MITOTIC KINESIN INHIBITORS AND METHODS OF USE THEREOF
20170066733 ยท 2017-03-09
Assignee
Inventors
- Jeremy Hans (Omaha, NE, US)
- Eli M. Wallace (Richardson, TX)
- Qian Zhao (El Cerrito, CA, US)
- Joseph P. Lyssikatos (Piedmont, CA)
- Thomas D. Aicher (Ann Arbor, MI)
- Ellen Laird (Boulder, CO, US)
- John Robinson (Boulder, CO, US)
- Shelley Allen (Boulder, CO)
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
C07D271/107
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
A61P43/00
HUMAN NECESSITIES
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
A61P9/04
HUMAN NECESSITIES
C07D285/12
CHEMISTRY; METALLURGY
A61P1/00
HUMAN NECESSITIES
C07D417/06
CHEMISTRY; METALLURGY
A61P37/06
HUMAN NECESSITIES
C07D413/06
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D285/12
CHEMISTRY; METALLURGY
C07D417/06
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
Abstract
This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors.
##STR00001##
Claims
1. A compound of the Formula ##STR00389## and resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof, wherein: X is S, R is ZNR.sup.2R.sup.3; R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, OR.sup.3, NR.sup.4OR.sup.5, CR.sup.b(NOR.sup.c), C(O)R.sup.a, or NR.sup.4R.sup.5, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, OCH.sub.2C(O)OR.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, OP(O)(OR.sup.a).sub.2, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; Ar.sup.1 is phenyl and Ar.sup.2 is imidazolyl, wherein said phenyl and imidazolyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heteorcycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OR.sup.a, O(CO)OR.sup.dOP(O)(OR.sup.a)(OR.sup.a), NR.sup.aR.sup.b, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, OCH.sub.2C(O)OR.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b and NR.sup.cC(O)NR.sup.aR.sup.b; R.sup.2 is hydrogen, C(O)R.sup.4, SO.sub.2R.sup.6, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, a natural or unnatural amino acid, or a polypeptide of two or more amino acids independently selected from natural and unnatural amino acids, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; R.sup.3 is hydrogen, C(O)R.sup.4, alkyl, alkenyl, alkynyl, or saturated or partially unsaturated cycloalkyl, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, OP(O)(OR.sup.a).sub.2, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NRC(O)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl, or R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the nitrogen atom to which said R.sup.2 and R.sup.3 are attached, selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; R.sup.4 and R.sup.5 are independently H, trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl, or R.sup.4 and R.sup.5 together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the heteroatoms to which said R.sup.4 and R.sup.5 are attached, selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; R.sup.6 is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; R.sup.a is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or saturated or partially unsaturated heterocyclylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.h, NR.sup.fSO.sub.2R.sup.h, SO.sub.2NR.sup.eR.sup.f, C(O)R.sup.e, C(O)OR.sup.e, OC(O)R.sup.e, NR.sup.fC(O)OR.sup.h, NR.sup.fC(O)R.sup.e, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, NR.sup.gC(O)NR.sup.eR.sup.f, NR.sup.cC(NCN)NR.sup.eR.sup.f, OR.sup.e, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl and heterocyclylalkyl; R.sup.b, R.sup.e, R.sup.f and R.sup.g are independently hydrogen or alkyl, or R.sup.a and R.sup.b together with the atom to which they are attached form a 4 to 10 membered saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the nitrogen atom to which said R.sup.a and R.sup.b are attached, selected from N, O and S; R.sup.d and R.sup.h are independently trifluoromethyl, alkyl, saturated or partially unsaturated cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl or heterocyclylalkyl; R.sup.e is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl or heterocyclylalkyl; and Z is alkylene having from 1 to 6 carbons, or alkenylene or alkynylene each having from 2 to 6 carbons, wherein said alkylene, alkenylene and alkynylene are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl.
2. The compound of claim 1, wherein Ar.sup.1 is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR.sup.a, NR.sup.aR.sup.b, NO.sub.2, CN, C(O)OR.sup.a, alkyl, and CF.sub.3.
3. The compound of claim 1, wherein Ar.sup.1 and Ar.sup.2 are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR.sup.a, NR.sup.aR.sup.b, NO.sub.2, CN, C(O)OR.sup.a, alkyl, and CF.sub.3.
4. The compound of claim 1, wherein Z is substituted or unsubstituted alkylene.
5. The compound of claim 4, wherein Z is substituted or unsubstituted propylene.
6. The compound of claim 4, wherein R.sup.2 and R.sup.3 are independently selected from H, alkyl, saturated or partially unsaturated cycloalkyl, an amino acid, and a dipeptide, wherein said alkyl and cycloalkyl are optionally substituted.
7. The compound of claim 1, wherein R.sup.1 is NR.sup.4OR.sup.5.
8. The compound of claim 7, wherein R.sup.4 and R.sup.5 are independently selected from H, alkyl, saturated or partially unsaturated cycloalkyl, and heteroaryl.
