Hz), 1.14 (d, 3H, J = 6Hz), 1.04 (d, 6H, J = 6Hz).

Example 12 (not according to the invention)

[0186]

<img file="PL1809280T3_D0023.tif" />

Preparation of 1- [5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2-phenyl- [1,3,4loxadiazol-3-yl-2-methylpropan-1-one Step A: Preparation 4 -hydroxy-1-phenylbutan-1-one: To a solution of dihydrofuran-2-one (5.71 g, 66 mmol) in diethyl ether (70 ml) at -78 ° C, phenyl lithium (24 ml, 40 mmol) is slowly added , 1.67 M solution in cyclohexane / diethyl ether). After stirring at -78 ° C for 2 hours, the reaction mixture was quenched by adding 10% NH₄CI (35 ml). The mixture is warmed to room temperature and the layers are separated. The aqueous layer was extracted with diethyl ether (2 x 40 mL). The combined organic layers are washed with water (2 x 40 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (2: 3 hexanes / ethyl acetate) to give the product (6.4 g, 97%) as a pale yellow oil.

Step B: Preparation of 4- (tert-butyldimethylsilanyloxy) -1-phenylbutan-1-one: To a solution of 4-hydroxy-1-phenylbutan-1-one (3.29 g, 20 mmol) in DMF (20 ml) is added tert-butylchlorodimethylsilane (4.5 g, 30 mmol) and imidazole (4.1 g, 60 mmol) are added. After stirring at room temperature for 14 hours, the reaction mixture was diluted with diethyl ether (150 ml) and washed with 1M HCl (2 x 70 ml), water (2 x 70 ml) and brine (100 ml). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (6% ethyl acetate in hexanes) to provide the product (5 g, 90%) as colorless oil.

Step C: Preparation of 2,5-difluorobenzoic acid [4- (tert-butyldimethylsilanyloxy) -1-phenylbutylideneol-hydrazide: For a solution of 4- (tert-butyldimethylsilanyloxy) -1-phenylbutan-1-one (420 mg, 1 , 5 mmol) in EtOH (4 mL), 2,5-difluorobenzoic acid hydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol) were added. The reaction mixture was stirred at 90 ° C for 5 hours, then more acetic acid (0.1 ml) was added. The mixture was stirred at 90 ° C for 40 hours and then concentrated under reduced pressure. The mixture of starting material and product is further reacted without further purification.

Step D: Preparation of 1- [5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2-phenyl- [1,3,4loxadiazol-3-yl] -2-methylpropan-1-one: Isobutyric anhydride (73 mg, 0.46 mmol) was added to a solution of crude 2,5-difluorobenzoic acid [4- (tert-butyldimethylsilanyloxy) -1phenylbutylidene] hydrazide from the previous step (200 mg) in dichloroethane (1 ml). After heating to 110 ° C for 8 hours, the mixture was concentrated under reduced pressure. The residue was chromatographed (7% ethyl acetate in hexanes) to provide the silane protected product (44 mg). To a solution of this product (28 mg, 0.056 mmol) in acetonitrile (1 mL) was added 48% aqueous HF (50 µL). After stirring at room temperature for 30 minutes, the mixture was diluted with saturated NaHCO₃ (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% ethyl acetate in hexanes) to give the product (9 mg, 45%) as a colorless film.

MS ESI (+) m / z 389 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.51 (m, 1H), 7.39 (m, 3H), 7.16 (m, 2H), 3.72 (m, 2H), 3.37 (m, 1H), 3.06 (m, 1H), 2.62 (m, 1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.21 (d, 3H, J = 7Hz), 1.15 (d, 3H, J = 7Hz).

[0191] The following examples were prepared as described in Examples 5 and 6 above, using the appropriate thiohydrazides, ketones and acid chloride or carbamoyl chloride.

Example 13

[0192]

<img file="PL1809280T3_D0024.tif" />

[2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-ylol-cyclopropylmethanone

[0193] MS APCI (+) m / z 384 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.40 (br, 2H), 7.52 (m, 2H), 7.44 (m, 1H), 7.35 (m, 4H), 7.22 (m, 1H), 7.13 (m, 1H), 3.32 (m, 1H), 3.04 (m, 1H), 2.98 (m, 1H), 2.74 (m, 1H), 2.42 (m, 1H) , 2.09 (m, 1H), 1.79 (m, 2H), 1.20 (m, 1H), 0.85 (m, 2H).

Example 14

[0194]

<img file="PL1809280T3_D0025.tif" />

- [2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-ylol-2-methoxyethanone

[0195] MS APCI (+) m / z 387 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.37 (br, 2H), 7.52 (m, 2H),

7.34 (m, 5H), 7.23 (m, 1H), 7.15 (m, 1H), 4.66 (d, 1H, J = 16Hz), 4.44 (d, 1H, J = 16Hz), 3.56 (m, 1H), 3.37 (s, 3H), 3.15 (m, 1H), 3.07 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 1.92 (m, 1H).

Example 15

[0196]

<img file="PL1809280T3_D0026.tif" />

₁£2_with£3_ZiAj22ilToproPY! Ol :: 5_:^^_withoh! orophenyloI_with2_withphenyl_withJ. _L.^_and4M [adiazole_with£ 3 2JHI_withHoI_with2_withmethoxYethanor2 MS APCI (+) m / z 404,406 (M + 1, C1 band) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.38 (br, 2H), 7.65 (s, 1H), 7.52 (d, 2H, J = 8Hz), 7.47 (d, 1H, J = 8Hz), 7, 41 (d, 1H, J = 8Hz), 7.32 (m, 3H), 7.24 (m, 1H), 4.67 (d, 1H, J = 16Hz), 7.45 (d, 1H, J = 16Hz), 3.57 (m, 1H), 3.37 (s, 3H), 3.16 (m, 1H), 3.07 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).

Example 16

[0198]

<img file="PL1809280T3_D0027.tif" />

(2- (3-Aminopropyl) -5- (3-chlorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (cyclopropyl) -methanone [0199] MS APCI (+) m / z 400,402 (M + 1, C1 band) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.40 (br, 2H), 7.71 (s, 1H), 7.50 (m, 3H), 7.40 (d, 1H), 7.34 (m, 3H), 7.23 (m, 1H), 3.32 (m, 1H), 3.03 (m, 1H), 2.97 (m, 1H), 2.75 (m, 1H), 2.43 (m, 1H) , 2.09 (m, 1H), 1.79 (m, 1H), 1.20 (m, 1H), 0.86 (m, 3H). Example 17

[0200]

<img file="PL1809280T3_D0028.tif" />

1- (2- (3-Aminopropyl) -5- (3-chlorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one [0201] MS APCI (+) m / z 402,404 (M + 1, C1 band) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.49 (br, 2H), 7.67 (s, 1H), 7.51 (m, 3H), 7.41 (d, 1H, J = 8Hz), 7.33 (m, 3H ), 7.23 (m, 1H), 3.44 (m, 2H), 3.07 (m, 2H), 2.43 (m, 1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.20 (d, 3H, J = 6Hz), 1.12 (d, 3H, J = 7Hz).

Example 18

[0202]

<img file="PL1809280T3_D0029.tif" />

[2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-yl-morpholin-4-ylmethanone

[0203] MS APCI (+) m / z 429 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.43 (br, 2H), 7.56 (d, 2H), 7.34 (m, 5H), 7.24 (m, 1H), 7.11 (m, 1H), 3.71 (m, 4H), 3.56 (m, 4H), 3.30 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.41 (m, 1H) , 2.08 (m, 1H), 1.89 (m, 1H).

Example 19

<img file="PL1809280T3_D0030.tif" />

[0204]

ManufactureijJlŁfSujminoioręyoylolJYfS ^^

[0205] MS ESI (+) m / z 358 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.45 (s, 1H), 7.42 (d, 1H, J = 9Hz), 7.36 (m, 4H), 7.28 (d, 1H ), 7.14 (m, 1H), 3.20 (m, 1H), 2.87 (m, 1H), 2.53 (m, 1H), 2.44 (s, 3H), 2.39 (m, 1H), 1.94 (m, 1H), 1.56 (m, 1H).

Example 20

[0206]

<img file="PL1809280T3_D0031.tif" />

(2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (cyclobutyl) -methanone MS ESI (+) m / z 398 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.46 (d, 2H, J = 7Hz), 7.41 (d, 1H, J = 11Hz), 7.35 (m, 4H), 7.27 (m, 1H), 7, 13 (m, 1H), 3.87 (m, 1H), 3.22 (m, 1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.39 (m, 1H ), 2.26 (m, 4H), 2.02 (m, 1H), 1.92 (m, 1H), 1.82 (m, 1H), 1.56 (m, 1H). Example 21

[0208]

<img file="PL1809280T3_D0032.tif" />

1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-ethylbutan-1-one

[0209] MS ESI (+) m / z 414 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.50 (d, 2H, J = 8Hz), 7.40 (m, 3H), 7.33 (m, 2H), 7.25 (m, 1H), 7.14 (m, 1H ), 3.26 (m, 2H), 2.98 (m, 2H), 2.58 (br, 2H), 2.42 (m, 1H), 1.96 (m, 1H), 1.71 (m, 1H), 1.63 (m, 1H), 1.51 (m, 3H), 0.95 (t, 3H, J = 7Hz), 0.83 (t, 3H, J = 7Hz ).

Example 22

[0210]

<img file="PL1809280T3_D0033.tif" />

1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3_l4-thiadiazol-3 (2H) -yl) -propan-1-one

[0211] MS ESI (+) m / z 372 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (m, 2H), 7.37 (m, 5H), 7.27 (m, 1H), 7.14 (m, 1H), 3.2 (m, 1H), 2.84 (m, 4H), 2.58 (br, 2H), 2.39 (m, 1H), 1.92 (m, 1H), 1.55 (m, 1H), 1.15 (t, 3H, J = 7 Hz).

Example 23

[0212]

<img file="PL1809280T3_D0034.tif" />

- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -butan-1-one

[0213] MS ESI (+) m / z 386 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 3H), 7.38 (m, 2H), 7.33 (d, 2H), 7.27 (m, 1H), 7.13 (m, 1H), 3.21 (m, 1H), 2.86 (br, 2H), 2.77 (m, 4H), 2.39 (m, 1H), 1.94 (m, 1H), 1.68 (m, 1H) , 1.55 (m, 2H), 0.97 (t, 3H, J = 7Hz).

Example 24

[0214]

<img file="PL1809280T3_D0035.tif" />

1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3_l4-thiadiazol-3 (2H) -yl) -2-methylbutan-1-one MS ESI (+) m / z 400 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (m, 3H), 7.34 (m, 4H), 7.26 (m, 1H), 7.14 (m, 1H), 3.36 (m, 1H), 3.23 (m, 1H), 2.86 (br, 2H), 2.39 (m, 3H), 1.93 (m, 1H), 1.75 (m, 1H), 1.54 (m, 1H) , 1.43 (m, 1H). 1.17 (dd, 3H, J = 6.9 Hz, 12.3 Hz), 0.90 (dt, 3H, J = 7.4 Hz, 37.6 Hz).

Example 25

[0216]

<img file="PL1809280T3_D0036.tif" />

1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -3-methylbutan-1-one [0217] MS ESI (+) m / z 400 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 2H), 7.38 (m, 3H), 7.32 (m, 2H), 7.26 (m, 1H), 7.14 (m, 1H), 3.45 (br, 2H), 3.23 (m, 1H), 2.87 (m, 2H), 2.74 (dd, 1H, J = 7Hz, 15Hz), 2.63 (dd, 1H, J = 7Hz, 15Hz), 2.39 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.56 (m, 1H), 0.95 (m, 6H).

Example 26

[0218]

<img file="PL1809280T3_D0037.tif" />

(2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (cyclopentyl) -methanone MS ESI (+) m / z 412 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 2H), 7.38 (m, 3H), 7.32 (m, 2H), 7.26 (m, 1H), 7.13 (m, 1H), 3.61 (m, 1H), 3.22 (m, 1H), 2.85 (m, 2H), 2.40 (m, 3H), 1.95 (m, 3H), 1.82 (m, 1H) , 1.63 (m, 6H).

Example 27

[0220]

<img file="PL1809280T3_D0038.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -ethanone

[0221] MS ESI (+) m / z 376 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.40 (m, 4H), 7.30 (m, 1H), 7.13 (m, 2H), 3.20 (m, 1H), 2.89 (m, 2H), 2.46 (s, 3H), 2.38 (m, 1H), 1.99 (m, 1H), 1.57 (m, 1H).

Example 28

[0222]

<img file="PL1809280T3_D0039.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one [0223 ] MS ESI (+) m / z 404 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.42 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H), 7.10 (m, 2H), 3.48 (m, 1H), 3.20 (m, 2H), 2.88 (m, 1H), 2.34 (m, 1H), 1.97 (m, 1H), 1.55 (m, 1H) , 1.18 (d, 3H, J = 8Hz), 1.16 (d, 3H, J = 8Hz).

Example 29

[0224]

<img file="PL1809280T3_D0040.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxyethanone MS ESI (+) m / z 406 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.53 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.12 (m, 2H), 4.55 (d, 1H, J = 16Hz), 4.48 (d, 1H, J = 16Hz), 3.46 (s, 3H), 3.28 (m, 1H), 2.89 (m, 2H ), 2.40 (m, 1H), 1.96 (m, 1H), 1.58 (m, 1H).

Example 30

[0226]

<img file="PL1809280T3_D0041.tif" />

2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -N, N-dimethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide MS ESI (+) m / z 405 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 2H), 7.45 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 3.12 (m, 1H), 3.01 (s, 6H), 2.85 (m, 1H), 2.36 (m, 1H), 1.95 (m, 1H), 1.65 (m, 1H) . 1.26 (m, 1H).

Example 31

[0228]

<img file="PL1809280T3_D0042.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2- (3-fluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -ethanone

[0229] MS ESI (+) m / z 394 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.57 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J = 8Hz), 7.11 (m, 3H), 6.97 (m, 1H ), 3.31 (m, 2H), 3.19 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.31 (m, 1H), 1.95 (m, 1H), 1.58 (m, 1H).

Example 32

[0230]

<img file="PL1809280T3_D0043.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2- (3-fluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one

[0231] MS ESI (+) m / z 422 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J = 8Hz), 7.11 (m, 3H), 6.96 (m, 1H ), 3.48 (m, 1H), 3.18 (m, 1H), 2.92 (m, 1H), 2.88 (m, 1H), 2.45 (br, 2H), 2.31 (m, 1H), 1.93 (m, 1H), 1.52 (m, 1H), 1.20 (d, 3H, J = 7Hz), 1.18 (d, 3H, J = 7Hz ).

Example 33

[0232]

<img file="PL1809280T3_D0044.tif" />

1- (2- (4-Aminobutan-2-yl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -2-methylpropan-1-one (a pair of diastereomers AND)

Step A: Preparation of tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate: To a solution of 3-methyl-2-pyrrolidinone (5.0 g, 50.4 mmol) in anhydrous THF (100 ml) at - 78 ° C n-Butyllithium (2.1 M solution, 25.2 mL, 53 mmol) is added. The mixture was stirred for 30 minutes then treated with a solution of Boc-anhydride (11.01 g, 50.4 mmol) in anhydrous THF (50 ml). After 3 h at -78 ° C, phenylmagnesium bromide (1.0 M solution, 65.6 mL, 65.6 mmol) is added via cannula. After a further 3 hours at -78 ° C, the mixture was treated with 2N HCl (100 ml), warmed to room temperature and extracted with ethyl acetate (3 x 100 ml). The combined organic phases are washed with brine (100 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was chromatographed (9: 1 to 4: 1 hexanes / ethyl acetate) to provide the product (2.6 g, 18%) as yellow oil.

[0234] Step B: Preparation of tert-butyl 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) butylcarbamate: For the 3-fluorobenzothiohydrazide solution Tert-Butyl 3-methyl-4-oxo-4-phenylbutylcarbamate (538 mg, 1.94 mmol) is added (300 mg, 1.76 mmol) in ethanol / DCM (6 ml / 2 ml). After stirring at room temperature for 16 hours, acetic acid (3 drops) was added and the mixture was stirred for a further 48 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9: 1 hexanes / ethyl acetate) to provide the product (366 mg, 48%) as a mixture of diastereomers as yellow foam.

Step C: Preparation of tert-butyl 3- (5- (3-fluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -butylcarbamate: To the solution Tert-Butyl 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -butylcarbamate (50mg, 116mmol) in dry DCM (5ml) isobutyryl chloride (16 µL, 151 mmol) is added followed by triethylamine (21 µL, 151 mmol). After stirring at room temperature for 16 hours, the mixture was partitioned between saturated NaHCO₃ (20 ml) and DCM (20 ml). The organic layer is extracted with DCM (10 ml) and the combined organics are washed with brine (20 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was chromatographed (19: 1, hexanes / ethyl acetate) to give two diastereomeric pairs, a pair of diastereomers A (more polar, 13.1 mg) and a pair of diastereomers B (less polar, 11 mg).

[0236] Step D: Preparation of 1- (2- (4-aminobutan-2-yl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- methylpropan-1-one (diastereomeric pair A): TFA (0.5 ml) is added to a solution of the diastereomeric A pair from the previous step (13.1 mg, 0.026 mmol) in DCM (2 ml). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.₃ (20 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic phases were washed with brine (10 ml), dried over Na₂SO₄ and concentrated under reduced pressure to give the product as a pair of diastereomers (10 mg, 96%) as a pale yellow oil.

[0237] MS ESI (+) m / z 400 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.72 (m, 2H), 7.48 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.25 (m, 1H), 7.16 (m, 1H), 3.76 (m, 1H), 3.34 (m, 1H), 2.91 (br, 1H), 2.30 (br, 1H), 1.68 (m, 1H) , 1.37 (m, 1H), 1.13 (m, 6H), 0.98 (m, 3H), 0.88 (m, 1H).

Example 34

[0238]

<img file="PL1809280T3_D0045.tif" />

1- (2 - (- 4-Aminobutan-2-yl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylDrooan-1- he (pair of B diastereomers)

[0239] Prepared as described in example 33 using the less polar pair of diastereomers B.

MS ESI (+) m / z 400 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.71 (m, 2H), 7.48 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.16 (m, 1H), 3.85 (m, 1H), 3.34 (m, 1H, J = 6Hz), 2.93 (br, 1H), 2.85 (br, 1H), 2.52 (br, 1H), 1.66 (m, 1H), 1.26 (m, 1H), 1.12 (dd, 6H, J = 6.8Hz, 14Hz), 0.96 (d, 3H , J = 7Hz), 0.84 (m, 1H).

[0240] The following examples were prepared analogously to example 7 above using the appropriate thiohydrazide, ketone and carboxylic acid.

Example 35

<img file="PL1809280T3_D0046.tif" />

(2R) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxy 2-phenylethanone (diastereomer A)

[0242] Coupling with (R) -2-methoxy-2-phenylacetic acid gave diastereomeric products which were isolated using silica gel chromatography (4: 1 hexanes / ethyl acetate). The more polar diastereomer (Boc-protected diastereomer A) is subjected to t-butoxycarbonyl removal as in Example 7 to give the product as a diHCl salt.

MS ESI (+) m / z 464 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.51 (br s, 3H), 7.4-7.0 (m, 14H), 5.60 (s, 1H), 3.8-3.1 (m, 6H), 2.6 -1.9 (m, 3H).

Example 36

[0243]

<img file="PL1809280T3_D0047.tif" />

(2R) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxy-2-phenylethanone (diastereomer B)

[0244] Produced as described in Example 35 using a less polar diastereomer (Boc-protected diastereomer B).