9. The compound of claim 1, wherein R.sup.1 is alkyl, cycloalkyl, heterocycloalkyl, O-alkyl, OR.sup.a, aryl, heteroaryl, CR.sup.b(NOR.sup.c), or C(O)R.sup.a, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from OR.sup.a, NR.sup.aR.sup.b, halogen, cycloalkyl, alkyl, aryl and CF.sub.3.
10. The compound of claim 1, which is ##STR00390## wherein: R.sup.x and R.sup.y are independently H, alkyl, saturated or partially unsaturated cycloalkyl or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, OCH.sub.2C(O)OR.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, or R.sup.x and R.sup.y together with the atom to which they are attached form a saturated or partially unsaturated carbocyclic ring or heterocyclic ring having one or more heteroatoms independently selected from N, O and S, wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.d, NR.sup.bSO.sub.2R.sup.d, SO.sub.2NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, NR.sup.bC(O)OR.sup.d, NR.sup.bC(O)R.sup.a, C(O)NR.sup.aR.sup.b, NR.sup.aR.sup.b, NR.sup.cC(O)NR.sup.aR.sup.b, NR.sup.cC(NCN)NR.sup.aR.sup.b, OR.sup.a, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; or R.sup.a and R.sup.x together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the oxygen atom to which said R.sup.a is attached, selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, O(CO)OR.sup.h, NR.sup.fSO.sub.2R.sup.h, SO.sub.2NR.sup.eR.sup.f, C(O)R.sup.e, C(O)OR.sup.e, OC(O)R.sup.e, NR.sup.fC(O)OR.sup.h, NR.sup.fC(O)R.sup.e, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, NR.sup.gC(O)NR.sup.eR.sup.f, NR.sup.cC(NCN)NR.sup.eR.sup.f, OR.sup.e, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl.
11. The compound of claim 10, wherein at least one of R.sup.x and R.sup.Y is not H.
12. The compound of claim 11, wherein R.sup.a is H or alkyl.
13. The compound of claim 12, wherein R.sup.x is alkyl.
14. The compound of claim 10, wherein R.sup.2 and R.sup.3 are independently selected from H, alkyl, saturated or partially unsaturated cycloalkyl, an amino acid, and a dipeptide, wherein said alkyl and cycloalkyl are optionally substituted.
15. The compound of claim 10, wherein R.sup.1 is NR.sup.4OR.sup.5.
16. The compound of claim 15, wherein R.sup.4 and R.sup.5 are independently selected from H, alkyl, saturated or partially unsaturated cycloalkyl, and heteroaryl.
17. The compound of claim 16, wherein R.sup.4 and R.sup.5 are alkyl.
18. The compound of claim 10, wherein R.sup.1 is alkyl, cycloalkyl, heterocycloalkyl, O-alkyl, OR.sup.a, aryl, heteroaryl, CR.sup.b(NOR.sup.c), or C(O)R.sup.a, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from OR.sup.a, NR.sup.aR.sup.b, halogen, cycloalkyl, alkyl, aryl and CF.sub.3.
19. The compound of claim 10, wherein Ar.sup.1 is optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR.sup.a, NR.sup.aR.sup.b, NO.sub.2, CN, C(O)OR.sup.a, alkyl, and CF.sub.3.
20. The compound of claim 10, wherein Ar.sup.1 and Ar.sup.2 are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR.sup.a, NR.sup.aR.sup.b, NO.sub.2, CN, C(O)OR.sup.a, alkyl, and CF.sub.3.
21. A compound of claim 1, selected from: ##STR00391## TABLE-US-00011 Ar.sup.2 Name 1-methyl-1H- (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- imidazol-2-yl (1-methyl-1H-imidazol-2-yl)-1,3,4-thiadiazol-3(2H)- yl)-2-methoxypropan-1-one and resolved enantiomers and diastereomers thereof.
Description
EXAMPLES
[0203] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other KSP inhibitors of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
[0204] In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), toluene, dioxane and 1,2-dichloroethane (DCE) were purchased from Aldrich in Sure seal bottles and used as received.
[0205] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
[0206] Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters).
[0207] .sup.1H-NMR spectra were recorded on a Varian instrument operating at 400 MHz. .sup.1H-NMR spectra were obtained as CDCl.sub.3, d.sub.6-DMSO, CD.sub.3OD or CDCl.sub.3:CD.sub.3OD solutions (reported in ppm), using trimethylsilane as the reference standard (0.00 ppm). When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
Example 1
[0208] ##STR00013##
Synthesis of 1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
Step A: Preparation of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester
[0209] To a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7.03 g, 38 mmol) in THF (130 mL) was added phenylmagnesium bromide (1.0 M solution, 50 mL) at 78 C. After stirring for 2 hour at 78 C., HCl (2 M, 35 mL) was added to quench the reaction, which was then warmed to room temperature and the aqueous layer was extracted with EtOAc (2100 mL). The combined organics were washed with brine (50 mL) and dried over Na.sub.2SO.sub.4, 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
[0210] To a solution of 2,5-difluorobenzoic acid (3.5 g, 22 mmol) in THF/DMF (20 mL/20 mL) was added EDCI (4.7 g, 24 mmol), DMAP (50 mg) and NH.sub.2NHBoc (3.07 g, 23.2 mmol). After stirring for 16 hours, the reaction 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 NaHCO.sub.3(20 mL), and brine (20 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude Boc-protected product, which was then dissolved in DCM (60 mL) at 0 C. TFA (50 mL) was 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 NaHCO.sub.3 (40 mL) and dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the desired crude product.