MS ESI (+) m / z 464 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.30 (br s, 3H), 7.6-7.1 (m, 14H), 5.54 (s, 1H), 3.4-2.3 (m, 8H), 1.7 (m, 1H).

Example 37

[0245]

<img file="PL1809280T3_D0048.tif" />

1- [2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4-thiadiazol-3-yl-2- (S) -methoxy-propan-1-one [0246]. as a mixture of diastereomers.

MS ESI (+) m / z 402 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.47 (br, 4H), 7.50 (m, 4H), 7.35 (m, 10H), 7.22 (m, 2H), 7.15 (m, 2H), 4.66 (m, 2H), 3.54 (m, 2H), 3.38 (s, 3H), 3.22 (s, 3H), 3.12 (m, 4H), 2.50 (m, 2H) , 2.15 (m, 2H), 1.88 (m, 1H), 1.78 (m, 1H), 1.54 (d, 3H, J = 6Hz), 1.37 (d, 3H, J = 7 Hz). Example 38 [0247]

<img file="PL1809280T3_D0049.tif" />

[2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazol-3-yl- (tetrahydrofuran-3-yl) -methanone [0248] Obtained as a mixture diastereomers:

MS ESI (+) m / z 414 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.19 (br, 3H), 7.52 (m, 2H), 7.35 (m, 5H), 7.24 (m, 1H), 7.14 (m, 1H), 4.06 -3.73 (m, 5H), 3.5-3.3 (m, 2H), 3.2-2.9 (m, 2H), 2.45-2.05 (m, 4H).

Example 39

[0249]

<img file="PL1809280T3_D0050.tif" />

N - ((S) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -3-methyl- 1-oxobutan-2-yl) -acetamide (diastereomer A)

[0250] Coupling with N-acetyl-L-valine gives diastereomeric products which are isolated using silica gel chromatography (1: 1 hexanes: ethyl acetate). The more polar diastereomer (Boc-protected diastereomer A) is subjected to t-butoxycarbonyl removal as in Example 7 to give the product as the di-HCl salt.

MS ESI (+) m / z 457 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.52-7.16 (m, 8H), 7.20 (m, 1H), 5.13 (d, 1H, J = 4Hz), 3.31-2.92 (m, 2H ), 2.98 (m, 1H), 2.40 (m, 1H), 2.07 (s, 3H), 1.84 (m, 1H), 1.69 (m, 1H), 1.41 (m, 1H), 1.08 (d, 3H, J = 6.3Hz), 0.87 (d, 3H, J = 7.0Hz).

Example 40

[0251]

<img file="PL1809280T3_D0051.tif" />

N - ((S) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -3-methyl- 1-oxobutan-2-yl) -acetamide (diastereomer B)

[0252] Prepared as described in example 39 using a less polar diastereomer (Boc-protected diastereomer B).

MS ESI (+) m / z 457 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.33 (br s, 3H), 7.50-7.13 (m, 8H), 6.76 (m, 1H), 5.43 (m, 1H), 3.31 (m, 1H ), 3.19-2.81 (m, 2H), 2.57 (m, 1H), 2.36 (1H), 2.16 (m, 1H), 1.81 (m, 4H), 1 . 04 (m, 3H), 0.93 (d, 3H, J = 7.8Hz).

Example 41

[0253]

<img file="PL1809280T3_D0052.tif" />

(2S) -1- (2- (3-Aminopropyl) -5- (3-chlorophenyl) -2-phenyl-1,3_l4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 one

[0254] Obtained as a mixture of diastereomers.

MS APCI (+) m / z 418,420 (M + 1, C1 band) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.46 (br, 4H), 7.65 (s, 2H), 7.50 (m, 6H), 7.42 (d, 2H, J = 8Hz), 7.32 (m, 6H ), 7.22 (m, 2H), 4.66 (m, 2H), 3.52 (m, 2H), 3.38 (s, 3H), 3.22 (s, 3H), 3.12 (m, 4H), 2.50 (m, 2H), 2.15 (m, 2H), 1.74 (m, 2H), 1.54 (d, 3H, J = 7Hz), 1.37 (d, 3H, J = 6Hz).

Example 42

[0255]

<img file="PL1809280T3_D0053.tif" />

Preparation of (2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one

[0256] To a solution of tert-butyl 3- (5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propylcarbamate (50 mg, 0.05 11 mmol) and (S) -2-methoxypropanoic acid (22 μΙ, 0.23 mmol) in DMF (1 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (55 mg, 0.29 mmol) ) and triethylamine (48 µΙ, 0.35 mmol). After stirring for 64 hours, the reaction mixture was partitioned between ethyl acetate (20 ml) and saturated NaHCO.₃ (20 ml). The aqueous layer was extracted with ethyl acetate (20 ml) and the combined organic phases were washed with water (5 x 10 ml) and brine (10 ml). The solution is dried over Na₂SO₄ and concentrated under reduced pressure. The residue was chromatographed (9: 1 to 4: 1 hexanes / ethyl acetate) to provide the Boc-protected product (33 mg, 55%) as a pale yellow gum. TFA (1 mL) was added to a solution of this product (33 mg, 0.06 mmol) in dichloromethane (4 mL) at 0 ° C. After stirring for 20 minutes, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 ml) and saturated NaHCO.₃ (20 ml). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic phases are washed with brine (10 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the product as a mixture of diastereomers as a colorless gum (26 mg, 97%).

MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) 7.52 (m, 1H), 7.45 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.14 (m, 2H), 4.71 ( m, 1H), 3.35 (d, 3H, J = 34Hz), 3.28 (m, 1H), 2.91 (br, 2H), 2.72 (br, 2H), 2.43 ( m, 1H), 1.98 (m, 1H), 1.56 (m, 1H), 1.47 (dd, 3H, J = 6.6Hz, 24.3Hz).

[0257] The following examples were prepared as described above in Example 42 using the appropriate thiohydrazide, ketone and acid.

Example 43

[0258]

<img file="PL1809280T3_D0054.tif" />

(2S) -1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylbutan-1-one

[0259] Obtained as a mixture of diastereomers.

MS ESI (+) m / z 418 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H), 7.11 (m, 2H), 3.34 (m, 1H), 3.22 (m, 1H), 2.87 (br, 2H), 2.73 (br, 2H), 2.38 (m, 1H), 1.96 (m, 1H) , 1.74 (m, 1H), 1.54 (m, 1H), 1.43 (m, 1H), 1.16 (m, 3H), 0.91 (dt, 3H, J = 7.4 Hz, 35.2 Hz).

Example 44

[0260]

<img file="PL1809280T3_D0055.tif" />

(2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (cyclopropyl) -methanone

[0261] MS ESI (+) m / z 402 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.60 (m, 1H), 7.43 (m, 2H), 7.35 (m, 2H), 7.26 (m, 1H), 7.10 (m, 2H), 3.30 (br, 1H), 3.16 (m, 1H), 2.87 (br, 1H), 2.75 (m, 1H), 2.35 (m, 1H), 1.97 (m, 1H) , 1.60 (m, 1H), 1.03 (m, 1H), 0.90 (m, 3H).

Example 45

[0262]

<img file="PL1809280T3_D0056.tif" />

MeO (2S) -1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2- (3-fluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) - 2-methoxypropan-1-one

[0263] Obtained as a mixture of diastereomers.

MS ESI (+) m / z 438 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J = 8Hz), 7.14 (m, 3H), 6.98 (m, 1H ), 4.68 (m, 1H), 3.37 (m, 1H), 3.35 (d, 3H, J = 34Hz), 2.93 (m, 2H), 2.40 (m, 1H ), 1.99 (m, 1H), 1.62 (m, 1H), 1.48 (dd, 3H, J = 6.6Hz, 26Hz), 1.36 (m, 1H), 1, 25 (m, 1H).

Example 46

[0264]

<img file="PL1809280T3_D0057.tif" />

Preparation of 1- [2- (3-dimethylaminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4l-thiadiazol-3-yl-2-methylpropan-1-one

[0265] To a solution of 1- (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one ( 9.0 mg, 0.02 mmol) in MeOH (1 mL) was added paraformaldehyde (10 mg, 0.40 mmol). The mixture was heated to 70 ° C for 2 hours. The mixture is allowed to cool to room temperature and sodium cyanoborohydride (0.07 ml, 0.07 mmol, 1M solution in THF) is added. After stirring for 40 minutes, the mixture was diluted with half saturated NaCl (50 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases are washed with saturated NaCl, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% triethylamine, 40% ethyl acetate in hexanes) to give the final product (3.0 mg, 30%) as a pale yellow film.

MS ESI (+) m / z 414 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (m, 3H), 7.36 (m, 5H), 7.14 (m, 1H), 3.51 (m, 1H), 3.17 (m, 1H), 2.40 (m, 3H), 2.23 (s, 6H), 1.92 (m, 1H), 1.53 (m, 1H), 1.20 (d, 3H, J = 7Hz), 1.18 (d, 3H, J = 7Hz).

Example 47

<img file="PL1809280T3_D0058.tif" />

[0266]

Preparation of 1- [5- (3-fluorophenyl) -2- (3-isopropylaminopropyl) -2-phenyl- [1,3,4] thiadiazol-3-yl] -2-methylpropan-1-one [0267] A mixture of 1- ( 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one (9.0 mg, 0.02 mmol) and acetone (20 mg, 0.40 mmol) in acetonitrile (0.5 ml) was stirred at room temperature for 1 hour. To this mixture is added sodium triacetoxyborohydride (33 mg, 0.20 mmol). After stirring at room temperature for 16 hours, more acetone (50 μΙ) and sodium triacetoxyborohydride (14 mg) were added. The reaction mixture was heated to 45 ° C for 40 hours and then diluted with 10% Na₂WHAT₃ (30 ml). The mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% thetylamine, 40% ethyl acetate in hexanes) to give the product (5.4 mg, 50%) as a pale yellow film.

MS ESI (+) m / z 428 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (d, 2H, J = 8Hz), 7.42 (d, 1H, J = 7Hz), 7.37 (m, 4H), 7.27 (m, 1H), 7, 14 (m, 1H), 3.50 (m, 1H), 3.21 (m, 1H), 2.80 (m, 1H), 2.73 (m, 2H), 2.39 (m, 1H ), 1.95 (m, 1H), 1.56 (m, 1H), 1.19 (d, 3H, J = 6Hz), 1.17 (d, 3H, J = 6Hz), 1, 05 (d, 6H, J = 6Hz).

Example 48

[0268]

<img file="PL1809280T3_D0059.tif" />

Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl [1,3,4] thiadiazole-3-carboxylic acid methylpyridin-2-ylamide

[0269] Thphosgene (110 mg, 0.37 mmol) is added to a solution of methylpyridin-2-ylamine (77 mg, 0.71 mmol) and thetylamine (150 mg, 0.15 mmol) in dichloroethane (3 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and diluted with dichloroethane (3 ml). To this solution is added {3- [5- (3-fluorophenyl) -2-phenyl-2,3-dihydro- [1,3,4] thiadiazol-2-yl] -propyl} -carbamic acid tert-butyl ester (250 mg, 0.60 mmol) and DMAP (20 mg). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (1: 8 ethyl acetate / hexanes) to provide the Boc-protected product (210 mg, 54%) . To this product (65 mg, 0.12 mmol) was added HCl (3 mL, 4M in dioxane) at 0 ° C. After warming to room temperature and stirring for 3 minutes, the mixture was concentrated to give the final product as the trihydrochloride salt (64mg, 97%).

MS APCI (+) m / z 450 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.62 (m, 3H), 7.60 (d, 2H, J = 6 Hz), 7.35 (m, 5H), 7.19 (d, 1H, J = 7 Hz), 7, 13 (m, 1H), 7.06 (d, 1H, J = 8Hz), 3.67 (s, 3H), 3.50 (m, 1H), 3.25 (m, 1H), 3. 13 (m, 1H), 2.50 (m, 1H), 2.23 (m, 2H).

Example 49

[0270]

<img file="PL1809280T3_D0060.tif" />

2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazole-3-carboxylic acid pyridin-3-ylamide

[0271] Prepared as described above in Example 48 using pyridin-3-amine in place of methylpyridin-2-ylamine.

MS APCI (+) m / z 436 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.75 (d, 1H), 8.29 (m, 1H), 7.78 (m, 1H), 7.73 (m, 1H), 7.52 (m, 3H), 7.40 (m, 3H), 7.35 (m, 2H), 7.18 (m, 1H), 3.39 (m, 2H), 3.23 (m, 1H) , 3.13 (m, 1H), 3.06 (m, 1H), 2.58 (m, 1H), 2.25 (br, 1H), 2.00 (br, 1H).

Example 50

[0272]

<img file="PL1809280T3_D0061.tif" />

Preparation of (2S) -1- (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxy-3-methylbutane- 1-one (diastereomer A)

Combine (S) -2-Hydroxy-3-methylbutyric acid (13.5mg, 0.11mmol) and PyBOP (60mg, 0.12mmol) in THF (0.4ml) and stir within 10 minutes. To this mixture is added {3- [5- (3-fluoro-phenyl) -2-phenyl-2,3-dihydro- [1,3,4] thiadiazol-2-yl] -propyl} carbamic acid tert-butyl ester (20 mg , 0.05 mmol) and DIEA (31 mg, 0.24 mmol). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 10% Na₂WHAT₃ (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was chromatographed (1: 4 ethyl acetate / hexanes) to provide the Boc-protected diastereomer A (less polar, 2.0 mg) and the Boc-protected diastereomer B (more polar, 4.2 mg). HCl (1 ml, 4M in dioxane) is added to the Boc-protected diastereomer A at 0 ° C. After it was warmed to room temperature and stirred for 1 hour, the mixture was concentrated under the N stream₂. The residue was dissolved in an ether / dioxane mixture and precipitated with hexanes. The precipitate was filtered off and washed with hexanes to give the final product as a yellow solid.

MS ESI (+) m / z 416 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.4 (br s, 3H), 7.5 (m, 2H), 7.43-7.28 (m, 4H), 7.24-7.11 (m, 3H), 4.66 (br s, 1H), 3.30 (br s, 1H), 3.15-2.92 (m, 2H), 2.73 (m, 1H), 2.30 (m, 1H), 2, 18 (m, 1H), 1.81-1.49 (m, 2H), 1.10 (brm, 3H), 0.9 (brm, 3H).

Example 51

[0274]

<img file="PL1809280T3_D0062.tif" />

(2S) -1- (2- (3-AminoDroDvlo) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxy-3-methylbutan-1 -on (diastereomer B)

[0275] Prepared as described above in Example 50 using the more polar Boc-protected B diastereomer.

MS ESI (+) m / z 416 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.3 (br s, 3H), 7.65 (m, 2H), 7.457.30 (m, 5H), 7.28-7.12 (m, 2H), 4.89 (br s, 1H), 3.86 (br m, 1H), 3.13 (br m, 1H) 3.05-2.82 (m, 2H), 2.27-2.14 (m, 2H), 2, 05 (brm, 1H), 1.91 (brm, 1H), 1.02 (d, 3H, J = 7.0Hz), 0.60 (d, 3H, J = 6.3Hz). Example 52

[0276]

<img file="PL1809280T3_D0063.tif" />

2-Amino-1- (2- (3-aminopropyl) -5- (2_l5-difluorophenyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -propan-1-one Step A: Preparation of 1- (2- (3-azidoDroDvlo) -5- (2,5-difluorophenyl) -2-phenyl-1 Tert-Butyl, 3,4-thiadiazol-3 (2H) -yl) -1-oxopropan-2-ylcarbamate: 2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro 1,3,4-thiadiazole (50 mg, 0.139 mmol; prepared as in Example 70) was dissolved in 2.0 mL of DMF. Then 2- (tert-butoxycarbonyl) propanoic acid (39 mg, 0.208 mmol), EDCI (40 mg, 0.208 mmol), HOBt (28 mg, 0.208 mmol) and TEA (0.058 ml, 0.417 mmol) are added and the mixture stirred. at 23 ° C. After 12 hours, the reaction mixture was quenched by the addition of saturated NaHCO solution₃, extracted (3 × 15 mL ethyl acetate), the combined organic phases are washed with water (1 × 50 mL) then dried over Na₂SO₄ and concentrated in vacuo. The crude residue was purified by chromatography (20% ethyl acetate / hexanes) to afford the product as a white foam (70 mg, 94%).

MS APCI (-) m / z 529 (M-1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.43 (m, 2H), 7.37 (t, 2H, J = 8Hz), 7.30 (m, 1H), 7.12 (m, 2H ), 5.23 (brs, 0.5H), 5.12 (brs, 0.5H), 3.44 (m, 2H), 3.19 (m, 1H), 2.47 (m, 1H), 1.57 (d, 2H, J = 9Hz), 1.43 (m, 12H), 0.89 (m, 1H).

Step B: Preparation of 2-amino-1- (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - propan-1-one: 1- (2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -1-oxopropan-2 tert-Butyl -ylcarbamate (70 mg, 0.131 mmol) is dissolved in 7.0 mL of EtOH. Then HCl (0.65 mL, 0.659 mmol) was added and the reaction mixture was stirred at 23 ° C for 4 hours. The reaction mixture was then concentrated and purified by chromatography (2-10% MeOH / DCM) to give the product (54 mg, 95%) as yellow oil.

MS ESI (+) m / z 431 (M + 1) detected; ¹1 H NMR (400 MHz, CD₃OD) δ 7.69 (m, 1H), 7.53 (d, 2H, J = 8Hz), 7.42 (t, 2H, J = 7Hz), 7.34 (m, 3H), 4 , 91 (m, 3H), 3.21 (m, 1H), 3.17 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1H), 1.99 (m, 1H), 1.73 (d, 1.5 H, J = 8Hz), 1.64 (d, 1.5H, J = 8Hz).

[0279] Step C: Preparation of 2-amino-1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - propan-1-one: 2-Amino-1 - (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -propane -1-one (50 mg, 0.116 mmol) is dissolved in 5.0 mL of MeOH. HCl (0.46 mL, 0.464 mmol) is added then N is introduced and removed again₂. Then Pd / C (12 mg, 0.011 mmol) is added followed by the introduction of the H balloon₂. After 40 h at 23 ° C, the reaction mixture was concentrated in vacuo to give the product (41 mg, 87%) as a cream / yellow foam.

MS ESI (+) m / z 405 (M + 1) detected; ¹1 H NMR (400 MHz, CD₃OD) δ 7.68 (m, 1H), 7.53 (m, 2H), 7.42 (t, 2H, J = 9Hz), 7.34 (m, 3H), 4.92 (m, 1H), 3.22 (m, 2H), 3.17 (m, 4H), 2.65 (m, 2H), 2.20 (m, 1H), 1.99 (m, 1H), 1. 72 (d, 1.5H, J = 8Hz), 1.66 (d, 1.5H, J = 8Hz).

Example 53

[0280]

<img file="PL1809280T3_D0064.tif" />

(2S) -1- (2- (3-AminoDroDvlo) -5- (2,5-difluorophenyl) -2- (3-hydroxyphenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxypropane -1 -on

[0281] Prepared as described above in Example 52 using the appropriate thiohydrazide, ketone and carboxylic acid to give the Boc-protected product. To this product (0.087 g, 0.167 mmol) dissolved in ether (5 mL) was added HCl (0.654 mL, 1.67 mmol, ether solution). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to yield the final product as a mixture of diastereomers.

MS ESI (+) m / z 422 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.43 (m, 2H), 7.36 (m, 3H), 7.33 (m, 1H), 7.15 (m, 2H), 5.03 (s, 1H), 4.83 (m, 1H), 3.19 (m, 1H), 2.93 (m, 2H), 2.42 (m, 1H), 1.57 (m, 4H), 1.49 (d, 3H) .