Step C: Preparation of {4-[(2,5-difluorobenzoyl)-hydrazono]-4-phenylbutyl}-carbamic acid tert-butyl ester
[0211] To a solution of (4-oxo-4-phenylbutyl)-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) was added HOAc (0.5 mL). The reaction was then heated to reflux and stirred for 3 days. The reaction mixture was then cooled to room temperature and concentrated to give desired product (5.1 g).
Step D: Preparation of {3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester
[0212] 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) was added isobutyric anhydride (2 mL). The reaction mixture was then sealed and heat to 110 C. and stirred for 5 hours. The reaction was 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-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one
[0213] To a solution of {3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (60 mg, 0.123 mmol) in DCM (2 mL) at 0 C. was added TFA (1 mL). After stirring for 10 minutes, the reaction was concentrated and the residue was purified by preparative thin layer chromatography (10:1:0.2 EtOAc/MeOH/30% NH.sub.4OH) to provide the desired product (25 mg, 53%). MS ESI (+) m/z 388 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.59 (m, 2H), 7.50 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 3.17 (m, 1H, J=7 Hz), 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=7 Hz), 1.13 (d, 3H, J=7 Hz).
[0214] The following compounds were synthesized in a similar manner using the appropriate hydrazide and anhydride.
Example 2
[0215] ##STR00014##
1-[2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-ethanone
[0216] MS ESI (+) m/z 360 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0217] ##STR00015##
1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0218] MS ESI (+) m/z 370 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.67 (d, 1H, J=8 Hz), 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=7 Hz), 3.05 (m, 1H), 2.85 (t, 2H, J=7 Hz), 2.52 (m, 1H), 1.62 (m, 2H), 1.17 (d, 3H, J=7 Hz), 1.11 (d, 3H, J=7 Hz).
Example 4
[0219] ##STR00016##
1-[2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0220] MS ESI (+) m/z 386 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (s, 1H), 7.77 (d, 1H, J=8 Hz), 7.54 (m, 2H), 7.46 (d, 1H, J=8 Hz), 7.4-7.34 (m, 4H), 3.37 (m, 1H, J=7 Hz), 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=7 Hz), 1.13 (d, 3H, J=7 Hz).
Example 5
[0221] ##STR00017##
Synthesis of 1-[2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one
Step A: Preparation of {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester
[0222] 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) was added 3-fluorothiobenzoic acid hydrazide (Takasugi, J. J.; Buckwalter, B. L. 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 (20:1Hexanes/EtOAc) to provide the product (2.65 g, 90%).
Step B: Preparation of {3-[5-(3-fluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester
[0223] 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 was quenched by the addition of methanol (0.1 mL). The reaction mixture was concentrated and purified by flash column chromatography (15:1Hexanes/EtOAc) to provide the product (350 mg, 75%).
Step C: Preparation of 1-[2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one
[0224] HCl (1 mL, 4 M in dioxane) was added to {3-[5-(3-fluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (100 mg, 0.21 mmol) at 0 C. After stirring for 0.5 hours, the reaction was concentrated to give the desired product as the dihydrochloride salt. MS ESI (+) m/z 386 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.1 (d, 3H, J=7 Hz).
Example 6
[0225] ##STR00018##
2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylic acid dimethylamide
[0226] This compound was synthesized in a manner similar to that described in Example 5, substituting dimethylcarbamyl chloride for isobutyryl chloride. MS ESI (+) m/z 387 (M+1) detected; .sup.1H NMR (di-TFA salt, 400 MHz, CDCl.sub.3) 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
[0227] ##STR00019##
Synthesis of [2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-pyridin-2-yl-methanone
[0228] 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 were 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.sub.3 (10 mL) were added to the reaction solution. The phases were separated and the aqueous layer was extracted with EtOAc (210 mL). The combined organics were dried over Na.sub.2SO.sub.4, 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 the product was cooled to 0 C., to which HCl (1 mL, 4 M in dioxane) was added. After stirring for 0.5 hours, the reaction was concentrated to give the desired product as the trihydrochloride salt. MS ESI (+) m/z 421 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0229] ##STR00020##
[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-pyridin-3-yl-methanone
[0230] The trihydrochloride salt of this compound was synthesized in a manner similar to that described in Example 7. MS ESI (+) m/z 421 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0231] ##STR00021##
Synthesis of 1-[5-(2,5-difluorophenyl)-2-(3-methylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0232] To a solution of {3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-methylcarbamic acid tert-butyl ester (13 mg, 0.027 mmol) in DMF (0.5 mL) was added to NaH (14 mg, 0.58 mmol, 60% dispersion in mineral oil) that was previously washed with hexanes. 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 NaHCO.sub.3(20 mL). The mixture was extracted with ethyl acetate (230 mL). The combined organics were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, 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. was added TFA (6 L). After 30 minutes, more TFA (100 L) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated under a stream of N.sub.2, diluted with dichloromethane (20 mL) and washed with 10% Na.sub.2CO.sub.3(20 mL). The mixture was extracted with dichloromethane (230 mL). The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (6:2:92 MeOH/triethylamine/ethyl acetate) to provide the final product (3.8 mg, 72%) as a yellow film. MS ESI (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 1.14 (d, 3H, J=7 Hz).
Example 10
[0233] ##STR00022##
Synthesis of 1-[5-(2,5-difluorophenyl)-2-(3-dimethylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0234] 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 paraforamldehyde (11 mg, 0.35 mmol). The reaction mixture was heated to 70 C. and stirred for 2 hours. After cooling to room temperature, a solution of sodium cyanoborohydride (0.070 mL, 0.070 mmol, 1M in THF) was added. The mixture stirred for 20 minutes and then was diluted with half saturated NaCl (50 mL) and extracted with ethyl acetate (325 mL). The combined organics were washed with saturated NaCl, dried over Na.sub.2SO.sub.4, 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 1.14 (d, 3H, J=7 Hz).
Example 11
[0235] ##STR00023##
Synthesis of 1-[5-(2,5-difluorophenyl)-2-(3-isopropylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0236] 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) was added acetone (60 L, 0.082 mmol) and sodium triacetoxyborohydride (10 mg, 0.045 mmol). After stirring at room temperature for 45 minutes, more sodium triacetoxyborohydride (10 mg, 0.045 mmol) was added. The mixture stirred at room temperature for 5 hours. The reaction mixture was diluted with 10% Na.sub.2CO.sub.3 (30 mL) and extracted with ethyl acetate (330 mL). The combined organics were washed with brine (45 mL), dried over Na.sub.2SO.sub.4, 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 provide the final product (3.3 mg, 25%). MS ESI (+) m/z 430 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.14 (d, 3H, J=6 Hz), 1.04 (d, 6H, J=6 Hz).
Example 12
[0237] ##STR00024##
Synthesis of 1-[5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
Step A: Preparation of 4-hydroxy-1-phenylbutan-1-one
[0238] To a solution of dihydrofuran-2-one (5.71 g, 66 mmol) in diethyl ether (70 mL) at 78 C. was slowly added phenyl lithium (24 mL, 40 mmol, 1.67 M solution in cyclohexane/diethyl ether). After stirring at 78 C. for 2 hours, the reaction mixture was quenched by the addition of 10% NH.sub.4Cl (35 mL). The mixture was warmed to room temperature and the layers separated. The aqueous layer was extracted with diethyl ether (240 mL). The combined organics were washed with water (240 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2:3 hexanes/ethyl acetate) to provide the product (6.4 g, 97%) as pale yellow oil.
Step B: Preparation of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one
[0239] To a solution of 4-hydroxy-1-phenyl-butan-1-one (3.29 g, 20 mmol) in DMF (20 mL) was added tert-butylchlorodimethyl-silane (4.5 g, 30 mmol) and imidazole (4.1 g, 60 mmol). After stirring at room temperature for 14 hours, the reaction mixture was diluted with diethyl ether (150 mL) and washed with 1M HCl (270 mL), water (270 mL) and brine (100 mL). The combined organics were dried over Na.sub.2SO.sub.4, 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 a colorless oil.
Step C: Preparation of 2,5-difluorobenzoic acid [4-(tert-butyldimethylsilanyloxy)-1-phenylbutylidene]-hydrazide
[0240] To a solution of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one (420 mg, 1.5 mmol) in EtOH (4 mL) was added 2,5-difluorobenzoic acid hydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol). After stirring the reaction mixture at 90 C. for 5 hours, 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 was carried forward without further purification.
Step D: Preparation of 1-[5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one
[0241] To a solution of crude 2,5-difluorobenzoic acid [4-(tert-butyl-dimethylsilanyloxy)-1-phenylbutylidene]-hydrazide from the previous step (200 mg) in dichloroethane (1 mL) was added isobutyric anhydride (73 mg, 0.46 mmol). After heating at 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% aq. HF (50 L). After stirring at room temperature for 30 minutes, the mixture was diluted with saturated NaHCO.sub.3 (30 mL) and extracted with ethyl acetate (320 mL). The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% ethyl acetate in hexanes) to provide the product (9 mg, 45%) as colorless film. MS ESI (+) m/z 389 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.15 (d, 3H, J=7 Hz).
[0242] The following examples were prepared as previously described in Examples 5 or 6 using the appropriate thiohydrazide, ketone and acid chloride or carbamoyl chloride.