Example 54

[0282]

<img file="PL1809280T3_D0065.tif" />

Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl [1,3,4] thiadiazole-3-carboxylic acid 2-methoxvetyl ester

[0283] Phosgene (54 mg, 0.54 mmol, 20 wt% in toluene) is added to a solution of 2-methoxyethanol (30 mg, 0.4 mmol) in acetonitrile (3 mL) at 0 ° C. After warming to room temperature and stirring for 6 hours, the mixture was concentrated under reduced pressure. Dichloromethane (4 ml), {3- [5- (3-fluorophenyl) -2-phenyl-2,3-dihydro- [1,3,4] thiadiazol-2-yl] -propyl acid tert-butyl ester are added to the residue } -carbamic acid (90 mg, 0.22 mmol), triethylamine (33 mg, 0.32 mmol) and DMAP (10 mg). After stirring for 1 hour, MeOH (0.5 mL) was added to quench the reaction mixture. The mixture was concentrated under reduced pressure and purified by flash column chromatography (8: 1 hexanes / ethyl acetate) to provide the Boc-protected product (90 mg, 80%). To 41 mg of this product was added HCl (3 mL, 4M in dioxane) at 0 ° C. After warming to room temperature and stirring for 1 hour, the mixture was concentrated to give the final product as the dihydrochloride salt (39 mg, 100%).

MS APCI (+) m / z 418 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.45 (br, 2H), 7.55 (m, 2H), 7.36 (m, 5H), 7.25 (m, 1H), 7.10 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.33 (s, 3H), 3.22 (m, 1H), 3.10 (m, 2H), 2.53 (m, 1H) , 2.18 (m, 1H), 1.91 (m, 1H), 1.77 (s, 2H).

Example 55

[0284]

<img file="PL1809280T3_D0066.tif" />

Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl- [1,3,4] thiadiazole-3-carboxylic acid ethylamide

[0285] To a solution of {3- [5- (3-fluorophenyl) -2-phenyl-2,3-dihydro [1,3,4] thiadiazol-2-yl] -propyl} -carbamic acid tert-butyl ester ( 40 mg, 0.096 mmol) in dichloroethane (3 ml) is added ethyl isocyanate (140 mg, 1.9 mmol). After stirring at 60 ° C for 1 hour, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (8: 1 hexanes / ethyl acetate) to provide the Boc-protected product (40 mg, 85%). To this product is added HCl (3 mL, 4M in dioxane) at 0 ° C. After warming to room temperature and stirring for 1 hour, the mixture was concentrated to afford the final product as the dihydrochloride salt (37mg, 98%).

MS APCI (+) m / z 387 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.44 (br, 2H), 7.49 (m, 2H), 7.34 (m, 5H), 7.24 (m, 1H), 7.10 (m, 1H), 6.19 (m, 1H), 3.26 (m, 3H), 3.04 (m, 1H), 2.99 (m, 1H), 2.44 (m, 1H), 2.11 (m, 1H) , 1.92 (m, 1H), 1.15 (t, 3H).

Example 56

[0286]

<img file="PL1809280T3_D0067.tif" />

MeO

Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -N- (2-methoxyethyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide

Step A: Preparation of 4-nitrophenyl 2- (3- (tert-butoxycarbonyl) -DroDvlo) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxylate: To a solution of tert-butyl 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propylcarbamate (350 mg, 0.84 mmol) in dichloromethane (3 ml), triethylamine (110 mg, 1.10 mmol) and 4-nitrophenyl chloroformate (220 mg, 1.00 mmol) are added. After stirring for 1 hour, the reaction mixture was diluted with 1M HCl (5 ml) and dichloromethane (10 ml). The organic layer is dried over Na₂SO₄, filtered, and concentrated under reduced pressure to provide the product.

Step B: Preparation of 2- (3-aminoDroDvlo) -5- (3-fluorophenyl) -N- (2-methoxvetyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) - carboxamide: For a solution of 4-nitrophenyl 2- (3- (tert-butoxycarbonyl) propyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3- (2H) -carboxylate (90 mg, 0 20 mmol) in dichloroethane (3 ml), 2-methoxy-N-methylethanamine (70 mg, 0.80 mmol) and DIEA (100 mg, 0.80 mmol) are added. After stirring at 50 ° C for 6 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (1:10 ethyl acetate / hexanes) to provide the Boc-protected product (60 mg, 70%). To this product is added HCl (3 mL, 4M in dioxane) at 0 ° C. After warming to room temperature and stirring for 1 hour, the mixture was concentrated to afford the final product as the dihydrochloride salt (50 mg, 83%).

MS APCI (+) m / z 431 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.41 (br, 2H), 7.55 (m, 2H), 7.32 (m, 6H), 7.09 (m, 1H), 3.63 (m, 3H), 3.35 (s, 3H), 3.01 (s, 3H), 2.41 (m, 1H), 2.05 (m, 1H), 1.80 (m, 2H), 1.26 (m, 2H) 0.88 (m, 1H).

[0289] The following examples were prepared as described above in Example 56 using the appropriate amine.

Example 57

[0290]

<img file="PL1809280T3_D0068.tif" />

2- (3-Aminopropyl) -N-cyclopropyl-5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide

[0291] MS APCI (+) m / z 399 (M + 1) detected.

Example 58

[0292]

<img file="PL1809280T3_D0069.tif" />

[0293] MS APCI (+) m / z 417 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.30 (br, 2H), 7.47 (m, 2H), 7.32 (m, 5H), 7.23 (m, 1H), 7.10 (m, 1H), 6.58 (m, 1H), 3.42 (m, 3H), 3.35 (s, 3H), 3.25 (m, 1H), 3.01 (m, 2H), 2.46 (m, 2H) , 2.10 (m, 1H), 1.88 (m, 1H).

Example 59

[0294]

<img file="PL1809280T3_D0070.tif" />

2- (3-Aminopropyl) -N-ethyl-5- (3-fluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide MS APCI (+) m / z 401 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.36 (br, 2H), 7.52 (m, 2H), 7.32 (m, 5H), 7.21 (m, 1H), 7.09 (m, 1H), 3.39 (m, 2H), 3.25 (m, 1H), 2.97 (m, 1H), 2.92 (s, 3H), 2.39 (m, 1H), 2.16 (m, 1H) , 2.06 (m, 1H), 1.84 (m, 1H), 1.22 (m, 3H).

Example 60

[0296]

<img file="PL1809280T3_D0071.tif" />

2- (3-Aminopropyl) -N_lN-diethyl-5- (3-fluorophenyl) -2-phenyl-1_l3_l4-thiadiazole-3 (2H) -carboxamide MS APCI (+) m / z 415 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.42 (br, 2H), 7.52 (m, 2H), 7.33 (m, 5H), 7.21 (m, 1H), 7.08 (m, 1H), 3.35 (m, 4H), 3.24 (m, 1H), 2.96 (m, 2H), 2.46 (m, 1H), 2.07 (m, 1H), 1.85 (m, 1H) . 1.20 (m, 6H).

Example 61

[0298]

<img file="PL1809280T3_D0072.tif" />

2- (3-Aminopropyl) -5- (3-chlorophenyl) -N_lN-dimethyl-2-phenyl-1_l3_l4-thiadiazole-3 (2H) -carboxamide MS APCI (+) m / z 403,405 (M + 1, band C1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.44 (br, 2H), 7.62 (s, 1H), 7.54 (d, 2H), 7.45 (d, 1H), 7.36 (d, 1H), 7.32 (m, 3H), 7.23 (m, 1H), 3.29 (m, 1H), 3.00 (s, 6H), 2.91 (m, 1H), 2.38 (m, 1H) , 2.07 (m, 1H), 1.87 (m, 1H), 1.72 (m, 1H).

Example 62

[0300]

<img file="PL1809280T3_D0073.tif" />

Preparation of (2R) -1- (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one (diastereomer A)

Step A: Preparation of 3- (3 - ((R) -2 - ((2,2-dimethyl-1,1-diphenylpropyl) -dimethylsilyloxy) propanoyl) -5- (3-fluorophenyl) -2-phenyl Tertbutyl -2,3-dihydro-1,3,4-thiadiazol-2-yl) propylcarbamate: For (R) -2 - ((2,2-dimethyl-1,1-diphenylpropyl) -dimethylsilyloxy) acid solution Propane (181 mg, 0.36 mmol) and DIEA (78 mg, 0.60 mmol) in acetonitrile (1 mL) is added HATU (137 mg, 0.36 mmol). After stirring at room temperature for 10 minutes, a solution of tert-3 (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -propylcarbamate is added. -butyl (100 mg, 0.24 mmol) in acetonitrile (1 mL). After stirring for 3 hours, PyBOP (150 mg), DIEA (100 µL) and more 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4 are added. -thiadiazol-2-yl) propyl tert-butyl carbamate (45 mg). After stirring for 16 hours, the reaction mixture was diluted with 10% Na₂WHAT₃ (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with brine (40 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue is chromatographed (1: 9 ethyl acetate / hexanes) to afford N-Boc-O-TBDPS-protected diastereomer A (more polar, 74 mg, 40%) and N-Boc-O-TBDPS-protected diastereomer B (less polar, 35 mg, 19%).

[0302] Step B: Preparation of (2R) -1 - (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- hv-hydroxypropan-1-one (diastereomer A): To a solution of N-Boc-O-TBDPS-protected diastereomer A (36 mg, 0.047 mmol) in THF (0.5 mL) is added TBAF (94 μΙ 1.0 M solution in THF). After stirring for 3 hours at room temperature, the mixture was diluted with half saturated NaHCO₃ (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with brine (30 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide NBoc-protected diastereomer A (18 mg, 80%). HCl (0.5 ml of a 4.0 M solution in dioxane) is added to a cooled (0 ° C) solution of this product in dioxane (0.5 ml). After warming to room temperature, the mixture was stirred for 4.5 hours. The reaction mixture was concentrated under reduced pressure and dissolved in a little dioxane and then precipitated with ether to afford the final product (3.9 mg, 70%).

MS ESI (+) m / z 388 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.40 (m, 8H), 7.19 (m, 1H), 4.98 (m, 1H), 3.32 (m, 1H), 3.05 (m, 2H), 2, 56 (m, 1H), 2.18 (m, 1H), 1.70 (m, 1H), 1.57 (m, 3H). Example 63 [0303]

<img file="PL1809280T3_D0074.tif" />

(2R) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one (diastereomer B)

[0304] Prepared as described above in Example 62 using diastereomer B protected N-Boc-O-TBDPS from step A of Example 62.

MS ESI (+) m / z 388 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.53-7.30 (m, 8H), 7.19 (m, 1H), 5.10 (m, 1H), 3.53 (m, 1H), 3.24-2.95 (m, 2H), 2.55 (m, 1H), 2.19 (m, 1H), 1.87 (m, 1H), 1.49 (m, 3H).

Example 64

[0305]

NH, La Ph \ // ^ ~ AN — NF

3.....

Preparation of (S) -1 - ((S) -2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 -on

Step A: Preparation of 3 - ((S) -3 - ((S) -2- (tert-butyl-diphenylsilyloxy) -propanoyl) -5- (3-fluorophenyl) 2-phenyl-2,3-dihydro-1 Tert-Butyl, 3,4-thiadiazol-2-yl) propylcarbamate: For a solution of 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) tert-Butyl-propylcarbamate (0.54 g, 1.30 mmol) and (S) -2- (tert-butyldiphenylsilyloxy) propanoic acid (0.64 g, 1.95 mmol) in DMF (10 ml) are added PyBOP (1.01 g, 1.95 mmol) followed by DIEA (0.34 g, 2.60 mmol). After stirring at room temperature for 14 hours, the reaction mixture was partitioned between 10% Na₂WHAT₃ (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (40 ml). The combined organic phases are washed with brine (100 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was chromatographed (1: 9 to 1: 4 ethyl acetate / hexanes) to provide the less polar diastereomer (180 mg, 19%) as a yellow syrup.

[0307] Step B: Preparation of 3 - ((S) -5- (3-fluorophenyl) -3 - ((S) -2-hydroxypropanoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol- Tert-Butyl 2-yl) propylcarbamate: For a cooled (0 ° C) solution of 3- (3 ((S) -2- (tert-butyldiphenylsilyloxy) propanoyl) -5- (3-fluorophenyl) -2-phenyl- Tert-Butyl 2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl carbamate (180 mg, 0.25 mmol) in THF (2.5 mL) is added TBAF (0.40 mL of a 1M solution of in THF). After being stirred at room temperature for 2 hours, the volume was reduced in vacuo and the mixture was diluted with half-saturated NaHCO.₃ (30 ml). The mixture is extracted with ethyl acetate (3 x 20 ml) and the combined organic phases are washed with brine (30 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (95 mg, 79%) as a sticky yellow syrup. [0308] Step C: Preparation of (S) -1 - ((S) -2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl ) -2-methoxy-Drooan-1-one: For the solution of 3 - ((S) -5- (3-fluorophenyl) -3 - ((S) -2-hydroxypropanoyl) 2-phenyl-2,3-dihydro-1, Tert-Butyl 3,4-thiadiazol-2-yl) propylcarbamate (64 mg, 0.13 mmol) in acetonitrile (1.3 ml) is added Ag₂O (150 mg, 0.66 mmol) followed by iodomethane (190 mg, 1.3 mmol). After stirring at room temperature for 9 hours, the mixture was filtered, concentrated under reduced pressure and chromatographed (20% ethyl acetate in hexanes) to provide the Boc-protected product (30 mg, 45%). To this product is added HCl (0.5 ml of a 4M solution in dioxane). After stirring at 0 ° C for 10 minutes, then at room temperature for 90 minutes, the mixture was concentrated under reduced pressure to provide the product (26 mg, 95%) as the di-HCl salt.

MS ESI (+) m / z 402 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.38 (m, 6H), 7.30 (m, 2H), 7.19 (m, 1H), 4.86 (br q, 1H, J = 6.3Hz), 3.43 (s, 3H), 3.36 (m, 1H), 3.12 (m, 2H), 2.56 (m, 1H), 2.21 (m, 2H), 1.44 (m, 3H) .

[0309] The absolute stereochemistry is determined by examining the co-crystal structure of the protein: Eg5 inhibitor and (S) -1 - (S) -2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1, 3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one.

Example 65

[0310] (2R) -1- (2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1-on

[0311] Prepared as described in Example 42 using appropriately substituted reagents.

MS (+) m / z 402 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.49-7.29 (m, 8H), 7.20 (m, 1H), 4.77 (br 1.1H, J = 6.3Hz), 3.35-3.26 ( m, 4H), 3.10 (m, 2H), 2.61 (m, 1H), 2.22 (m, 1H), 1.68 (m, 1H), 1.52 (m, 3H).

Example 66

[0312]

<img file="PL1809280T3_D0075.tif" />

(S) -1 - ((S) -2- (3-Aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-ethoxypropane -1on

[0313] Prepared as described in Example 64 using ethyl iodide in place of methyl iodide.

MS (+) m / z 416 (M + 1) detected; ¹H NMR (400 MHz, 10: 1 CDCl₃: CD₃OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J = 6.3Hz), 3.68- 3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H), 2.21 (m, 1H), 1.72 (m , 1H), 1.47 (d, 3H, J = 6.3Hz), 1.24 (m, 3H).

Stereochemistry was determined by interference with (S) -1 - ((S) -2- (3-aminopropyl) -5- (3-fluorophenyl) -2phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-methoxypropan-1-one.

Example 67

[0314]

<img file="PL1809280T3_D0076.tif" />

Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazolo-3 (2H) -carboxamide

Step A: Preparation of 3- (5- (3-fluorophenyl) -3- (1-carbonyl-3-methylimidazoliodide) -2-phenyl-2,3-dihvdro-1,3,4-thiadiazol-2- tert-Butyl-yl) -propylcarbamate: For a solution of tert-butyl 3- (5- (3-fluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -propylcarbamate (500 mg, 1.20 mmol) in THF (8 ml) 1,1'-carbonyldiimidazole (234 mg, 1.44 mmol) is added. After heating to 70 ° C in a sealed vessel for 2 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 ml) and washed with 0.5 M HCl (2 x 10 ml). The organic layer is dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude imidazole intermediate. To this product, acetonitrile (3 mL) is added followed by methyl iodide (854 mg, 6.02 mmol). After stirring at room temperature for hours, the mixture was concentrated under reduced pressure to afford the crude product (778 mg, 99%).

Step B: Preparation of 2- (3-aminopropyl) -5- (3-fluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide: To the solution Tert-Butyl 3- (5- (3-fluorophenyl) -3- (1-carbonyl-3-methylimidazoliiodide) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -propylcarbamate N-methoxymethanamine hydrochloride (47 mg, 0.48 mmol) is added (157 mg, 0.241 mmol) and triethylamine (122 mg, 1.21 mmol) in THF (3 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure and chromatographed (10: 1 hexanes / ethyl acetate) to provide the Boc-protected product (87 mg, 72%). To this product is added HCl (2 ml of a 4M solution in dioxane). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure to afford the final product as the dihydrochloride salt.

MS APCI (+) m / z 403 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.43 (br, 2H), 7.54 (br, 2H), 7.36 (m, 5H), 7.22 (m, 1H), 7.11 (m, 1H), 3.74 (s, 3H), 3.34 (br, 1H), 3.16 (s, 3H), 3.06 (br, 2H), 2.50 (br, 1H), 2.12 (br, 1H) , 1.91 (br, 1H).

[0317] The following examples were prepared as described above in Example 67 using the appropriate thiohydrazides, ketones and alkoxyamine or alcohol.

Example 68

[0318]

OMe

2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide

[0319] MS ESI (+) m / z 421 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.79 (br, 3H), 7.47 (m, 1H), 7.40 (d, 2H), 7.34 (m, 2H), 7.28 (d, 1H), 7.11 (m, 2H), 3.68 (s, 3H), 3.17 (s, 3H), 3.13 (m, 1H), 3.06 (m, 1H), 2.97 (m, 1H) , 2.31 (m, 1H), 2.11 (m, 1H), 1.74 (m, 1H).

Example 69

[0320] nh₂

Methyl 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxylate MS APCI (+) m / z 374 (M + 1) detected.

Example 70

[0322]

<img file="PL1809280T3_D0077.tif" />

Ethyl 2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxylate

[0323] MS APCI (+) m / z 388 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.44 (br, 2H), 7.55 (br, 2H), 7.35 (m, 5H), 7.24 (m, 1H), 7.10 (m, 1H), 4.22 (br, 1H), 4.11 (br, 1H), 3.26 (br, 1H), 3.08 (br, 2H), 2.50 (br, 1H), 2.17 (br, 1H) , 1.91 (br, 1H), 1.26 (br, 3H).

Example 71

[0324]

<img file="PL1809280T3_D0078.tif" />

Preparation of (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3.4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 -on

Step A: Preparation of 4-Azido-1-phenylbutan-1-one: To a solution of 4-chloro-1-phenylbutan-1-one (26.4 ml, 164 mmol) in DMSO (200 ml) is added the azide sodium (12.8 g, 197 mmol). The solution was heated to 55 ° C and stirred for 16 hours. The cooled mixture was then treated with water (600 ml) and extracted with ether (3 x 200 ml). The combined organic phases are washed with water (8 x 100 ml) and brine (100 ml) then dried over MgSO₄ and concentrated to give the product as an orange oil (30.7 g, 99%).