Example 13
[0243] ##STR00025##
[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-cyclopropylmethanone
[0244] MS APCI (+) m/z 384 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0245] ##STR00026##
1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methoxyethanone
[0246] MS APCI (+) m/z 387 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=16 Hz), 4.44 (d, 1H, J=16 Hz), 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
[0247] ##STR00027##
1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxyethanone
[0248] MS APCI (+) m/z 404, 406 (M+1, Cl pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.38 (br, 2H), 7.65 (s, 1H), 7.52 (d, 2H, J=8 Hz), 7.47 (d, 1H, J=8 Hz), 7.41 (d, 1H, J=8 Hz), 7.32 (m, 3H), 7.24 (m, 1H), 4.67 (d, 1H, J=16 Hz), 7.45 (d, 1H, J=16 Hz), 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
[0249] ##STR00028##
(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopropyl)methanone
[0250] MS APCI (+) m/z 400, 402 (M+1, Cl pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0251] ##STR00029##
1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one
[0252] MS APCI (+) m/z 402, 404 (M+1, Cl pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.49 (br, 2H), 7.67 (s, 1H), 7.51 (m, 3H), 7.41 (d, 1H, J=8 Hz), 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=6 Hz), 1.12 (d, 3H, J=7 Hz).
Example 18
[0253] ##STR00030##
[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-morpholin-4-yl-methanone
[0254] MS APCI (+) m/z 429 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0255] ##STR00031##
Synthesis of 1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)ethanone
[0256] MS ESI (+) m/z 358 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (s, 1H), 7.45 (s, 1H), 7.42 (d, 1H, J=9 Hz), 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
[0257] ##STR00032##
(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclobutyl)methanone
[0258] MS ESI (+) m/z 398 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46 (d, 2H, J=7 Hz), 7.41 (d, 1H, J=11 Hz), 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
[0259] ##STR00033##
1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethylbutan-1-one
[0260] MS ESI (+) m/z 414 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (d, 2H, J=8 Hz), 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=7 Hz), 0.83 (t, 3H, J=7 Hz).
Example 22
[0261] ##STR00034##
1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one
[0262] MS ESI (+) m/z 372 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.44 (m, 2H), 7.37 (m, 5H), 7.27 (m, 1H), 7.14 (m, 1H), 3.21 (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
[0263] ##STR00035##
1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)butan-1-one
[0264] MS ESI (+) m/z 386 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz).
Example 24
[0265] ##STR00036##
1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylbutan-1-one
[0266] MS ESI (+) m/z 400 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0267] ##STR00037##
1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methylbutan-1-one
[0268] MS ESI (+) m/z 400 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz, 15 Hz), 2.63 (dd, 1H, J=7 Hz, 15 Hz), 2.39 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.56 (m, 1H), 0.95 (m, 6H).
Example 26
[0269] ##STR00038##
(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopentyl)methanone
[0270] MS ESI (+) m/z 412 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0271] ##STR00039##
1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)ethanone
[0272] MS ESI (+) m/z 376 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0273] ##STR00040##
1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one
[0274] MS ESI (+) m/z 404 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=8 Hz), 1.16 (d, 3H, J=8 Hz).
Example 29
[0275] ##STR00041##
1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxyethanone
[0276] MS ESI (+) m/z 406 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=16 Hz), 4.48 (d, 1H, J=16 Hz), 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
[0277] ##STR00042##
2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0278] MS ESI (+) m/z 405 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0279] ##STR00043##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)ethanone
[0280] MS ESI (+) m/z 394 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.57 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J=8 Hz), 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
[0281] ##STR00044##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one
[0282] MS ESI (+) m/z 422 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J=8 Hz), 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=7 Hz), 1.18 (d, 3H, J=7 Hz).
Example 33
[0283] ##STR00045##
1-(2-(4-aminobutan-2-vyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (diastereomer pair A)
Step A: Preparation of tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate
[0284] To a solution of 3-methyl-2-pyrrolidinone (5.0 g, 50.4 mmol) in anhydrous THF (100 mL) at 78 C. was added n-butyllithium (2.1 M solution, 25.2 mL, 53 mmol). The mixture was stirred for 30 min then treated with a solution of Boc-anhydride (11.01 g, 50.4 mmol) in anhydrous THF (50 mL). After 3 hours at 78 C., phenyl magnesium bromide (1.0 M solution, 65.6 mL, 65.6 mmol) was added via cannula. After a further 3 hours at 78 C. the mixture was treated with 2 N HCl (100 mL), warmed to room temperature and extracted with ethyl acetate (3100 mL). The combined organic phases were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 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 a yellow oil.
Step B: Preparation of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate
[0285] To a solution of 3-fluorobenzothiohydrazide (300 mg, 1.76 mmol) in ethanol/DCM (6 mL/2 mL) was added tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate (538 mg, 1.94 mmol). After stirring at room temperature for 16 hours, acetic acid (3 drops) was added and the mixture stirred for another 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 a 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
[0286] To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate (50 mg, 116 mmol) in anhydrous DCM (5 mL) was added isobutyryl chloride (16 L, 151 mmol) followed by triethylamine (21 L, 151 mmol). After stirring at room temperature for 16 hours the mixture was partitioned between sat. NaHCO.sub.3(20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic phases were washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was chromatographed (19:1, hexanes/ethyl acetate) to afford two diastereomeric pairs, diastereomer pair A (more polar, 13.1 mg) and diastereomer pair B (less polar, 11 mg).
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 (diastereomer pair A)
[0287] To a solution of diastereomer pair A from the previous step (13.1 mg, 0.026 mmol) in DCM (2 mL) was added TFA (0.5 mL). After stirring at room temperature for 2 hours the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.sub.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 Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide the product as a diastereomer pair (10 mg, 96%) as a pale yellow oil.