Step B: Preparation of 2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole: For the solution of 2,5-difluorobenzothiohydrrazide (1 5 g, 7.97 mmol) in EtOH / dichloromethane (3: 1, 16 mL) is added 4-azido-1-phenylbutan-1-one (1.36 g, 7.17 mmol). After stirring at room temperature for 16 hours, acetic acid (2 drops) was added and the mixture was stirred for a further 16 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9: 1 hexanes / ethyl acetate) to provide the product (1.41 g, 41%) as a light yellow syrup.

[0327] Step C: Preparation of (S) -1 - ((S) -2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- (t-butyldiphenyloxy) -propan-1-one and (S) -1 - ((R) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1 , 3,4-Thiadiazol-3 (2H) -yl) -2- (t-butyldiphenylsilyloxy) -propan-1-one: For (S) -2- (t-butyldiphenylsilyloxy) -propanoic acid solution (339 mg, 1 0.09 mmol) in acetonitrile (6 mL) is added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 1 minute, a solution of 2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.₃ (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2 x 30 ml) and the combined organic phases were washed with brine (20 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9: 1 hexanes / ethyl acetate) to give the less polar diastereomer, (S) -1 - ((S) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2 -phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2 (t-butyldiphenylsilyloxy) -propan-1-one (121 mg) and a more polar diastereomer, (S) -1 - ((R) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- (t-butyldiphenylsilyloxy) propan-1-one ( 175 mg) as a pale yellow oil. The absolute stereochemistry is determined by studying the co-crystalline structure of the protein: Eg5 inhibitor and (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3, 4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one.

[0328] Step D: Preparation of (S) -1 - ((S) -2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one: For the solution of (S) -1 - ((S) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4 -thiadiazol-3 (2H) -yl) -2- (t-butyldiphenylsilyloxy) -propan-1-one (121 mg, 0.18 mmol) in THF (5 ml) at 0 ° C TBAF (0, 31 ml, 1M, 0.31 mmol). After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the mixture was treated with saturated NaHCO.₃ (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with brine (20 ml), dried over Na₂SO₄, filtered and concentrated. The brown oil was chromatographed (4: 1 hexanes / ethyl acetate) to provide the product (41 mg, 53%) as a pale yellow oil.

[0329] Step E: Preparation of (S) -1- (S) -2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one: For the solution of (S) -1 - ((S) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4- thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one (41 mg, 0.095 mmol) in DMF (2 mL) is added methyl iodide (50 µL, 0.48 mmol) at 0 ° C and then sodium hydride (10 mg, 60%). After stirring at 0 ° C for 30 minutes and at room temperature for 3 hours, the mixture was treated with saturated NH₄Cl (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with water (6 x 10 ml) and brine (10 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the product (40 mg, 94%) as a yellow oil.

[0330] Step F: Preparation of (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one: For the suspension of (S) -1 - ((S) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4 -thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one (102 mg, 0.23 mmol) in MeOH (2.2 mL) was added concentrated HCl (57 µL, 0.69 mmol) and then 10% Pd / C (10 mg, wet, Degussa type). It mixes under the H balloon₂ for 1 hour, then the mixture was filtered and concentrated under reduced pressure. The colorless glassy product was triturated with diethyl ether and filtered to give the product as the di-HCl salt as a white solid (89 mg, 79%).

MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.13 (m, 2H), 4.70 (m, 1H), 3.40 (s, 3H), 3.27 (m, 1H), 2.88 (m, 2H), 2.43 (m, 1H), 1.96 (m, 1H) , 1.57 (m, 1H), 1.45 (d, 3H, J = 7Hz). The absolute stereochemistry is determined by studying the co-crystalline structure of the protein: Eg5 inhibitor and (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2phenyl-1,3, 4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one.

Example 72

[0331]

<img file="PL1809280T3_D0079.tif" />

(S) -1 - ((R) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1 -on

[0332] Prepared as described above in example 71 using (S) -1 - ((R) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4- thiadiazol-3 (2H) -yl) -2- (tert-butyldiphenylsilyloxy) propan-1-one from Step C.

MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.71 (q, 1H, J = 6Hz), 3.32 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.43 (m, 1H), 1.93 (m, 1H), 1.50 (d, 3H, J = 6Hz), 1.44 (m, 2H), 1.34 (m, 1H). Stereochemistry is determined by interference with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol3 (2H) - yl) -2-methoxypropan-1-one.

Example 73

[0333]

<img file="PL1809280T3_D0080.tif" />

HO

Preparation of (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one

[0334] To the solution of (S) -1 - ((S) -2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) -2-hydroxypropan-1-one prepared as described in Example 71 (74 mg, 0.172 mmol) in MeOH (5 ml) is added 1N HCl / MeOH (0.5 ml) followed by 10% Pd / C (10 mg, wet, Degussa type). It mixes under the H balloon₂ for 1 hour, then the mixture was filtered and concentrated under reduced pressure. The colorless glassy material was triturated with diethyl ether and filtered to give the product as the di-HCl salt as a white solid (54 mg, 66%).

MS ESI (+) m / z 406 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.47 (m, 2H), 7.39 (t, 2H, J = 7Hz), 7.32 (t, 1H, J = 7Hz), 7, 15 (m, 2H), 4.89 (q, 1H, J = 6Hz), 3.18 (m, 1H), 2.84 (m, 2H), 2.42 (m, 1H), 1. 92 (m, 1H), 1.58 (br, 2H), 1.52 (d, 2H, J = 6.7Hz), 1.48 (d, 3H, J = 6.7Hz). Stereochemistry is determined by interference with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one.

Example 74

[0335]

<img file="PL1809280T3_D0081.tif" />

2 - ((S) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl Tert-butyl) -1-oxopropan-2-yloxy) -acetate

[0336] Prepared as described in Example 71 above using tert-butyl 2-bromoacetate in place of methyl iodide.

MS ESI (+) m / z 520 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.50 (m, 1H), 7.46 (d, 2H, J = 8Hz), 7.34 (m, 2H), 7.27 (m, 1H), 7.13 (m, 2H ), 4.93 (q, 1H, J = 6Hz), 4.18 (d, 1H, J = 16Hz), 3.96 (d, 1H, J = 16Hz), 3.30 (m, 1H), 2.96 (m, 2H), 2.45 (m, 1H), 2.01 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J = 6 Hz), 1.46 (s, 9H). Stereochemistry is determined by interference with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one.

Example 75

[0337]

<img file="PL1809280T3_D0082.tif" />

° \ (R) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one

[0338] Prepared as described above in Example 71 using (R) -2- (t-butyldiphenylsilyloxy) propanoic acid instead of (S) -2- (t-butyldiphenylsilyloxy) propanoic acid.

MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.46 (d, 2H, J = 7Hz), 7.37 (t, 2H, J = 8Hz), 7.30 (t, 1H, J = 7 Hz), 7.13 (m, 2H), 4.71 (q, 1H, J = 6Hz), 3.32 (s, 3H), 3.24 (m, 1H), 2.83 (m, 2H), 2.43 (m, 1H), 1.92 (m, 1H), 1.51 (d, 3H, J = 6Hz), 1.45 (m, 1H). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one and (S) -1 - ((R) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -2-methoxypropan-1-one.

Example 76

[0339]

<img file="PL1809280T3_D0083.tif" />

(R) -1 - ((R) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1 -on

[0340] Prepared as described above in example 75 using (R) -1 - ((R) -2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4- thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one.

MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.44 (d, 2H, J = 7Hz), 7.35 (t, 2H, J = 8Hz), 7.29 (t, 1H, J = 7 Hz), 7.13 (m, 2H), 4.68 (q, 1H, J = 6Hz), 3.41 (s, 3H), 3.24 (m, 1H), 2.85 (m, 2H), 2.43 (m, 1H), 1.95 (m, 1H), 1.54 (br, 3H), 1.46 (d, 3H, J = 6Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one and (S) -1 - ((R) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -2-methoxypropan-1-one.

Example 77

[0341]

<img file="PL1809280T3_D0084.tif" />

O \ (S) -1 - ((S) -5- (2_l5-difluorophenyl) -2- (3- (dimethylamino) propyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one

[0342] Prepared as described above in example 47 using (S) - ((S) -2- (3aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -2-methoxypropan-1-one instead of 1 - (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H ) -yl) -2-methylpropan-1-one.

MS ESI (+) m / z 448 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.56 (m, 1H), 7.49 (d, 2H, J = 7Hz), 7.39 (m, 2H), 7.32 (m, 1H), 7.17 (m, 2H) , 4.73 (m, 1H), 3.44 (s, 3H), 3.26 (m, 1H), 2.56 (m, 1H), 2.49 (m, 2H), 2.34 ( s, 6H), 2.05 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J = 7Hz).

Example 78

[0343] \ NH

<img file="PL1809280T3_D0085.tif" />

Preparation of (S) -1 - ((S) -5- (2,5-difluorophenyl) -2- (3- (methylamino) propyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl ) -2-methoxypropan-1-one

[0344] Step A: Preparation of 3 - ((S) -5- (2,5-difluorophenyl) -3 - ((S) -2-methoxypropanoyl) -2-phenyl-2,3-dihydro-1,3,4- tert-Butyl thiadiazol-2-yl) -propylcarbamate: For a cooled (0 ° C) solution of (S) -1 ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one (50mg, 0.12mmol) in THF (2ml) Boc-anhydride (31mg, 0.14mmol) is added mmoles). After slowly warming to room temperature and stirring for 64 hours, the reaction mixture was concentrated under reduced pressure and chromatographed (DCM to 2% MeOH in DCM) to give the product as a colorless oil (62 mg, 100%).

[0345] Step B: Preparation of (S) -1 - ((S) -5- (2,5-difluorophenyl) -2- (3- (methylamino) propyl) -2-phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -2-methoxypropan-1-one: For a cooled (0 ° C) solution of 3 - ((S) -5- (2,5-difluorophenyl) -3 - ((S) -2-methoxypropanoyl) Tert-Butyl -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propylcarbamate (62 mg, 0.12 mmol) in DMF (2 ml) is added methyl iodide (37 μΙ, 0.6 mmol) followed by NaH (10 mg, 60%). After slowly warming to room temperature and stirring for 16 hours, the mixture was quenched with saturated NH₄Cl (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are washed with water (5 x 20 ml) and brine (20 ml) and then dried over Na₂SO₄. The mixture was concentrated under reduced pressure and chromatographed (9: 1 to 4: 1 hexanes / ethyl acetate) to provide the Boc-protected product (38 mg, 0.071 mmol). To this product are added DCM (2 ml) and TFA (0.5 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.₃ (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic phases are washed with NaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give a yellow oil. The oil is dissolved in ether (2 mL) and treated with 2N HCl in ether (2 mL). The mixture was stirred for 30 minutes, concentrated, and triturated with ether to give the di-HCl product as a yellow solid (31 mg, 51%).

MS ESI (+) m / z 434 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.44 (d, 2H), 7.35 (m, 2H), 7.27 (m, 1H), 7.12 (m, 2H), 4.68 (q, 1H, J = 6Hz), 3.40 (s, 3H), 3.25 (m, 1H), 2.76 (m, 2H), 2.46 (s, 3H), 2.45 (m, 1H), 2.00 (m, 2H), 1.61 (m, 1H), 1.45 (d, 3H, J = 6Hz).

Example 79

[0346]

<img file="PL1809280T3_D0086.tif" />

Preparation of (S) -1 - ((S) -1- (3 - ((S) -5- (2,5-difluorophenyl) -3 - ((S) -2-methoxypropanoyl) -2-phenyl-2, 3dihvdro-1,3,4-thiadiazol-2-yl) -propylamino) -1-oxopropan-2-vlamino) -1-oxopropan-2-vlamino For a solution of (S) -1 - ((S) - 2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) -2-methoxypropan-1-one (25 mg, 0.051 mmol ) and Boc-Ala-Ala-OH (19.8 mg, 0.0766 mmol) in DMF (1 mL) is added PyBOP (52.8 mg, 0.102 mmol) followed by DIEA (44 µL, 0.25 mmol). ). After stirring at room temperature for 64 hours, the mixture was partitioned between saturated NaHCO₃ (20 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases are washed with water (5x10 ml), brine (10 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The orange residue was chromatographed (0-3% MeOH in DCM) to give the Boc-protected product as a colorless glassy substance (30 mg, 89%). TFA (0.5 ml) is added to a cooled (0 ° C) solution of this product in DCM (2 ml). After stirring for 5 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO₃ (10 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organics were washed with brine (10 ml), dried over Na₂SO₄ and concentrated under reduced pressure to give the product as a colorless glassy substance (25mg, 98%).

MS ESI (+) m / z 562 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.79 (br, 1H), 7.50 (m, 1H), 7.42 (d, 2H, J = 8Hz), 7.36 (t, 2H, J = 7Hz), 7, 30 (t, 1H, J = 7Hz), 7.13 (m, 2H), 7.04 (t, 1H, J = 5Hz), 4.65 (q, 1H, J = 6Hz), 4 , 39 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.36 (s, 3H), 3.23 (m, 1H), 3.07 (m, 1H), 2.24 (m, 1H), 1.96 (m, 1H), 1.56 (m, 1H), 1.41 (d, 3H, J = 7Hz), 1.34 (d, 3H, J = 7Hz), 1.26 (m, 3H).

Example 80

[0348]

<img file="PL1809280T3_D0087.tif" />

Preparation of 1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one

Step A: Preparation of 1- (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2,2- dimethylpropan-1-one: To a cooled (0 ° C) solution of 2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole (100 mg , 0.278 mmol) in DCM (5 mL), added triethylamine (50.4 µL, 0.362 mmol) followed by pivaloyl chloride (45 µL, 0.362 mmol). After slowly warming to room temperature and stirring for 16 hours, the mixture was partitioned between DCM (10 mL) and saturated NaHCO.₃ (10 ml). The aqueous layer was extracted with DCM (10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was chromatographed (19: 1 hexanes / ethyl acetate) to provide the product as a pale yellow oil (114 mg, 92%).

Step B: Preparation of 1- (2- (3-aminoDroovlo) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2,2- dimethylpropan-1-one: For the solution of 1- (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2.2 -Dimethylpropan-1-one (100mg, 0.225mmol) in MeOH (3ml) is added 1N HCl / MeOH (1ml) followed by 10% Pd / C (40mg, wet, Degussa type). He mixes under the H balloon₂ for 3 hours, then the mixture was filtered and concentrated under reduced pressure to afford the product as a white foam.

MS ESI (+) m / z 418 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.47 (m, 1H), 7.43 (d, 2H, J = 7Hz), 7.35 (t, 2H, J = 7Hz), 7.25 (m, 1H), 7, 11 (m, 2H), 3.47 (m, 1H), 3.22 (m, 1H), 2.85 (m, 2H), 2.33 (m, 1H), 1.92 (m, 1H) ), 1.48 (m, 2H), 1.39 (s, 9H).

Example 81

[0351]

<img file="PL1809280T3_D0088.tif" />

1- (2- (3-AminoDroDro) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylDrooan-1-one (Enantiomer AND)

[0352] Prepared as described above in Example 80 using isobutyryl chloride in place of pivaloyl chloride. The enantiomers of 1- (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one are separated into chiral column (Chiralcel OJ-H 250 x 10 mm), eluting with 1: 1 EtOH / hexanes to give the more polar A enantiomer and the less polar B enantiomer. Reduction of the azide group of enantiomer A gives the final product.

MS ESI (+) m / z 404 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (d, 2H, J = 8Hz), 7.35 (t, 2H, J = 7Hz), 7.25 (m, 1H), 7, 11 (m, 2H), 3.48 (m, 1H), 3.22 (m, 1H), 2.87 (m, 2H), 2.36 (m, 1H), 1.95 (m, 1H ), 1.57 (m, 3H), 1.18 (dd, 6H, J = 11Hz, 6Hz).

Example 82

[0353]

<img file="PL1809280T3_D0089.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one (Enantiomer B)

[0354] Prepared as described in Example 81 using the less polar B enantiomer.

MS ESI (+) m / z 404 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (d, 2H, J = 8Hz), 7.35 (t, 2H, J = 8Hz), 7.28 (m, 1H), 7, 10 (m, 2H), 3.48 (m, 1H), 3.24 (m, 1H), 2.88 (m, 2H), 2.36 (m, 1H), 2.11 (br, 2H ), 1.96 (m, 1H), 1.57 (m, 1H), 1.18 (dd, 6H, J = 7Hz, 13Hz).

Example 83 (not according to the invention)

[0355]

<img file="PL1809280T3_D0090.tif" />

Preparation of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxy-methoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl-2 -methoxypropan-1-one

Step A: Preparation of 2- (methoxymethoxy) -1-phenylethanone: To a cooled (0 ° C) solution of 2-hydroxyacetophenone (1.0 g, 7.3 mmol) in DMF (50 ml) is added lithium hydride ( 74 mg, 95%, 8.8 mmol). After stirring for 30 minutes, MOM-Cl (0.73 mL, 9.5 mmol) was slowly added via a syringe and the mixture was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture is treated with saturated NH₄Cl (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases are washed with water (6 x 50 ml) and brine (50 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The brown residue was chromatographed (9: 1 to 4: 1 hexanes / ethyl acetate) to give the product as a colorless oil (0.60 g, 45%).

Step B: Preparation of 5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole: For the solution of 2- (methoxymethoxy) -1-phenylethanone (0.60 g, 3.33 mmol) in EtOH / DCM (3: 1, 12 mL) is added 2,5-difluorobenzothiohydrazide (0.63 g, 3.33 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The brown residue was chromatographed (9: 1 hexanes / ethyl acetate) to provide the product as a yellow oil (0.73 g, 63%).

[0358] Step C: Preparation of (S) -2- (t-butyldiphenylsilyloxy) -1 - ((R) -5- (2,5-difluorophenyl) -2 ((methoxymethoxy) methyl) -2-phenyl-1 , 3,4-thiadiazol-3 (2H) -yl) -propan-1-one: To a solution of (S) -2 (tert-butyldiphenylsilyloxy) -propanoic acid (0.70 g, 2.14 mmol) in DMF ( 20 ml) is added 5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.50 g, 1.43 mmol ) followed by PyBOP (1.11 g, 2.14 mmol) and DIEA (497 µL, 2.85 mmol). After stirring at room temperature for 16 hours, the mixture was treated with saturated NaHCO₃ (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with water (6 x 30 ml) and brine (30 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The yellow residue is chromatographed (19: 1 to 9: 1 hexanes / ethyl acetate) to give the less polar (S) -2 (tert-butyldiphenylsilyloxy) -1 - ((R) -5- (2,5-difluorophenyl) diastereomer) -2 - ((methoxymethoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -propan-1-one (110 mg, 12%) and more polar diastereomer (S) -2- (tert-butyldiphenylsilyloxy) -1 - ((S) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-1, 3,4-thiadiazol-3 (2H) -yl) -propan-1-one (146 mg 1: 1 mixture with the starting material) as yellow oils. The absolute stereochemistry is determined by interference with (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 (hydroxymethyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one.

Step D: Preparation of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 ( 2H) -yl) -2-hydroxypropan-1-one: For a cooled (0 ° C) solution of (S) -2- (tert-butyldiphenylsilyloxy) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -propan-1-one (110 mg, 0.17 mmol) in THF (10 ml) is added TBAF ( 0.28 mL, 1.0 M, 0.28 mmol). After slowly warming to room temperature and stirring for 16 hours, the mixture was treated with 0.5 N HCl (30 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic phases are washed with NaHCO₃ (30 mL) and brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The pale yellow residue was chromatographed (9: 1 to 4: 1 hexanes / ethyl acetate) to give the product as a white solid (0.045 g, 64%).

[0360] Step E: Preparation of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl-2-phenyl-1,3,4-thiadiazol-3 (2H) ) -yl) -2-methoxypropan-1-one: For a cooled (0 ° C) solution of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) - 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxypropan-1-one (45 mg, 0.11 mmol) in DMF is added methyl iodide (100 μΙ, 1.6 mmol), then sodium hydride (10 mg). After slowly warming to room temperature and stirring for 16 hours, the mixture was treated with saturated NH₄Cl (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic phases are washed with water (6 × 10 mL) and brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The pale yellow residue was chromatographed (4: 1 to 2: 1 hexanes / ethyl acetate) to give the product as a pale yellow oil (0.040 g, 86%).

MS ESI (+) m / z 437 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.54 (m, 1H), 7.42 (m, 2H), 7.35 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.80 (s, 2H), 4.78 (d, 1H, J = 10Hz), 4.71 (q, 1H, J = 7Hz), 4.59 (d, 1H, J = 10Hz), 3. 43 (s, 3H), 3.39 (s, 3H), 1.48 (d, 3H, J = 7Hz). Stereochemistry is determined by interference with (S) -1 - ((R) -5- (2,5-difluorophenyl) -2- (hydroxymethyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) 2-methoxypropan-1-one.

Example 84 (not according to the invention)

[0361]

<img file="PL1809280T3_D0091.tif" />

S-1 - ((S) -5- (2,5-Difluorophenyl) -2 - ((methoxy methoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1 -on

[0362] Prepared as described above in example 83 using (S) -2- (tert-butyldiphenylsilyloxy) -1 - ((S) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) - 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -propan-1-one from Step C.

MS ESI (+) m / z 437 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.53 (m, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.11 (m, 2H), 4.76 (m, 4H), 4.47 (d, 1H, J = 10Hz), 3.41 (s, 3H), 3.35 (s, 3H), 1.47 (d, 3H, J = 7Hz ). Stereochemistry is determined by interference with (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 (hydroxymethyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl ) -2-methoxypropan-1-one.

Example 85 (not according to the invention)

[0363]

..... °\

Preparation of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2- (hydroxymethyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 -on

[0364] To the solution of (S) -1 - ((R) -5- (2,5-difluorophenyl) -2 - ((methoxymethoxy) methyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxy-1-one (16 mg, 0.037 mmol) in MeOH (2 mL) is added HCl (300 µL of a 6 M solution). After being stirred at 50 ° C for 5 hours, the mixture was cooled to room temperature and partitioned between saturated NaHCO.₃ (20 ml) and ethyl acetate (10 ml). The aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic phases are washed with brine (10 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The pale yellow residue was chromatographed (9: 1 to 2: 1 hexanes / ethyl acetate) to give the product as a colorless gum (4.2 mg, 29%).

MS ESI (+) m / z 393 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.37 (m, 5H), 7.13 (m, 2H), 4.74 (m, 2H), 4.48 (d, 1H, J = 11Hz ), 4.19 (d, 1H, J = 10Hz), 3.44 (s, 3H), 1.59 (m, 3H). The absolute stereochemistry is determined by studying the co-crystalline structure of the protein: Eg5 inhibitor and (S) 1 - ((R) -5- (2,5-difluorophenyl) -2- (hydroxymethyl) -2-phenyl-1,3,4 -thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one.

Example 86 (not according to the invention)

[0365]

<img file="PL1809280T3_D0092.tif" />

Preparation of 1- (2- (3-aminopropyl) -5- (5-chloro-2-methylphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) 2,2-dimethylpropan-1 -on

Step A: Preparation of N '- (4-azido-1-phenylbutylidene) -5-chloro-2-methylbenzohydrazide: To a solution of 5-chloro-2-methylbenzohydrazide (2.70 g, 14.62 mmol) prepared as in Example 1, Step B, 4-azido-1-phenylbutan-1-one (3.04 g, 16.1 mmol) prepared as in Example 70, Step A is added in toluene (100 mL), followed by acid monohydrate p-toluenesulfonic acid (0.28 g, 1.46 mmol). The reaction mixture is heated to reflux and stirred using a Dean-Stark trap for 16 hours. The cooled mixture is diluted with EtOAc (300 mL) and washed with NaHCO₃ (100 ml). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic phases were washed with brine (100 mL), dried over Na₂SO₄ and concentrates. The residue was triturated with ether and filtered to give the product (3.09 g, 59%) as a tan solid.

[0367] Step B: Preparation of 1- (2- (3-azidopropyl) -5- (5-chloro-2-methylphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2, 2-dimethylpropan-1-one: To a solution of N '- (4-azido-1-phenylbutylidene) -5chloro-2-methylbenzohydrazide (100 mg, 0.28 mmol) in pyridine (1 ml) pivaloyl chloride (70 μΙ , 0.56 mmol). After stirring at room temperature for 16 hours, the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases are washed successively with 10% NaHSO₄ (2x10 ml), NaHCO₃ (10 mL) and brine (10 mL) then dried over Na₂SO₄ and concentrates. The residue was purified by preparative TLC (9: 1 hexanes / EtOAc) to provide the product (62 mg, 50%) as colorless oil.

[0368] Step C: Preparation of 1- (2- (3-aminopropyl) -5- (5-chloro-2-methylphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2, 2-dimethylpropan-1-one: For the solution of 1- (2- (3-azidopropyl) -5- (5-chloro-2-methylphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one (62 mg, 0.141 mmol) in methanol (2 ml) PtO is added₂ (5 mg) followed by 1N HCl / MeOH (0.42 mL, 0.42 mmol). The mixture was hydrogenated under a balloon atmosphere for 4 hours, then filtered through GF paper and the filtrate was concentrated. The residue was purified by flash column chromatography (CH₂CI₂ to 3% MeOH / CH₂CI₂ to 10%) to give the product di-HCl which was triturated with hexanes and filtered to give a white solid (18mg, 26%).

MS ESI (+) m / z 414 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.54 (d, 2H, J = 7Hz), 7.33 (m, 4H), 7.22 (d, 1H, J = 9Hz), 3, 36 (m, 1H), 3.08 (m, 1H), 2.99 (m, 1H), 2.63 (s, 3H), 2.46 (m, 1H), 1.78 (m, 2H ). 1.33 (s, 9H).

[0369] The following examples are prepared using the appropriately substituted benzohydrazides, ketones, and acid chlorides.

Example 87 (not according to the invention)

[0370]

<img file="PL1809280T3_D0093.tif" />

(2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (phenyl) -methanone dihydrochloride

[0371] MS ESI (+) m / z 421.9 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.95 (d, 2H, J = 8 Hz), 7.67 (d, 2H, J = 8 Hz), 7.46 (m, 1H), 7.36 (m, 6H), 7, 12 (m, 2H), 3.37 (m, 1H), 3.00 (br s, 2H), 2.63 (m, 1H), 1.86 (m, 2H).

Example 88 (not according to the invention)

<img file="PL1809280T3_D0094.tif" />

[0372]

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one dihydrochloride

[0373] MS ESI (+) m / z 402 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.54 (m, 2H), 7.45 (m, 1H), 7.33 (m, 3H), 7.14 (m, 2H), 3.29 (m, 1H), 3.04 (m, 2H), 2.51 (m, 1H), 1.79 (m, 2H), 1.33 (s, 9H).

Example 89 (not according to the invention)

[0374]

NH,

ZK ⁰ \ - / F '2HCI

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -3-methylbutan-1-one dihydrochloride

[0375] MS ESI (+) m / z 402 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.59 (d, 2H, J = 8Hz), 7.51 (m, 1H), 7.34 (m, 3H), 7.15 (t, 2H, J = 8Hz), 3, 20 (m, 1H), 3.02 (m, 2H), 2.64 (m, 2H), 2.49 (m, 1H), 2.11 (m, 1H), 1.82 (m, 2H ). 0.89 (t, 6H, J = 7Hz).

Example 90 (not according to the invention)

[0376]

<img file="PL1809280T3_D0095.tif" />

1- (2- (3-aminopropyl) -5- (5-chloro-2-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methylpropan-1-one dihydrochloride

[0377] MS ESI (+) m / z 404.4 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.77 (m, 1H), 7.57 (m, 2H), 7.41 (m, 1H), 7.35 (m, 3H), 7.13 (t, 1H, J = 9Hz ), 3.31 (m, 1H), 3.21 (m, 1H), 3.04 (brs, 2H), 2.56 (m, 1H), 1.80 (m, 2H), 1.17 (d, 3H, J = 7Hz), 1.07 (d, 3H, J = 7Hz).

Example 91 (not according to the invention)

[0378]

<img file="PL1809280T3_D0096.tif" />

1- (2- (3-Aminopropyl) -5- (2-chloro-5-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methylpropan-1-one dihydrochloride

[0379] MS ESI (+) m / z 404 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) 8 7.56 (m, 3H), 7.45 (m, 1H), 7.33 (m, 3H), 7.11 (m, 1H), 3.30 (m, 1H), 3.21 (m, 1H), 3.06 (brs, 2H), 2.58 (m, 1H), 1.83 (m, 2H), 1.19 (d, 3H, J = 7Hz), 1.09 (d, 3H, J = 7Hz).

Example 92 (not according to the invention)

[0380]

<img file="PL1809280T3_D0097.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-dichlorophenyl) -2-phenyl-1,3,4-oxadiazole-3 (2H) -2-methylpropan-1-one dihydrochloride

[0381] MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.80 (d, 1H, J = 2Hz), 7.57 (d, 2H, J = 8Hz), 7.42 (d, 1H, J = 8Hz), 7.34 (m, 4H), 3.30 (m, 2H), 3.21 (m, 1H), 3.07 (brs, 1H), 2.57 (m, 1H), 1.82 (m, 2H), 1. 19 (d, 3H, J = 7Hz), 1.09 (d, 3H, J = 7Hz).

Example 93 (not according to the invention)

[0382]

<img file="PL1809280T3_D0098.tif" />

(2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (cyclopropyl-methanone) dihydrochloride

[0383] MS ESI (+) m / z 386 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.58 (m, 2H), 7.52 (m, 1H), 7.36 (m, 3H), 7.16 (m, 2H), 3.02 (m, 1H), 2.84 (brs, 2H), 2.58 (m, 3H), 1.65 (m, 2H), 1.05 (m, 1H), 0.98 (m, 1H), 0.87 (m, 2H) .

Example 94 (not according to the invention)

[0384]

<img file="PL1809280T3_D0099.tif" />

1- (2- (3-Aminopropyl) -5- (2-chloro-5-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2,2-dimethylpropan-1 dihydrochloride -on

[0385] MS ESI (+) m / z 418 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.54 (m, 3H), 7.47 (m, 1H), 7.33 (m, 3H), 7.10 (m, 1H), 3.28 (m, 1H), 3.02 (m, 2H), 2.52 (m, 1H), 1.79 (m, 2H), 1.35 (s, 9H).

Example 95 (not according to the invention)

[0386]

NH,

With α ⁰⁼y- 2HCI ^Cl

1- (2 (-3-Aminopropyl) -5- (2,5-dichlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one dihydrochloride

[0387] MS ESI (+) m / z 435 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.77 (d, 1H, J = 2Hz), 7.55 (d, 2H, J = 6Hz), 7.40 (d, 1H, J = 9Hz), 7.34 (m, 4H), 3.32 (m, 1H), 3.08 (m, 1H), 3.00 (m, 1H), 2.50 (m, 1H), 1.79 (m, 2H), 1. 35 (s, 9H).

Example 96 (not according to the invention)

[0388] .NH,

2— ^{2hci Cl}

1- (2- (3-Aminopropyl) -5- (5-chloro-2-methylphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methylpropan-1-one dihydrochloride

[0389] MS ESI (+) m / z 400 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.56 (d, 2H, J = 8 Hz), 7.33 (m, 4H), 7.22 (d, 1H, J = 9 Hz), 3, 26 (m, 2H), 3.03 (m, 2H), 2.58 (s, 3H), 2.53 (m, 1H), 1.80 (m, 2H), 1.18 (d, 3H , J = 7Hz), 1.07 (d, 3H, J = 7Hz).

Example 97 (not according to the invention)

[0390]

<img file="PL1809280T3_D0100.tif" />

1- (2- (3-Aminopropyl) -5- (2-fluoro-5- (trifluoromethyl) -phenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2- dihydrochloride dimethylpropan-1-one

[0391] MS ESI (+) m / z 452 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H, J = 6 Hz), 7.73 (m, 1H), 7.55 (d, 2H, J = 6 Hz), 7.34 (m, 4H), 3.38 ( m, 1H), 3.12 (m, 1H), 3.01 (m, 1H), 2.48 (m, 1H), 1.82 (m, 2H), 1.34 (s, 9H).

Example 98 (not according to the invention)

[0392]

1- (2- (3-Aminopropyl) -2-phenyl-5- (thiophen-2-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one dihydrochloride

[0393] MS ESI (+) m / z 372 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.53 (m, 3H), 7.46 (d, 1H, J = 6Hz), 7.32 (m, 3H), 7.07 (m, 1H), 3.20 (m, 1H ), 2.95 (m, 2H), 2.50 (m, 1H), 1.72 (m, 2H), 1.33 (s, 9H). Example 99 (not according to the invention)

[0394]

1- (2- (3-Aminopropyl) -2-phenyl-5- (thiophen-3-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one dihydrochloride

[0395] MS ESI (+) m / z 372 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.80 (d, 1H, J = 3 Hz), 7.53 (d, 2H, J = 6 Hz), 7., 8 (d, 1H, J = 5 Hz), 7.33 (m , 4H), 3.24 (m, 1H), 2.99 (br s, 2H), 2.48 (m, 1H), 1.73 (m, 2H), 1.33 (s, 9H).

Example 100 (not according to the invention)

[0396]

OS ^ /^Cl

1- (2- (3-Aminopropyl) -5- (5-chlorothiophen-2-yl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one

[0397] MS ESI (+) m / z 406 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (d, 2H, J = 9 Hz), 7.33 (m, 3H), 7.30 (d, 1H, J = 4 Hz), 6.89 (d, 1H, J = 4 Hz), 3.23 (m, 1H), 2.95 (m, 2H), 2.47 (m, 1H), 1.72 (m, 2H), 1.31 (s, 9H).

Example 101 (not according to the invention)

[0398]

<img file="PL1809280T3_D0101.tif" />

The dihydrochloride

1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (4-fluorophenyl) -1,3,4-oxadiazole

3 (2H) -yl) -2,2-dimethylpropan-1-one

[0399] MS ESI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.54 (m, 2H), 7.45 (m, 1H), 7.15 (m, 2H), 7.02 (m, 2H), 3.19 (m, 1H), 2.97 (br s, 2H), 2.48 (m, 1H), 1.70 (m, 2H), 1.34 (s, 9H).

Example 102 (not according to the invention)

[0400]

<img file="PL1809280T3_D0102.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-p-tolyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1 - dihydrochloride onu

[0401] MS ESI (+) m / z 416 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.42 (m, 3H), 7.13 (m, 4H), 3.26 (m, 1H), 3.04 (m, 2H), 2.51 (m, 1H), 2.29 (s, 3H), 1.78 (m, 2H), 1.33 (s, 9H).

Example 103 (not according to the invention)

[0402]

<img file="PL1809280T3_D0103.tif" />

1- (2- (3-Aminopropyl) -2- (4-chlorophenyl) -5- (2,5-difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropane- dihydrochloride 1-onu

[0403] MS ESI (+) m / z 436 (M + 1) detected; ¹H NMR (400 MHz, CDCl 3) δ 7.51 (d, 2H, J = 9 Hz), 7.44 (m, 1H), 7.30 (d, 2H, J = 9 Hz), 7.15 ( m, 2H), 3.25 (m, 1H), 3.01 (m, 2H), 2.48 (m, 1H), 1.74 (m, 2H), 1.33 (s, 9H).

Example 104 (not according to the invention)

[0404]

<img file="PL1809280T3_D0104.tif" />

1- (2- (3-Aminopropyl) -2- (4-bromophenyl) -5- (2,5-difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropane- dihydrochloride 1-onu

[0405] MS ESI (+) m / z 480 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 5H), 7.15 (m, 2H), 3.28 (m, 1H), 3.05 (brs, 2H), 2.48 (m, 1H), 1.77 (m, 2H). 1.33 (s, 9H).

Example 105 (not according to the invention)

[0406]

<img file="PL1809280T3_D0105.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2- (3,4-dimethylphenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2- dihydrochloride dimethylpropan-1-one

[0407] MS ESI (+) m / z 429.9 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (m, 1H), 7.30 (s, 1H), 7.25 (m, 1H), 7.10 (m, 3H), 3.25 (m, 1H), 3.04 (m, 2H), 2.50 (m, 1H), 2.22 (s, 3H), 2.19 (s, 3H), 1.80 (m, 2H), 1.33 (s, 9H) .

Example 106 (not according to the invention)

[0408]

<img file="PL1809280T3_D0106.tif" />

1- (2- (3-Aminopropyl) -2- (4-tert-butylphenyl) -5- (2,5-difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2- dihydrochloride dimethylpropan-1-one

[0409] MS ESI (+) m / z 458 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.47 (d, 2H, J = 9 Hz), 7.41 (m, 1H), 7.34 (d, 2H, J = 9 Hz), 7.12 (m, 2H), 3, 29 (m, 1H), 3.04 (br s, 2H), 2.52 (m, 1H), 1.78 (m, 2H), 1.35 (s, 9H), 1.24 (s, 9H ).

Example 107 (not according to the invention)

[0410]

<img file="PL1809280T3_D0107.tif" />

1- (2- (3-Aminopropyl) -5- (2_l5-difluorophenyl) -2-m-tolyl-1,3_l4-oxadiazol-3 (2H) -yl) 2,2-dimethylpropan-1-one

[0411] MS ESI (+) m / z 416 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (m, 1H), 7.32 (d, 2H, J = 9Hz), 7.22 (t, 1H, J = 7Hz), 7.13 (m, 3H), 3, 25 (m, 1H), 3.04 (br s, 2H), 2.50 (m, 1H), 2.33 (s, 3H), 1.78 (m, 2H), 1.33 (s, 9H ).

Example 108 (not according to the invention)

[0412]

<img file="PL1809280T3_D0108.tif" />

1- (2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2- (3,5-dimethylphenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2- dihydrochloride dimethvlopropan-1-one

[0413] MS ESI (+) m / z 429.9 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 1H), 7.14 (m, 4H), 6.95 (s, 1H), 3.24 (m, 1H), 3.04 (m, 2H), 2.49 (m, 1H), 2.28 (s, 6H), 1.99 (m, 2H), 1.33 (s, 9H).

Example 109 (not according to the invention)

[0414]

<img file="PL1809280T3_D0109.tif" />

Preparation of N- (3- (5- (2,5-difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl) propyl) -isobutyramide

[0415] For a solution of 1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1 dihydrochloride -one prepared as in the above examples (50 mg, 0.11 mmol) in anhydrous CH₂CI₂ (1 mL) DIEA (95 µΙ, 0.54 mmol) was added followed by isobutyryl chloride (17 µΙ, 0.16 mmol). After stirring at room temperature for 16 hours, the mixture was treated with 1N HCl (10 ml) and extracted with CH₂CI₂ (2 x 10 ml). The combined organic phases are washed with brine (10 mL) then dried over Na₂SO₄ and concentrates. The residue was chromatographed (4: 1 to 2: 1 hexanes / EtOAc) to provide the product (31 mg, 62%) as a colorless gum.

MS ESI (+) m / z 458.1 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.55 (m, 3H), 7.36 (m, 3H), 7.17 (m, 2H), 3.33 (m, 3H), 3.04 (m, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 1.77 (m, 1H), 1.56 (m, 1H), 1.16 (m, 12H).