[0288] MS ESI (+) m/z 400 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0289] ##STR00046##
1-(2-(-4-aminobutan-2-yl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (diastereomer pair B)
[0290] Prepared as described in Example 33 using the less polar diastereomer pair B. MS ESI (+) m/z 400 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 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=6.8 Hz, 14 Hz), 0.96 (d, 3H, J=7 Hz), 0.84 (m, 1H).
[0291] The following examples were prepared as previously described in Example 7 using the appropriate thiohydrazide, ketone and carboxylic acid.
Example 35
[0292] ##STR00047##
(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone (diastereomer A)
[0293] Coupling with (R)-2-methoxy-2-phenylacetic acid provided diastereomeric products that were isolated using silica gel chromatography (4:1 hexanes/ethyl acetate). The more polar diastereomer (Boc-protected diastereomer A) was subjected to t-butoxycarbonyl group removal as in Example 7 to afford the product as the di-HCl salt. MS ESI (+) m/z 464 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0294] ##STR00048##
(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone (diastereomer B)
[0295] Prepared as described in Example 35 using the less polar diastereomer (Boc-protected diastereomer B). MS ESI (+) m/z 464 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0296] ##STR00049##
1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-(S)-methoxypropan-1-one
[0297] Obtained as a mixture of diastereomers. MS ESI (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 1.37 (d, 3H, J=7 Hz).
Example 38
[0298] ##STR00050##
[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-(tetrahydrofuran-3-yl)-methanone
[0299] Obtained as a mixture of diastereomers: MS ESI (+) m/z 414 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0300] ##STR00051##
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)
[0301] Coupling with N-acetyl L-valine provided diastereomeric products that were isolated using silica gel chromatography (1:1 hexanes:ethyl acetate). The more polar diastereomer (Boc-protected diastereomer A) was subjected to t-butoxycarbonyl group removal as in Example 7 to afford the product as the di-HCl salt. MS ESI (+) m/z 457 (M+1) detected; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 7.52-7.16 (m, 8H), 7.20 (m, 1H), 5.13 (d, 1H, J=4 Hz), 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=6.3 Hz), 0.87 (d, 3H, J=7.0 Hz).
Example 40
[0302] ##STR00052##
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)
[0303] Prepared as described in Example 39 using the less polar diastereomer (Boc-protected diastereomer B). MS ESI (+) m/z 457 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7.8 Hz).
Example 41
[0304] ##STR00053##
(2 S)-1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0305] Obtained as a mixture of diastereomers. MS APCI (+) m/z 418, 420 (M+1, Cl pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.46 (br, 4H), 7.65 (s, 2H), 7.50 (m, 6H), 7.42 (d, 2H, J=8 Hz), 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=7 Hz), 1.37 (d, 3H, J=6 Hz).
Example 42
[0306] ##STR00054##
Synthesis of (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0307] 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, 0.11 mmol) and (S)-2-methoxypropanoic acid (22 L, 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 L, 0.35 mmol). After stirring for 64 hours, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated NaHCO.sub.3(20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organics were washed with water (510 mL) and brine (10 mL). The solution was dried over Na.sub.2SO.sub.4 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. To a solution of this product (33 mg, 0.06 mmol) in dichloromethane (4 mL) at 0 C. was added TFA (1 mL). After stirring for 20 minutes, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and saturated NaHCO.sub.3(20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organics were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide the product as a mixture of diastereomers as a colorless gum (26 mg, 97%). MS ESI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=34 Hz), 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=6.6 Hz, 24.3 Hz).
[0308] The following examples were prepared as previously described in Example 42 using the appropriate thiohydrazide, ketone and acid.
Example 43
[0309] ##STR00055##
(2S)-1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylbutan-1-one
[0310] Obtained as a mixture of diastereomers. MS ESI (+) m/z 418 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0311] ##STR00056##
(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopropyl)methanone
[0312] MS ESI (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0313] ##STR00057##
(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0314] Obtained as a mixture of diastereomers. MS ESI (+) m/z 438 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (m, 1H), 7.32 (m, 1H), 7.23 (d, 1H, J=8 Hz), 7.14 (m, 3H), 6.98 (m, 1H), 4.68 (m, 1H), 3.37 (m, 1H), 3.35 (d, 3H, J=34 Hz), 2.93 (m, 2H), 2.40 (m, 1H), 1.99 (m, 1H), 1.62 (m, 1H), 1.48 (dd, 3H, J=6.6 Hz, 26 Hz), 1.36 (m, 1H), 1.25 (m, 1H).
Example 46
[0315] ##STR00058##
Synthesis of 1-[2-(3-dimethylaminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one
[0316] 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 was allowed to cool to room temperature and sodium cyanoborohydride (0.07 mL, 0.07 mmol, 1M solution in THF) was added. After stirring for 40 minutes, the mixture was diluted with half saturated NaCl (50 mL) and extracted with ethyl acetate (325 mL). The combined organics were washed with saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% triethylamine, 40% ethyl acetate in hexanes) to provide the final product (3.0 mg, 30%) as pale yellow film. MS ESI (+) m/z 414 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.18 (d, 3H, J 7 Hz).