Example 110 (not according to the invention)

[0416]

<img file="PL1809280T3_D0110.tif" />

N- (3- (5- (2,5-Difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl) propyl) methanesulfonamide

[0417] Prepared as described in Example 109 using methanesulfonyl chloride in place of isobutyryl chloride.

MS ESI (+) m / z 466.1 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.51 (m, 3H), 7.38 (m, 3H), 7.17 (m, 2H), 3.41 (m, 1H), 3.21 (m, 2H), 3.04 (m, 1H), 2.95 (s, 3H), 2.59 (m, 1H), 1.74 (m, 2H), 1.21 (d, 3H, J = 6.8Hz), 1 , 15 (d, 3H, J = 6.8Hz).

Example 111 (not according to the invention)

[0418]

<img file="PL1809280T3_D0111.tif" />

Preparation of (2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 - onu

[0419] Step A: Preparation of (S) -2-methoxypropanoic acid anhydride: To a solution of (S) 2-methoxypropanoic acid (0.25 g, 4.80 mmol) in CH₂CI₂ (2 ml) EDCI (0.46 g, 2.38 mmol) was added. After stirring at room temperature for 1 hour, hexanes were added and the mixture was filtered to provide the product (0.24 g, 53%).

Step B: Preparation of (2S) -1 - (2- (3-azvdopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - 2-methoxy-1-one: To a solution of N '- (4-azido-1-phenylbutylidene) -2.5-difluorobenzohydrazide (100 mg, 0.29 mmol), prepared as in Example 85, Step A, in DCE (1 ml), (S) -2-methoxypropanoic acid anhydride from the previous step (277 mg, 1.46 mmol) is added. After stirring at reflux for 48 hours, the crude mixture was chromatographed (CH₂CI₂ to 2.5% MeOH / CH₂CI₂) to give the product (81 mg, 65%) as a clear oil.

[0421] Step C: Preparation of (2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - 2-methoxypropan-1-one: (2S) -1- (2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxy-1-one (50 mg, 0.11 mmol) was reduced as described in Example 86, Step C to give the product (32 mg, 68%) as a colorless oil.

MS ESI (+) m / z 404 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.62 (m, 1H), 7.56 (m, 1H), 7.52 (m, 1H), 7.34 (m, 3H), 7.17 m, 2H), 4.58 ( q, 0.5H, J = 7Hz), 4.52 (q, 0.5H, J = 7Hz), 3.38 (s, 1.5H), 3.22 (s, 1.5H), 3. 10 (m, 2H), 2.60 (m, 1H), 1.90 (m, 3H), 1.49 (d, 1.5H, J = 7Hz), 1.27 (d, 1.5H , J = 7 Hz), 1: 1 mixture of diastereomers.

Example 112

[0422]

<img file="PL1809280T3_D0112.tif" />

(S) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2 -methonobutane-one

[0423] Prepared as described in example 71 using (S) -2- (tert-butyldiphenylsilyloxy) -butanoic acid in place of (S) -2- (tert-butyldiphenylsilyloxy) propanoic acid.

MS APCI (+) m / z 434 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.48 (m, 3H), 7.35 (app t, 2H, J = 8 Hz), 7.28 (m, 1H), 7.13 (m, 2H), 4.53 (dd, 1H, J = 7Hz, 4Hz), 3.40 (s, 3H), 3.26 (m, 1H), 2.86 (m, 2H), 2.42 (m, 1H), 1.94 (m, 2H), 1.74 (m, 2H), 0.96 (t, 3H, J = 8Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H ) -yl) -2-methoxypropan-1-one.

Example 113

[0424]

<img file="PL1809280T3_D0113.tif" />

(S) -1 - ((R) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxybutane -1-on

[0425] Prepared as described in Example 71 using (S) -2- (tert-butyldiphenylsilyloxy) -butanoic acid in place of (S) -2- (tert-butyldiphenylsilyloxy) propanoic acid.

MS APCI (+) m / z 434 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.46 (m, 3H), 7.36 (app t, 2H, J = 8 Hz), 7.13 (m, 2H), 4.54 (dd, 1H, J = 8 Hz, 4 Hz ), 3.31 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.44 (m, 1H), 1.94 (m, 2H), 1.78 (m, 1H), 1.48 (m, 1H), 1.08 (t, 3H, J = 7Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H ) -yl) -2-methoxypropan-1-one.

Example 114

[0426]

<img file="PL1809280T3_D0114.tif" />

(S) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxy-3-methylbutan-1-one

[0427] Prepared as described in example 71 using 2- (tert-butyldiphenylsilyloxy) -3-methylbutanoic acid instead of (S) -2- (tert-butyldiphenylsilyloxy) propanoic acid. The product obtained is a 2: 1 mixture of diastereomers.

MS APCI (+) m / z 448 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.49 (m, 3H), 7.35 (m, 2H), 7.29 (m, 1H), 7.13 (m, 2H), 4.45 (d, 0.33H, J = 5 Hz), 4.10 (d, 0.66H, J = 5Hz), 3.39 (s, 2H), 3.27 (m, 2H), 2.87 (m, 2H), 2.44 (m, 1H), 2.22 (m, 1H), 1.95 (m, 1H), 1.53 (m, 1H), 1.09 (d, 0.85H, J = 7Hz), 0 . 99 (m, 3H). 0.82 (d, 2.15H, J = 7Hz).

Example 115

[0428]

<img file="PL1809280T3_D0115.tif" />

(S) -1 - ((R) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxy-3-methylbutan-1-one

[0429] Prepared as described in Example 71 using 2- (tert-butyldiphenylsilyloxy) -3-methylbutanoic acid instead of (S) -2- (tert-butyldiphenylsilyloxy) propanoic acid.

MS APCI (+) m / z 448 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.47 (m, 3H), 7.35 (m, 2H), 7.28 (m, 1H), 7.12 (m, 2H), 4.45 (d, 1H, J = 4Hz ), 3.27 (s, 3H), 3.25 (m, 1H), 2.87 (m, 2H), 2.49 (m, 1H), 2.23 (m, 1H), 1.97 (m, 1H), 1.52 (m, 1H), 1.09 (d, 3H, J = 7Hz), 0.99 (d, 3H, J = 7Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one.

Example 116

[0430]

<img file="PL1809280T3_D0116.tif" />

(S) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxybutane -1-on

[0431] Obtained as described in Example 73.

MS APCI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.50 (m, 3H), 7.38 (m, 2H), 7.32 (m, 1H), 7.14 (m, 2H), 4.78 (dd, 1H, J = 7Hz , 4 Hz), 3.19 (m, 1H), 2.86 (m, 2H), 2.41 (m, 1H), 1.98 (m, 2H), 1.64 (m, 2H), 0.96 (t, 3H, J = 7Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxypropan-1-one. Example 117 [0432]. ^ NH, θ / υΗ, F. HO '(S) -1 - ((R) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxybutan-1-one

[0433] Obtained as described in Example 73.

MS APCI (+) m / z 420 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (m, 3H), 7.38 (app t, 2H, J = 8 Hz), 7.31 (m, 1H), 7.14 (m, 2H), 4.77 (dd, 1H, J = 7Hz, 3Hz), 3.16 (m, 1H), 2.85 (m, 2H), 2.49 (m, 1H), 1.99 (m, 2H), 1.70 (m, 2H), 1.07 (t, 3H, J = 7Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H ) -yl) -2-methoxypropan-1-one.

Example 118

[0434]

<img file="PL1809280T3_D0117.tif" />

(S) -1 - ((S) -2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2 -hydroxy-3-methylbutan-1-one

[0435] Obtained as described in Example 73. The obtained product is a 2: 1 mixture of diastereomers.

MS APCI (+) m / z 434 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.49 (m, 3H), 7.38 (app t, 2H, J = 8 Hz), 7.32 (m, 1H), 7.15 (m, 2H), 4.71 (m, 1H), 3.20 (m, 1H), 2.86 (m, 2H), 2.41 (m, 2H), 1.92 (m, 1H), 1.51 (m, 1H), 1. 14 (d, 1H, J = 7Hz), 1.12 (m, 3H), 0.87 (d, 1.4H, J = 7Hz), 0.66 (d, 1.6H, J = 6 Hz). Example 119

[0436]

<img file="PL1809280T3_D0118.tif" />

(S) -1 - ((R) -2- (3-Aminopropyl) -5- (2_l5-difluorophenyl) -2-phenyl-1_l3_l4-thiadiazol-3 (2H) -yl) -2-hydroxy-3-methylbutan-1-one

[0437] Obtained as described in Example 73.

MS APCI (+) m / z 434 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.46 (m, 3H), 7.34 (app t, 2H, J = 8Hz), 7.26 (m, 1H), 7.11 (m, 2H), 4.65 (d, 1H, J = 3Hz), 3.24 (m, 1H), 2.98 (t, 2H, J = 6Hz), 2.64 (m, 1H), 2.28 (m, 1H), 2 , 12 (m, 1H), 1.66 (m, 1H), 1.08 (d, 3H, J = 7Hz), 0.86 (d, 3H, J = 7Hz). Stereochemistry is determined by comparison with (S) -1 - ((S) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) - yl) -2-methoxy-1-one.

Example 120

[0438]

<img file="PL1809280T3_D0119.tif" />

2- (3-Aminopropyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide (Enantiomer A)

[0439] Prepared as described above in Example 68. Enantiomers 3- (5- (2,5-difluorophenyl) -3 (methoxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3 The tert-butyl 4-thiadiazol-2-yl) propylcarbamate is separated on a chiral column (Chiralcel ODH 250 x 20mm) eluting with 2% EtOH / hexanes to give a less polar A enantiomer and a more polar B enantiomer. The final product is obtained by Boc-protection from the A enantiomer.

MS ESI (+) m / z 421 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.44 (br, 3H), 7.52 (m, 3H), 7.34 (m, 2H), 7.24 (m, 1H), 7.08 (m, 2H), 3.35 (m, 1H), 3.16 (s, 3H), 3.06 (m, 2H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 (m, 1H) , 1.61 (s, 3H).

Example 121

[0440]

<img file="PL1809280T3_D0120.tif" />

2- (3-Aminopropyl) -5- (2_l5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1_l3_l4-thiadiazole-3 (2H) carboxamide (Enantiomer B)

[0441] Prepared as described in Example 120 using the more polar B enantiomer.

MS ESI (+) m / z 421 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 8.44 (br, 3H), 7.52 (m, 3H), 7.34 (m, 2H), 7.24 (m, 1H), 7.08 (m, 2H), 3.35 (m, 1H), 3.16 (s, 3H), 3.06 (m, 2H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 (m, 1H) , 1.61 (s, 3H).

Example 122

[0442]

<img file="PL1809280T3_D0121.tif" />

Preparation of 2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazolo-3 (2H) -carboxamide

[0443] Step A: Preparation of (2- (3-Azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) - (1H-imidazole -1-yl) -methanone: For a solution of 2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.492g, 1.37 1,1'-carbonyldiimidazole (0.266 g, 1.64 mmol) is added in THF (8 mL). After stirring at 75 ° C for 2 hours, the reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane (20 ml). The solution was washed with HCl (0.5 M), dried over Na₂SO₄ and concentrated to give the crude product.

[0444] Step B: Preparation of (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) - (3-methylimidazoli- iodec-1-yl) -methanone: For the solution of (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (1 H-imidazol-1-yl) -methanone (0.621 g, 1.37 mmol) in acetonitrile (5 ml) is added iodomethane (0.972 g, 6.85 mmol). After stirring in a sealed flask for 24 hours, the mixture was concentrated to give the crude product.

[0445] Step C: Preparation of 2- (3-azidopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide: To the solution (2- (3-azidopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (3-methylimidazoli-iodide-1-yl) -methanone (0.112 g, 0.188 mmol) and O- (tert-butyl) -hydroxylamine hydrochloride (0.047 g, 0.376 mmol) in dichloromethane (3 mL) are added triethylamine (0.095 g, 0.941 mmol). After stirring for 1 hour, the mixture was concentrated under reduced pressure and chromatographed (10: 1 hexanes / ethyl acetate) to provide the product (0.078 g, 87%).

[0446] Step D: Preparation of 2- (3-azidopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) - carboxamide: To a cooled (0 ° C) solution of 2- (3-azidopropyl) -Ntert-butoxy-5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide Sodium hydride (0.006 g, 0.26 mmol) was added (0.061 g, 0.13 mmol) and iodomethane (0.18 g, 1.3 mmol) in DMF (4 mL). After stirring at 0 ° C for 30 minutes and then at room temperature for 1 hour, the mixture was partitioned between ethyl acetate (10 ml) and saturated NH₄CI (5 ml). The organic layer was washed with water (2 x 5 ml), dried and concentrated under reduced pressure to give the crude product.

[0447] Step E: Preparation of 2- (3-aminopropyl) -N-tert-butoxy-5-yl- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H ) -carboxamide: For a solution of 2- (3-azidopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide HCl (5.3 M in dioxane, 0.05 ml) was added (0.032 g, 0.065 mmol) and platinum oxide (15 mg) in methanol (3 mL). After stirring under a hydrogen balloon for 1 hour, the mixture was filtered and the filtrate concentrated under reduced pressure to provide the product.

Step F: Preparation of 2- (3-aminoDroDvlo) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide: To 2- (3-aminopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide (0.023 g, 0 0.05 mmol) TFA (2 mL) is added. After stirring for 18 hours, the mixture was concentrated and chromatographed (10: 1: 0.2 dichloromethane / methanol / 30% NH₄OH) to give the product (0.01 g, 49%).

MS ESI (+) m / z 407 (M + 1) detected; ¹1 H NMR (400 MHz, CDCl₃) δ 7.45 (d, 2H), 7.36 (m, 3H), 7.29 (m, 1H), 7.11 (m, 2H), 3.28 (s, 3H), 3.12 (m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.62 (m, 1H) .

[0449] The following examples are prepared using the above-described methods using appropriately substituted reagents.

<img file="PL1809280T3_D0122.tif" />

<td>R¹</td><td>Name</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (pyridin-3-yl) methanone</td>

<td>P.</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (pyridin-2-yl) methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (3-methylfuran-2-yl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (2-methylthiazol-5-yl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (5-methylthiophen-2-yl) -methanone</td>

<td>R¹</td><td>Name</td>

<td></td><td></td>

<td>zj:</td><td>(3-aminophenyl) - (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -methanone</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) propan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) butan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylbutan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-ethylbutan-1-one</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (cyclobutyl) -methanone</td>

<td>V)</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (cyclopentyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (tetrahydrofuran-2-yl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (2-fluorocyclohexyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (1-methylcyclopropyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) - (1-</td>

<td>R¹</td><td>Name</td>

<td> #^F1</td><td>(trifluoromethyl) cyclopropyl) methanone</td>

<td>XI o Here</td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxypropane-1 - he</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxypropane-1 - he</td>

<td></td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxybutan-1 - he</td>

<td>And Fr.</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxybutan-1 - he</td>

<td>^ θ^Η</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxy-3- methylbutan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-hydroxy-3, 3-dimethylbutan-1-one</td>

<td>y&gt;^OHAND</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-cyclopropyl-2- hydroxyethanone</td>

<td>&gt; γΝΗ₂AND</td><td>(2S) -2-amino-1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-cyclopropylethanone</td>

<td>H. Γ</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-cyclopropyl-2- (methylamino) ethanone</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-ethoxypropan-1 - he</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -</td>

<td>R¹</td><td>Name</td>

<td>^ ° 'CF₃</td><td>yl) -2- (trifluoromethoxy) -propan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-cyclopropoxypropan-1 - he</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methoxy-3- methylbutan-1-one</td>

<td> -^^0H</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (1-hydroxycyclopropyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) (1-methoxycyclopropyl) -methanone</td>

<td>^ OH</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-hydroxy-2-methylpropan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxy-2-methylpropan-1-one</td>

<td>Y</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methoxypropan-1 - he</td>

<td>'Xx ° \</td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methoxybutan-1 - he</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methoxy-3, 3-dimethylbutan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-isobutoxypropan-1 - he</td>

<td>^ νθν ^</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-isopropoxypropane-1 - he</td>

<td colspan="2">R¹</td><td>Name</td>

<td></td><td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-tert-butoxypropane- 1 -on</td>

<td colspan="2"></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (2-methoxyethoxy ) -propan-1-one</td>

<td colspan="2"></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-phenoxypropan-1 - he</td>

<td></td><td>f— 'w</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (pyridin-2 -yloxy) -propan-1-one</td>

<td></td><td>at</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (pyridin-3 -yloxy) -propan-1-one</td>

<td colspan="2">* object</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (benzyloxy) - propan-1-one</td>

<td colspan="2">/ about</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2-methoxy-2- phenylethanone</td>

<td colspan="2">/&gt; ^ ο^χ</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -3-methoxypropan-1-one</td>

<td colspan="2">ąA O ^ NH</td><td>N - ((S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -3-methyl- 1-Oxobutan-2-yl) -acetamide</td>

<td colspan="2">7γΛ</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) propane-1,2-dione</td>

<td colspan="2">Ύ * 'οη</td><td>(Z) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (hydroxyimino) - propane-1-one</td>

<td>R¹</td><td>Name</td>

<td>'Zy^N'cT</td><td>(Z) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) yl) -2- (methoxyimino) - propane-1-one</td>

<img file="PL1809280T3_D0123.tif" />

<td>Ar²</td><td>R¹</td><td>Name</td>

<td>4-methylphenyl</td><td>(S) -1-methoxyethyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-p-tolyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>4-chlorophenyl</td><td>(S) -1-methoxyethyl</td><td>1- (2- (3-aminopropyl) -2- (4-chlorophenyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>4-bromophenylmethoxyethyl</td><td>(S) -1-</td><td>1- (2- (3-aminopropyl) -2- (4-bromophenyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>4-t-butylphenyl</td><td>(S) -1-methoxyethyl</td><td>1- (2- (3-aminopropyl) -2- (4-tert-butylphenyl) -5- (2.5- difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>3,4-dimethylphenyl</td><td>(S) -1-methoxyethyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3,4- dimethylphenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan1-one</td>

<td>3-methylphenyl</td><td>(S) -1-methoxyethyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-m-tolyl-1,3,4oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>3,5-dimethylphenyl</td><td>(S) -1-methoxyethyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3.5- dimethylphenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>2-chlorophenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -2- (2-chlorophenyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>2-ethylphenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (2-ethylphenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>3-nitrophenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-nitrophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>3-hydroxyphenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3- hydroxyphenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan1-one</td>

<td>Ar²</td><td>R¹</td><td>Name</td>

<td>3-aminophenyl</td><td>t-butyl</td><td>1- (2- (3-aminophenyl) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>3-carboxyphenyl</td><td>t-butyl</td><td>3- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -3-pivaloyl- acid 2,3-dihydro-1,3,4-oxadiazol-2-yl) benzoic</td>

<td>3-cyanophenyl</td><td>t-butyl</td><td>4- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -3-pivaloyl-2,3-dihydro-1,3,4-oxadiazol-2-yl) -benzonitrile</td>

<td>3,4-dichlorophenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -2- (3,4-dichlorophenyl) -5- (2.5- difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>3-fluorophenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-fluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>3-chlorophenyl</td><td>t-butyl</td><td>1- (2- (3-aminopropyl) -2- (3-chlorophenyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>4-fluorophenyl</td><td>(S) -2-methoxyethyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (4- fluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>3-fluorophenyl</td><td>(S) -2-methoxyethyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3- fluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>2-chlorophenyl</td><td>(S) -2-methoxyethyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (2-chlorophenyl) -5- (2,5-difluorophenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropane -1 on</td>