Example 47
[0317] ##STR00059##
Synthesis of 1-[5-(3-fluorophenyl)-2-(3-isopropylaminopropyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one
[0318] 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 the mixture was added sodium triacetoxyborohydride (33 mg, 0.20 mmol). After stirring at room temperature for 16 hours, more acetone (50 L) and sodium triacetoxyborohydride (14 mg) was added. The reaction mixture was heated to 45 C. for 40 hours and then diluted with 10% Na.sub.2CO.sub.3 (30 mL). The mixture was extracted with ethyl acetate (330 mL). The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% triethylamine, 40% ethyl acetate in hexanes) to provide the product (5.4 mg, 50%) as pale yellow film. MS ESI (+) m/z 428 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.45 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=7 Hz), 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=6 Hz), 1.17 (d, 3H, J=6 Hz), 1.05 (d, 6H, J=6 Hz).
Example 48
[0319] ##STR00060##
Synthesis of 2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylic acid methyl-pyridin-2-yl-amide
[0320] To a solution of methyl-pyridin-2-yl-amine (77 mg, 0.71 mmol) and triethylamine (150 mg, 0.15 mmol) in dichloroethane (3 mL) was added triphosgene (110 mg, 0.37 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and diluted with dichloroethane (3 mL). To the solution was 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 provide the final product as the trihydrochloride salt (64 mg, 97%). MS APCI (+) m/z 450 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=8 Hz), 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
[0321] ##STR00061##
2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylic acid pyridin-3-ylamide
[0322] Prepared as previously described in Example 48 using pyridin-3-amine in place of methylpyridin-2-yl-amine. MS APCI (+) m/z 436 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0323] ##STR00062##
Synthesis of (2S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one (diastereomer A)
[0324] (S)-2-hydroxy-3-methylbutyric acid (13.5 mg, 0.11 mmol) and PyBOP (60 mg, 0.12 mmol) were combined in THF (0.4 mL) and stirred for 10 minutes. To this mixture was added {3-[5-(3-fluorophenyl)-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% Na.sub.2CO.sub.3 (20 mL) and extracted with ethyl acetate (320 mL). The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:4 ethyl acetate/hexanes) to provide Boc-protected diastereomer A (less polar, 2.0 mg) and Boc-protected diastereomer B (more polar, 4.2 mg). To the Boc-protected diastereomer A was added HCl (1 mL, 4M in dioxane) at 0 C. After warming to room temperature and stirring for 1 hour, the mixture was concentrated under a stream of N.sub.2. The residue was dissolved in an ether/dioxane mixture and precipitated with hexanes. The solid was filtered and washed with hexanes to provide the final product as yellow solid. MS ESI (+) m/z 416 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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 (br m, 3H), 0.9 (br m, 3H).
Example 51
[0325] ##STR00063##
(2 S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one (diastereomer B)
[0326] Prepared as previously described in Example 50 using the more polar Boc-protected diastereomer B. MS ESI (+) m/z 416 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.3 (br s, 3H), 7.65 (m, 2H), 7.45-7.30 (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 (br m, 1H), 1.91 (br m, 1H), 1.02 (d, 3H, J=7.0 Hz), 0.60 (d, 3H, J=6.3 Hz).
Example 52
[0327] ##STR00064##
2-amino-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one
Step A: Preparation of tert-butyl 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-ylcarbamate
[0328] 2-(3-Azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (50 mg, 0.139 mmol; as prepared in example 70) was dissolved in 2.0 mL of DMF. 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) were then added and the reaction allowed to stir at 23 C. Following 12 hours, the reaction was quenched by addition of saturated NaHCO.sub.3 solution, extracted (315 mL ethyl acetate), combined organics washed with water (150 mL) then dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude reaction was purified by chromatography (20% ethyl acetate/Hex) affording the product as a white foam (70 mg, 94%). MS APCI () m/z 529 (M-1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.59 (m, 1H), 7.43 (m, 2H), 7.37 (t, 2H, J=8 Hz), 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=9 Hz), 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
[0329] tert-Butyl 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-ylcarbamate (70 mg, 0.131 mmol) was dissolved in 7.0 mL of EtOH. HCl (0.65 mL, 0.659 mmol) was then added and the reaction stirred at 23 C. for 4 hours. The reaction was then concentrated and purified by chromatography (2-10% MeOH/DCM), yielding the product (54 mg, 95%) as a yellow oil. MS ESI (+) m/z 431 (M+1) detected; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.69 (m, 1H), 7.53 (d, 2H, J=8 Hz), 7.42 (t, 2H, J=7 Hz), 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, 1.5H, J=8 Hz), 1.64 (d, 1.5H, J=8 Hz).