<td>3-methylphenyl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-m-tolyl-1,3,4oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>3-ethylphenyl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-ethylphenyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>3-pyridyl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (pyridin-3-yl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>5-methylthiophen-2-yl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (5-methylthiophen-2-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropane -1 -on</td>

<td>1-methyl-1Himidazol-2-yl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>2-methylthiazol-4-yl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (2-methylthiazol-4-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropane -1 -on</td>

<td>2-methylphenyl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-o-tolyl-1,3,4oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>Ar²</td><td>R¹</td><td>Name</td>

<td>2-pyridyl</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (pyridin-2-yl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>2- (1H-imidazol-4-yl)</td><td>isopropyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (1H-imidazol-4-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropane -1 -on</td>

<td>3-amino-1H-pyrazol-5-yl</td><td>isopropyl</td><td>1- (2- (3-amino-1H-pyrazol-5-yl) -2- (3-aminopropyl) -5- (2.5- difluorophenyl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<img file="PL1809280T3_D0124.tif" />

<td>NO²R³</td><td>Ar¹</td><td>Name</td>

<td>nh₂</td><td>2-fluorophenyl</td><td>1- (2- (3-aminopropyl) -5- (2-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>nh₂</td><td>2-chlorophenyl</td><td>1- (2- (3-aminopropyl) -5- (2-chlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>NH-Ala-Ala</td><td>2.5- difluorophenyl</td><td>1- (1- (3- (5- (2,5-difluorophenyl) -3 - (- 2-methylpropanoyl) -2-phenyl- 2,3-dihydro-1,3,4-oxadiazol-2-yl) propylamino) -1 - oxopropan-2-ylamino) -1-oxopropan-2-ylamine</td>

<td>NHC (= O) (CH₂)₂NMe₂</td><td>2.5- difluorophenyl</td><td>N- (3- (5- (2,5-difluorophenyl) -3-isobutyryl-2-phenyl-2,3-dihydro- 1,3,4-oxadiazol-2-yl) -propyl) -3- (dimethylamino) -propanamide</td>

<td></td><td>2.5- difluorophenyl</td><td>1 - (5- (2,5-difluorophenyl) -2-phenyl-2- (3- (pyrrolidin-1-yl) propyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td></td><td>2.5- difluorophenyl</td><td>1 - (5- (2,5-difluorophenyl) -2-phenyl-2- (3- (piperidin-1-yl) propyl) - 1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td></td><td>2.5- difluorophenyl</td><td>1- (5- (2,5-difluorophenyl) -2- (3- (4-methylpiperazin-1-yl) propyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<img file="PL1809280T3_D0125.tif" />

<td>R¹</td><td>Ar¹</td><td>Name</td>

<td>t-butyl</td><td>2-fluorophenyl</td><td>1- (2- (3-aminopropyl) -5- (2-fluorophenyl) -2-phenyl-1,3,4oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>2-chlorophenyl</td><td>1- (2- (3-aminopropyl) -5- (2-chlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>3-fluorophenyl</td><td>1- (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>3-chlorophenyl</td><td>1- (2- (3-aminopropyl) -5- (3-chlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>2-fluoro-5-chlorophenyl</td><td>1- (2- (3-aminopropyl) -5- (5-chloro-2-fluorophenyl) -2-phenyl- 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>2-chloro-5-methylphenyl</td><td>1- (2- (3-aminopropyl) -5- (2-chloro-5-methylphenyl) -2-phenyl- 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>2-trifluoromethyl-5-fluorophenyl</td><td>1- (2- (3-aminopropyl) -5- (5-fluoro-2- (trifluoromethyl) -phenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropane -1 -on</td>

<td>(S) -2-methoxyethyl</td><td>2-chloro-5-fluorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-chloro-5-fluorophenyl) -2-phenyl- 1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>2,5-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-dichlorophenyl) -2-phenyl1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>2-chlorophenyl</td><td>(2S) -1 - (2- (3-aminopropyl) -5- (2-chlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>2-fluorophenyl</td><td>(2S) -1 - (2- (3-aminopropyl) -5- (2-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>3-chlorophenyl</td><td>(2S) -1 - (2- (3-aminopropyl) -5- (3-chlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>3-fluorophenyl</td><td>(2S) -1 - (2- (3-aminopropyl) -5- (3-fluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>2-fluoro-5-methoxyphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-fluoro-5-methoxyphenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>R¹</td><td>Ar¹</td><td>Name</td>

<td>(S) -2-methoxyethyl</td><td>2,3-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,3-dichlorophenyl) -2-phenyl1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>3,4-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3,4-dichlorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>3,5-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3,5-dichlorophenyl) -2-phenyl1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>thiophen-2-yl</td><td>(2S) -1 - (2- (3-aminopropyl) -2-phenyl-5- (thiophen-2-yl) -1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>thiophen-3-yl</td><td>(2S) -1 - (2- (3-aminopropyl) -2-phenyl-5- (thiophen-3-yl) -1,3,4oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>5-chlorothiophen-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (5-chlorothiophen-2-yl) -2-phenyl 1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>(S) -2-methoxyethyl</td><td>2-pyridyl</td><td>(2S) -1- (2- (3-aminopropyl) -2-phenyl-5- (pyridin-2-yl) -1,3,4oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>3-pyridyl</td><td>(2S) -1 - (2- (3-aminopropyl) -2-phenyl-5- (pyridin-3-yl) -1,3,4oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>(S) -2-methoxyethyl</td><td>4-chloropyridin-3-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (4-chloropyridin-3-yl) -2-phenyl1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>(S) -2-methoxyethyl</td><td>3-chloropyridin-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3-chloropyridin-2-yl) -2-phenyl 1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>acetyl</td><td>2,5-difluorophenyl</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -ethanone</td>

<td>t-butyl</td><td>2-fluoro-5-methoxyphenyl</td><td>1- (2- (3-aminopropyl) -5- (2-fluoro-5-methoxyphenyl) -2-phenyl- 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>3,6-difluoropyridin-2yi</td><td>1- (2- (3-aminopropyl) -5- (3,6-difluoropyridin-2-yl) -2-phenyl- 1,3,4-oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<td>t-butyl</td><td>4-fluoropyridin-3-yl</td><td>1- (2- (3-aminopropyl) -5- (4-fluoropyridin-3-yl) -2-phenyl-1,3,4oxadiazol-3 (2H) -yl) -2,2-dimethylpropan-1-one</td>

<img file="PL1809280T3_D0126.tif" />

100

<td>R¹</td><td>Name</td>

<td>p</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) (phenyl) -methanone</td>

<td>Ό</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (pyridin-2-yl) methanone</td>

<td>p</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (pyridin-3-yl) methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (3-methylfuran-2-yl) -methanone</td>

<td>^s\</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (2-methylthiazol-5-yl) -methanone</td>

<td>p</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (5-methylthiophen-2-yl) -methanone</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -3-methylbutan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) propan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) butan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-ethylbutan-1-one</td>

<td>^yABOUT</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) (cyclobutyl) -methanone</td>

<td></td><td></td>

101

<td>R¹</td><td>Name</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) (cyclopentyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (tetrahydrofuran-2-yl) -methanone</td>

<td>F.</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) (2-fluorocyclohexyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (1-methylcyclopropyl) -methanone</td>

<td></td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (1 (trifluoromethyl) -cyclopropyl) -methanone</td>

<td></td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-hydroxypropan-1-one</td>

<td>y&gt; OH</td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-hydroxybutan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-hydroxy-3,3-dimethylbutan-1-one</td>

<td>^ ° HA</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-cyclopropyl-2-hydroxyethanone</td>

<td>ΊγΝΗ₂AND</td><td>(2S) -2-amino-1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -2-cyclopropylethanone</td>

<td>X ^^OH△</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (1-hydroxycyclopropyl) -methanone</td>

<td></td><td></td>

102

<td>R¹</td><td>Name</td>

<td>χ⁰</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (1-methoxycyclopropyl) -methanone</td>

<td>Ϊ ^ ΖΟΗ</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-hydroxy-2-methylpropan-1-one</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxy-2-methylpropan-1-one</td>

<td>about /</td><td>(2R) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-methoxybutan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-methoxy-3,3-dimethylbutan-1-one</td>

<td>T.</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-cyclopropyl-2-methoxyethanone</td>

<td>HT</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-cyclopropyl-2- (methylamino) -ethanone</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-ethoxypropan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-isobutoxypropan-1-one</td>

<td>ΎΥ</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-isopropoxypropan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-cyclopropoxypropan-1-one</td>

<td> '^0^</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-tert-butoxypropane-1-one</td>

103

<td>R¹</td><td>Name</td>

<td></td><td>(2S) -1 - (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2- (2-methoxyethoxy) propan-1-one</td>

<td></td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2- (benzyloxy) propan-1-one</td>

<td>Τίο</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2-phenoxypropan-1-one</td>

<td>υό</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2- (pyridin-2-yloxy) -propan-1-one</td>

<td>ό</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2- (pyridin-3-yloxy) -propan-1-one</td>

<td>ο</td><td>acid 2 - ((2S) -1 - (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol- 3 (2H) -yl) -1-oxopropan-2-yloxy) -acetic</td>

<td>Ύ ° 'ΟΡ₃</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - 2- (trifluoromethoxy) propan-1-one</td>

<td>/ ο / = \</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) 2-methoxy-2- phenylethanone</td>

<td>Ύ °</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) - (tetrahydrofuran-3-yl) -methanone</td>

<td></td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -3-methoxypropan-1-one</td>

<td>/ d</td><td>Methyl 2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxylate</td>

<td></td><td>Ethyl 2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxylate</td>

104

<td>R¹</td><td>Name</td>

<td>Ą.AO ^ NH</td><td>N - ((2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) -3-methyl -1-oxobutan-2-yl) -acetamide</td>

<td>&gt; yo</td><td>1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) propane-1,2-dione</td>

<td></td><td>(Z) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- (hydroxyimino) -propan-l-one</td>

<td></td><td>(Z) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- (methoxyimino) -propan-1-one</td>

r²... »r³

<img file="PL1809280T3_D0127.tif" />

<td>R⁴</td><td>R⁵</td><td>NO²R³</td><td>Name</td>

<td>H.</td><td>H.</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>Me</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>Et</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-ethyl-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Et</td><td>Et</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N, N-diethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>Et</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-ethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>3-pyridyl</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-N (pyridin-3-yl) -1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>cyclopropyl</td><td>nh₂</td><td>2- (3-aminopropyl) -N-cyclopropyl-5- (2,5- difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -</td>

105

<td>R⁴</td><td colspan="2">R⁵</td><td>no²r³</td><td>Name</td>

<td></td><td colspan="2"></td><td></td><td>carboxamide</td>

<td>Me</td><td colspan="2">2-pyridyl</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-methyl-2-phenyl-N- (pyridin-2-yl) -1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>H.</td><td colspan="2"></td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N- (2-methoxyethyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td colspan="2">c &lt;</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N- (2- methoxyethyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td></td><td>^ OH</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N - ((S) -2-hydroxy-1-phenylethyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td colspan="3"></td><td>nh₂</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl- 1,3,4-thiadiazol-3 (2H) -yl) - (morpholino) methanone</td>

<td>H.</td><td colspan="2">OH</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2">OMe</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2">OEt</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-ethoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2">X ° —o-</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N- (2-methoxyethoxy) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>H.</td><td></td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2"></td><td>nh₂</td><td>2- (3-aminopropyl) -N- (cyclopropylmethoxy) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td colspan="2">OH</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

106

<td>R⁴</td><td>R⁵</td><td>no²r³</td><td>Name</td>

<td>Me</td><td>OEt</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-ethoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N- (2-methoxyethoxy) -N-methyl-2-phenyl-1,3,4-thiadiazolo-3 (2H) -carboxamide</td>

<td>Me</td><td>^ L</td><td>nh₂</td><td>2- (3-aminopropyl) -N-tert-butoxy-5- (2,5-difluorophenyl) - N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -N- (cyclopropylmethoxy) -5- (2,5-difluorophenyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>and Propyl</td><td>OH</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-hydroxy-Nisopropyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td colspan="2"></td><td>nh₂</td><td>(2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl- 1,3,4-thiadiazol-3 (2H) -yl) - (isoxazolidin-2-yl) -methanone</td>

<td>Phenyl</td><td>^Xob</td><td>nh₂</td><td>2- (3-aminopropyl) -N- (benzyloxy) -5- (2,5-difluorophenyl) -N, 2-diphenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>H.</td><td>^X° V</td><td>nh₂</td><td>2- (3-aminopropyl) -N-cyclopropoxy-5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>H.</td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N (fluoromethoxy) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N (fluoromethoxy) -N-methyl-2-phenyl-1,3,4-thiadiazole- 3 (2H) -carboxamide</td>

<td>H.</td><td>^ O ^ CFj</td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-phenyl-N (2,2,2-trifluoroethoxy) -1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td></td><td>nh₂</td><td>2- (3-aminopropyl) -5- (2,5-difluorophenyl) -N-methyl-2-phenyl-N- (2,2,2-trifluoroethoxy) -1,3,4-thiadiazole-3 (2H) -</td>

107

<td>R⁴</td><td>R⁵</td><td>NO²R³</td><td>Name</td>

<td></td><td>^ .O ^ CFa</td><td></td><td>carboxamide</td>

<td>Me</td><td>OMe</td><td>NHMe</td><td>5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2- (3 (methylamino) propyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td>OMe</td><td>NHMe</td><td>5- (2,5-difluorophenyl) -2- (3- (dimethylamino) propyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td>OMe</td><td>_vol g Η 7</td><td>2- (3 - ((S) -2 - ((S) -2-aminopropanamido) -propanamido) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3 , 4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>OEt</td><td>NHMe</td><td>5- (2,5-difluorophenyl) -N-ethoxy-N-methyl-2- (3 (methylamino) propyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td>OEt</td><td>NMe₂</td><td>5- (2,5-difluorophenyl) -2- (3- (dimethylamino) propyl) -Netoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td>OEt</td><td>that ZI with AND M.</td><td>2- (3 - ((S) -2 - ((S) -2-aminopropanamido) -propanamido) propyl) -5- (2,5-difluorophenyl) -N-ethoxy-N-methyl-2-phenyl-1,3 , 4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>OEt</td><td>H.</td><td>2- (3- (cyclopentylamino) propyl) -5- (2,5-difluorophenyl) N-ethoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<img file="PL1809280T3_D0128.tif" />

R⁴

<td>R⁴</td><td>R⁵</td><td>n</td><td>Y</td><td>Name</td>

<td>H.</td><td>OH</td><td> 2</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (2-hydroxyethyl) -2-phenyl- 1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>OH</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (3-hydroxypropyl) -2-</td>

108

<td>R⁴</td><td>R^b</td><td>n</td><td>Y</td><td>Name</td>

<td></td><td></td><td></td><td></td><td>phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Η</td><td>OH</td><td> 2</td><td>OP (O) (OH)₂</td><td>2- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (hydroxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) ethyl</td>

<td>Η</td><td>OH</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (hydroxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>Me</td><td>OH</td><td> 1</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (hydroxymethyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>OH</td><td> 2</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (2-hydroxyethyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>OH</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (3-hydroxypropyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>OH</td><td> 1</td><td>OP (O) (OH)₂</td><td>(5- (2,5-difluorophenyl) -3- (hydroxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) methyl dihydrogen phosphate</td>

<td>Me</td><td>OH</td><td> 2</td><td>OP (O) (OH)₂</td><td>2- (5- (2,5-difluorophenyl) -3- (hydroxy-) dihydrogen phosphate (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) ethyl</td>

<td>Me</td><td>OH</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (hydroxy) dihydrogen phosphate (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>H.</td><td>OMe</td><td> 1</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (hydroxymethyl) -N-methoxy-2-phenyl- 1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>OMe</td><td> 2</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (2-hydroxyethyl) -N-methoxy-2-phenyl- 1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>OMe</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>OMe</td><td> 1</td><td>OP (O) (OH)</td><td>dihydrogen phosphate (5- (2,5-difluorophenyl) -3- (methoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) methyl</td>

<td>H.</td><td>OMe</td><td> 2</td><td>OP (O) (OH)₂</td><td>2- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (methoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) ethyl</td>

<td>H.</td><td>OMe</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (methoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -</td>

109

<td>R⁴</td><td colspan="2">R^b</td><td>n</td><td>Y</td><td>Name</td>

<td></td><td colspan="2"></td><td></td><td></td><td>propyl</td>

<td>Me</td><td colspan="2">OMe</td><td> 1</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (hydroxymethyl) -N-methoxy-N-methyl2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td colspan="2">OMe</td><td> 2</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (2-hydroxyethyl) -N-methoxy-N-methyl- 2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td colspan="2">OMe</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td colspan="2">OMe</td><td> 4</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (4-hydroxybutyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td colspan="2">OMe</td><td> 1</td><td>OP (O) (OH)₂</td><td>dihydrogen phosphate (5- (2,5-difluorophenyl) -3- (methoxy- (methyl) - carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -methyl</td>

<td>Me</td><td colspan="2">OMe</td><td> 2</td><td>OP (O) (OH)₂</td><td>2- (5- (2,5-difluorophenyl) -3- (methoxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) ethyl dihydrogen phosphate</td>

<td>Me</td><td colspan="2">OMe</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (methoxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogenphosphate</td>

<td>Me</td><td colspan="2">OMe</td><td> 4</td><td>OP (O) (OH)₂</td><td>4- (5- (2,5-difluorophenyl) -3- (methoxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) -butyl dihydrogenphosphate</td>

<td>H.</td><td colspan="2">OEt</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-ethoxy-2- (3-hydroxypropyl) -2-phenyl- 1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2">OEt</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (ethoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>H.</td><td colspan="2"> —'0^</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N- (2- methoxyethoxy) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td colspan="2"></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (2- methoxyethoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>H.</td><td></td><td></td><td> 3</td><td>OH</td><td>N-tert-butoxy-5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td></td><td></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3- (tert-butoxycarbamoyl) -5- (2.5-) dihydrogen phosphate difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

110

<td>R⁴</td><td colspan="2">R^b</td><td>n</td><td>Y</td><td>Name</td>

<td>Η</td><td colspan="2"></td><td> 3</td><td>OH</td><td>N- (cyclopropylmethoxy) -5- (2,5-difluorophenyl) -2- (3- hydroxypropyl) -2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Η</td><td colspan="2"></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3- (cyclopropylmethoxycarbamoyl) -5 (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogenphosphate</td>

<td>Me</td><td colspan="2">OEt</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-ethoxy-2- (3-hydroxypropyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td colspan="2">OEt</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (ethoxy- (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogen phosphate</td>

<td>Me</td><td colspan="2"></td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N- (2-methoxyethoxy) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td colspan="2">x ° —0-</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3 - ((2- methoxyethoxy) - (methyl) carbamoyl) -2-phenyl-2,3-dihydro 1,3,4-thiadiazol-2-yl) propyl</td>

<td>Me</td><td></td><td></td><td> 3</td><td>OH</td><td>N-tert-butoxy-5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>N. °^x</td><td></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3- (tert-Butoxy- (methyl) carbamoyl) -5 (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogenphosphate</td>

<td>Me</td><td colspan="2"></td><td> 3</td><td>OH</td><td>N- (cyclopropylmethoxy) -5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>Me</td><td colspan="2"></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3 - ((cyclopropylmethoxy) - (methyl) - dihydrogen phosphate carbamoyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>ipropyl</td><td colspan="2">OH</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N-hydroxy-2- (3-hydroxypropyl) -Nisopropyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>ipropyl</td><td colspan="2">OH</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (hydroxy) dihydrogen phosphate (isopropyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td colspan="3"></td><td> 3</td><td>OH</td><td>(5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2-phenyl-1,3,4-</td>

111

<td>R⁴</td><td>R⁵</td><td>n</td><td>Y</td><td>Name</td>

<td></td><td></td><td></td><td></td><td>thiadiazol-3 (2H) -yl) - (isoxazolidin-2-yl) -methanone</td>

<td></td><td></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (isoxazolidine-2-carbonyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogen phosphate</td>

<td>Phenyl</td><td>'about b</td><td> 3</td><td>OH</td><td>N- (benzyloxy) -5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) - N, 2-diphenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Phenyl</td><td>b</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3- (Benzyloxy- (phenyl) carbamoyl) -5- (2,5-difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogenphosphate</td>

<td>H.</td><td></td><td> 3</td><td>OH</td><td>N-cyclopropoxy-5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) - 2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>χ⁰^</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (3- (cyclopropoxycarbamoyl) -5- (2.5-) dihydrogen phosphate difluorophenyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>H.</td><td>X °^F.</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N- (fluoromethoxy) -2- (3-hydroxypropyl) - 2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td>X ° \ ^^F.</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- dihydrogen phosphate (fluoromethoxycarbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl</td>

<td>Me</td><td>X ° \ x^F.</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -N- (fluoromethoxy) -2- (3-hydroxypropyl) - N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>F.</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3 - ((fluoromethoxy) (methyl) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl dihydrogen phosphate</td>

<td>H.</td><td>^ O ^ / CFj</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2-phenyl-N- (2,2,2-trifluoroethoxy) -1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>H.</td><td></td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -2-phenyl-3- (2,2,2-) dihydrogen phosphate trifluoroethoxycarbamoyl) -2,3-dihydro-1,3,4-thiadiazol-2-yl) -</td>

112

<td>R⁴</td><td>R⁵</td><td>n</td><td>Y</td><td>Name</td>

<td></td><td>^ 0 ___ cf₃</td><td></td><td></td><td>propyl</td>

<td>Me</td><td>^ O ^ CFj</td><td> 3</td><td>OH</td><td>5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -N-methyl-2-phenylN- (2,2,2-trifluoroethoxy) -1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>Me</td><td>nęO ^ CF₃</td><td> 3</td><td>OP (O) (OH)₂</td><td>3- (5- (2,5-difluorophenyl) -3- (methyl- (2,2,2-) dihydrogenphosphate) trifluoroethoxy) carbamoyl) -2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl) propyl</td>

<img file="PL1809280T3_D0129.tif" />

<td>Ar²</td><td>Name</td>

<td>4-fluorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (4-fluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>4-methylphenyl</td><td>(25) -1 - (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-p-tolyl-1,3,4-thiadiazol-3 (2H) yl) -2-methoxypropane- 1 -on</td>

<td>4-chlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (4-chlorophenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>4-bromophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (4-bromophenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>4-t-butylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (4-tert-butylphenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxypropan-1-one</td>

<td>3,4-dimethylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3,4-dimethylphenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxypropan-1-one</td>

<td>3-methylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2-m-tolyl-1,3,4-thiadiazol-3 (2H) yl) -2-methoxypropane- 1 -on</td>

<td>3,5-dimethylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2 (3,5-dimethylphenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2- methoxypropan-1-one</td>

<td>2-chlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (2-chlorophenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>2-ethylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (2-ethylphenyl) -1,3,4-</td>

113

<td>Ar²</td><td>Name</td>

<td></td><td>thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>3-nitrophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-nitrophenyl) -1,3,4-thiadiazol- 3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>3-hydroxyphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-hydroxyphenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>3-aminophenyl</td><td>(2S) -1- (2- (3-Aminophenyl) -2- (3-aminopropyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>3-carboxyphenyl</td><td>3- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -3 - ((S) -2-methoxypropanoyl) - 2,3-dihydro-1,3,4-thiadiazol-2-yl) benzoic</td>

<td>3-cyanophenyl</td><td>3- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -3 - ((S) -2-methoxypropanoyl) -2,3-dihydro-1,3,4-thiadiazol-2-yl) - benzonitrile</td>

<td>3,4-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (3,4-dichlorophenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxypropan-1-one</td>

<td>3-chlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -2- (3-chlorophenyl) -5- (2,5-difluorophenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>3-ethylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (3-ethylphenyl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane -1-on</td>

<td>3-pyridyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (pyridin-3-yl) -1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxypropan-1-one</td>

<td>2-pyridyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (pyridin-2-yl) -1,3,4-thiadiazol-3 (2H) -yl) -2 -methoxypropan-1-one</td>

<td>5-methylthiophen-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (5-methylthiophen-2-yl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>1-methyl-1Himidazol-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) - 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>5-methylthiazol-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-difluorophenyl) -2- (5-methylthiazol-2-yl) -1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

114

<img file="PL1809280T3_D0130.tif" />

<td>R</td><td>Ar¹</td><td>Name</td>

<td></td><td>2-fluorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-fluorophenyl) -2-phenyl 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td></td><td>2-chlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-chlorophenyl) -2-phenyl1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td></td><td>2-chloro-5-fluorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-chloro-5-fluorophenyl) 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 on</td>

<td></td><td>2-fluoro-5-chlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (5-chloro-2-fluorophenyl) 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 on</td>

<td></td><td>2,5-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,5-dichlorophenyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>^^^ nh₂</td><td>5-chloro-2-methylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (5-chloro-2-methylphenyl) 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 on</td>

<td></td><td>2-fluoro-5- trifluoromethylphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-fluoro-5- (trifluoromethyl) -phenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) yl) -2-methoxypropan-1-one</td>

<td></td><td>2-fluoro-5-methoxyphenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2-fluoro-5- methoxyphenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>NH₂</td><td>2,3-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (2,3-dichlorophenyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td> -'^&lt;'^^x^ NH₂</td><td>3,4-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3,4-dichlorophenyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

115

<td>R</td><td>Ar¹</td><td>Name</td>

<td></td><td>3,5-dichlorophenyl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3,5-dichlorophenyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td></td><td>thiophen-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -2-phenyl-5- (thiophen-2-yl) 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 - he</td>

<td></td><td>thiophen-3-yl</td><td>(2S) -1- (2- (3-aminopropyl) -2-phenyl-5- (thiophen-3-yl) 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxy-1 - he</td>

<td></td><td>5-chlorothiophen-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (5-chlorothiophen-2-yl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td></td><td>2-pyridyl</td><td>(2S) -1- (2- (3-aminopropyl) -2-phenyl-5- (pyridin-2-yl) 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 - he</td>

<td></td><td>3-pyridyl</td><td>(2S) -1- (2- (3-aminopropyl) -2-phenyl-5- (pyridin-3-yl) 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 - he</td>

<td></td><td>3-chloropyridin-2-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (3-chloropyridin-2-yl) -2phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td></td><td>4-chloropyridin-3-yl</td><td>(2S) -1- (2- (3-aminopropyl) -5- (4-chloropyridin-3-yl) -2phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1 -he</td>

<td>&gt; &lt;^ nh₂</td><td>2,5-difluorophenyl</td><td>(2S) -1- (2- (2-Aminoethyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>V ™ NH₂</td><td>2,5-difluorophenyl</td><td>(2S) -1- (2- (aminomethyl) -5- (2,5-difluorophenyl) -2-phenyl 1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>H.</td><td>2,5-difluorophenyl</td><td>(2S) -1- (5- (2,5-difluorophenyl) -2- (3- (isopropylamino) propyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 -on</td>

<td></td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2-phenyl-2- (3- (pyrrolidin-1-yl) propyl) -1,3,4-thiadiazol-3 (2H) -yl ) -2-methoxypropan-1-one</td>

<td></td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2-phenyl-2- (3- (piperidin-</td>

116

<td>R</td><td>Ar¹</td><td>Name</td>

<td></td><td></td><td>1-yl) propyl) -1,3,4-thiadiazol-3 (2H) -110) -2-methoxypropan-1-one</td>

<td></td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2- (3- (4-methylpiperazin-1-yl) propyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>Η</td><td>2,5-difluorophenyl</td><td>(2S) -1- (5- (2,5-difluorophenyl) -2- (2- (methylamino) ethyl) 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2- methoxypropane-1 he</td>

<td></td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2- (2- (dimethylamino) ethyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropane- 1 -on</td>

<td></td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2- (3-hydroxypropyl) -2phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>&gt; ^^ OH</td><td>2,5-difluorophenyl</td><td>(2S) -1 - (5- (2,5-difluorophenyl) -2- (2-hydroxyethyl) -2- phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>X ^ \ x ^_N^ SO₂Me H</td><td>2,5-difluorophenyl</td><td>N- (3- (5- (2,5-difluorophenyl) -3 - ((S) -2- methoxypropanoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl) methanesulfonamide</td>

<td> 0</td><td>2,5-difluorophenyl</td><td>N- (3- (5- (2,5-difluorophenyl) -3 - ((S) -2- methoxypropanoyl) -2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl) propyl) -isobutyramide</td>

<td> 0</td><td>2,5-difluorophenyl</td><td>N- (3- (5- (2,5-difluorophenyl) -3 - ((S) -2- methoxypropanoyl) -2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl) propyl) -3- (dimethylamino) propanamide</td>

^R\-^R1

<img file="PL1809280T3_D0131.tif" />

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>S.</td><td>(S) -2-</td><td></td><td>(2S) -1- (2- (3- (cyclopent-2-enylamino) propyl) -5- (2.5-</td>

117

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td></td><td>methoxyethyl</td><td>H.</td><td>difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>s</td><td>(S) -2-methoxyethyl</td><td>H.</td><td>(2S) -1- (2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>s</td><td>(S) -2-methoxyethyl</td><td>yN — ę 2</td><td>(2S) -1- (2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>s</td><td>(S) -2-methoxyethyl</td><td>η / Λ v^N \_7</td><td>(2S) -1- (2- (3- (cyclohex-3-enylamino) -propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>s</td><td>(S) -2-methoxyethyl</td><td>^hy^N—\ j)</td><td>(2S) -1- (2- (3 - ((Z) -Cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-thiadiazol-3 (2H ) -yl) -2-methoxypropan-1-one</td>

<td>s</td><td>i-propyl</td><td>H _ v^NABOUT</td><td>1- (2- (3- (cyclopent-2-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>s</td><td>i-propyl</td><td>H _</td><td>1- (2- (3- (cyclopent-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>s</td><td>i-propyl</td><td>H v^N\ /</td><td>1- (2- (3- (cyclohex-2-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>s</td><td>i-propyl</td><td>η</td><td>1- (2- (3- (cyclohex-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-thiadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>s</td><td>NMe₂</td><td>v^NABOUT</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NMe₂</td><td>H _</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) - N, N-dimethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

118

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>s</td><td>NMe₂</td><td>^ n — ę 2</td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NMe₂</td><td>^hx^N &lt;_/</td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOH</td><td>Η _Λ</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOH</td><td>H v^NABOUT</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOH</td><td>Η / = \</td><td>2- (3- (cyclohex-2-enylamino) -propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOH</td><td>η γ^Ν~\ /</td><td>2- (3- (cyclohex-3-enylamino) -propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOH</td><td>Η / '' ii γ^Ν \ lj</td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) - N-hydroxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OH</td><td>Η _Λ</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OH</td><td>Η</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OH</td><td>η / ^ Χ γ^Ν \ /</td><td>2- (3- (cyclohex-2-enhenylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OH</td><td>^Η / Ά γ^Ν-\_/</td><td>2- (3- (cyclohex-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

119

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>s</td><td>N (Me) OH</td><td>H / 'ΐΐ</td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) carboxamide</td>

<td>s</td><td>NHOMe</td><td>Η _Λ</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOMe</td><td>H.</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOMe</td><td>γΝ — ę y</td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOMe</td><td>H / \</td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>NHOMe</td><td>Η γ^Ν \ J</td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) - N-methoxy-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OMe</td><td>H. V^NABOUT</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OMe</td><td>H v^NABOUT</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OMe</td><td>H /⁼\ ^, n-ę 2</td><td>2- (3- (cyclohex-2-enylamino) -propyl-5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OMe</td><td>^h / \ y^N~\ /</td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

<td>s</td><td>N (Me) OMe</td><td>^H. / 'Ti γΝ-ς JJ</td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) - N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxamide</td>

120

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>ο</td><td>(S) -2-methoxyethyl</td><td>Η</td><td>(2S) -1- (2- (3- (cyclopent-2-enylamino) -propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>ο</td><td>(S) -2-methoxyethyl</td><td>H _ v^NABOUT</td><td>(2S) -1- (2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>ο</td><td>(S) -2-methoxyethyl</td><td></td><td>(2S) -1- (2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>ο</td><td>(S) -2-methoxyethyl</td><td></td><td>(2S) -1- (2- (3- (cyclohex-3-enylamino) -propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methoxypropan-1-one</td>

<td>ο</td><td>(S) -2-methoxyethyl</td><td>^H. / '' hyⁿaJ</td><td>(2S) -1- (2- (3 - ((Z) -Cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) -2-phenyl-1,3,4-oxadiazol-3 (2H ) -yl) -2-methoxypropan-1-one</td>

<td>ο</td><td>i-propyl</td><td>Η _Λ</td><td>1- (2- (3- (cyclopent-2-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>ο</td><td>i-propyl</td><td>Η _Λ</td><td>1- (2- (3- (cyclopent-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>ο</td><td>i-propyl</td><td>Η / = \ ^ n — ę y</td><td>1- (2- (3- (cyclohex-2-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>ο</td><td>i-propyl</td><td> \'ⁿABOUT</td><td>1- (2- (3- (cyclohex-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) - 2-phenyl-1,3,4-oxadiazol-3 (2H) -yl) -2-methylpropan-1-one</td>

<td>ο</td><td>NMe₂</td><td>v^NABOUT</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

121

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>ο</td><td>NMe₂</td><td>Η _Λ</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΜθ₂</td><td>^ n — ę 2</td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΜθ₂</td><td>η ^ N — 2</td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) N, N-dimethyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΗΟΗ</td><td>_VN ^</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΗΟΗ</td><td>H.</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΗΟΗ</td><td>H / = \ Y^N—\ 2</td><td>2- (3- (cyclohex-2-enylamino) -propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>ΝΗΟΗ</td><td>η y^N \ /</td><td>2- (3- (cyclohex-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>ο</td><td>N (Me) OH</td><td>Η _ΛV^N0</td><td>2- (3- (cyclopent-2-enylamino) -propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

<td>ο</td><td>N (Me) OH</td><td>ν^κΌ</td><td>2- (3- (cyclopent-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

<td>ο</td><td>N (Me) OH</td><td></td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

<td>ο</td><td>N (Me) OH</td><td>H f ~ X^NABOUT</td><td>2- (3- (cyclohex-3-enhenylamino) propyl) -5- (2,5-difluorophenyl) -N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

<td></td><td></td><td></td><td></td>

122

<td>X</td><td>R¹</td><td>NO²R³</td><td>Name</td>

<td>about</td><td>NHOMe</td><td>Η _Λ</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>NHOMe</td><td>H.</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>NHOMe</td><td>H ^ N — 2</td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>NHOMe</td><td></td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>NHOMe</td><td></td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

<td>about</td><td>N (Me) OMe</td><td>Η _Λ</td><td>2- (3- (cyclopent-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>N (Me) OMe</td><td>H vⁿABOUT</td><td>2- (3- (cyclopent-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>N (Me) OMe</td><td>^ n — ę 2</td><td>2- (3- (cyclohex-2-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>N (Me) OMe</td><td>Η r ~</td><td>2- (3- (cyclohex-3-enylamino) propyl) -5- (2,5-difluorophenyl) -N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) -carboxamide</td>

<td>about</td><td>N (Me) OMe</td><td>H / Tl jj</td><td>(Z) -2- (3- (cyclohept-4-enylamino) propyl) -5- (2,5-difluorophenyl) N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3 (2H) carboxamide</td>

Example 123

[0450] The activity of the compounds of the present invention can be determined as follows. The tests are carried out at 30 ° C on Costar 3695 plates (96 wells, polystyrene,¹/ 2-fields. transparent) with a final volume of 50 pl. ATP hydrolysis is monitored in the system in which

123 the ADP product is coupled to the oxidation of NADH using pyruvate kinase and lactate dehydrogenase. The tested mixtures contain the following: 20 mM K⁺Pipes, pH 7.0, 0.01% Triton X100, 2% DMSO, 25 mM KCI, 2 mM MgCl₂, 1 mM DTT, 25 μΜ ATP, 1 mM phospho (enol) pyruvate, 200 μΜ NADH, 7.9 U / ml pyruvate kinase, 9 U / ml lactate dehydrogenase, 0.25 μΜ bovine microtubules, 20 μΜ paclitaxel and 20 nM Eg5. The inhibitor concentration is typically in the range 10-200,000 nM. The reaction is monitored kinetically in an absorbance-based plate reader for 10 minutes. Velocities are assessed from linear fitting to progress curves and are expressed as POC (Percentage of Uninhibited Control Wells). IC values₅o is determined from the POC data using a standard 4-parameter logistic model and compared to the inhibitor control results in each plate. The compounds of the invention show an IC value in this test₅less than 50 pM.

Example 124

[0451] The ability of the compounds of the present invention to inhibit cell viability is determined as follows. Cells from a variety of established cancer cell lines, e.g. HeLa, is plated in 96-well Costar 3904 plates in cell line growth medium (for HeLa: DMEM glucose, L-glutamine, 20 mM Hepes, 10% FBS), at a density that allows logarithmic growth of the test sample over 72 hours (HeLa: 1000 cells / well), and incubated at 37 ° C, 5% CO₂ through the night. The next day, a tenth volume of a 10Χ compound concentration is added to the wells of an 11-point dilution series. The dilution series is made up of an initial 1: 2 dilution in DMSO, followed by a 1:20 dilution in growth medium to a final cell DMSO concentration of 0.5%. Control wells are treated with 0.5% DMSO. The typical range of dilutions is 2.5 µM to 1 nM, which increases to 50 pM to 50 pM depending on compound strength. After the compound is added to the cells, the plates are incubated as described above. After 72 hours of incubation, 20 µl of resazurin solution (Cell Titer Blue, Promega G8081) is added to all wells and the plates are incubated for a further 2 hours. Living cells convert resazurin to resorufin, a fluorescent end product. The plate is read on a fluorescent plate reader at excitation 560 nm / emission 590 nm. The fluorescence signal of the control wells is defined as 100% and the percent of the control signal for each well in the compound dilution series is defined as: (treated well fluorescent signal) X (mean of control well fluorescent signal)^-1 X 100. The value of ΕΟ₅₀ for life inhibition, it is determined from the inflection point of a standard 4-parameter logistic curve determined from the values ​​obtained. The compounds of the invention show a value of wartość in this test₅₀ less than 50 pM.

[0452] The foregoing description is considered to be merely illustrative of the principles of the invention. Moreover, since numerous modifications and variations are apparent to those skilled in the art, it is not desirable to limit the invention to the particular structure and method set forth in the above description. Accordingly, all appropriate modifications and equivalents are considered to fall within the scope of the invention as defined in the following claims.

[0453] The terms "comprises", "comprising", "include", "comprising" and "comprises", when used in this specification and the following claims, are intended to denote the presence of the listed features,

124 numbers, components or steps, but do not exclude the presence or addition of one or more other features, numbers, components, steps or groups thereof.

Array Biopharma, Inc., USA

Proxy

ΕΡ 1 809 280

Ζ-8773/11