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
[0330] 2-Amino-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (50 mg, 0.116 mmol) was dissolved in 5.0 mL of MeOH. HCl (0.46 ml, 0.464 mmol) was added followed by evacuation/re-vacuation with N.sub.2. Pd/C (12 mg, 0.011 mmol) was then added followed by H.sub.2 balloon. Following 40 hours at 23 C., the reaction was concentrated in vacuo, affording the product (41 mg, 87%) as a cream/yellow colored foam. MS ESI (+) m/z 405 (M+1) detected; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.68 (m, 1H), 7.53 (m, 2H), 7.42 (t, 2H, J=9 Hz), 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=8 Hz), 1.66 d, 1.5H, J=8 Hz).
Example 53
[0331] ##STR00065##
(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one
[0332] Prepared as previously described in Example 52 using the appropriate thiohydrazide, ketone and carboxylic acid to provide 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, solution in ether). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to provide the final product as a mixture of diastereomers. MS ESI (+) m/z 422 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0333] ##STR00066##
Synthesis of 2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylic acid 2-methoxyethyl ester
[0334] To a solution of 2-methoxyethanol (30 mg, 0.4 mmol) in acetonitrile (3 mL) at 0 C. was added phosgene (54 mg, 0.54 mmol, 20% wt in toluene). After warming to room temperature and stirring for 6 hours, the mixture was concentrated under reduced pressure. To the residue was added dichloromethane (4 mL), {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (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. 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 provide the final product as the dihydrochloride salt (39 mg, 100%). MS APCI (+) m/z 418 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0335] ##STR00067##
Synthesis of 2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylic acid ethylamide
[0336] 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) was 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 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 provide the final product as the dihydrochloride salt (37 mg, 98%). MS APCI (+) m/z 387 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0337] ##STR00068##
Synthesis 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)propyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate
[0338] 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) was added triethylamine (110 mg, 1.10 mmol) and 4-nitrophenylchloroformate (220 mg, 1.00 mmol). After stirring for 1 hour, the reaction mixture was diluted with 1M HCl (5 mL) and dichloromethane (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to provide the product.
Step B: Preparation of 2-(3-aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0339] To 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) was added 2-methoxy-N-methylethanamine (70 mg, 0.80 mmol) and DIEA (100 mg, 0.80 mmol). 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 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 provide the final product as the dihydrochloride salt (50 mg, 83%). MS APCI (+) m/z 431 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
[0340] The following examples were prepared as previously described in Example 56 using the appropriate amine.
Example 57
[0341] ##STR00069##
2-(3-Aminopropyl)-N-cyclopropyl-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0342] MS APCI (+) m/z 399 (M+1) detected.
Example 58
[0343] ##STR00070##
2-(3-Aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0344] MS APCI (+) m/z 417 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0345] ##STR00071##
2-(3-Aminopropyl)-N-ethyl-5-(3-fluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0346] MS APCI (+) m/z 401 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0347] ##STR00072##
2-(3-Aminopropyl)-N,N-diethyl-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0348] MS APCI (+) m/z 415 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0349] ##STR00073##
2-(3-Aminopropyl)-5-(3-chlorophenyl)-N,N-dimethyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0350] MS APCI (+) m/z 403, 405 (M+1, Cl pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0351] ##STR00074##
Synthesis of (2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one (diastereomer A)
Step A: Preparation of tert-butyl 3-(3-((R)-2-((2,2-dimethyl-1,1-diphenylpropyl)dimethylsiloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate
[0352] To a solution of (R)-2-((2,2-dimethyl-1,1-diphenylpropyl)dimethylsilyloxy)propanoic acid (181 mg, 0.36 mmol) and DIEA (78 mg, 0.60 mmol) in acetonitrile (1 mL) was added HATU (137 mg, 0.36 mmol). After stirring at room temperature for 10 minutes, a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (100 mg, 0.24 mmol) in acetonitrile (1 mL) was added. After stirring for 3 hours, PyBOP (150 mg), DIEA (100 L), and more tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (45 mg) was added. After stirring for 16 hours, the reaction mixture was diluted with 10% Na.sub.2CO.sub.3 (30 mL) and extracted with ethyl acetate (320 mL). The combined organics were washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was chromatographed (1:9 ethyl acetate/hexanes) to provide the N-Boc-O-TBDPS-protected diastereomer A (more polar, 74 mg, 40%) and the N-Boc-O-TBDPS-protected diastereomer B (less polar, 35 mg, 19%)
Step B: Preparation of (2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one (diastereomer A)
[0353] To a solution of the N-Boc-O-TBDPS-protected diastereomer A (36 mg, 0.047 mmol) in THF (0.5 mL) was added TBAF (94 L of 1.0 M solution in THF). After stirring for 3 hours at room temperature, the mixture was diluted with half saturated NaHCO.sub.3 (30 mL) and extracted with ethyl acetate (320 mL). The combined organics were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the N-Boc-protected diastereomer A (18 mg, 80%). To a cooled (0 C.) solution of this product in dioxane (0.5 mL) was added HCl (0.5 mL of 4.0 M solution in dioxane). After warming to room temperature, the mixture was stirred for 4.5 hours. The reaction mixture was concentrated under reduced pressure and dissolved in minimal dioxane and then precipitated with ether to provide the final product (3.9 mg, 70%). MS ESI (+) m/z 388 (M+1) detected; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 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
[0354] ##STR00075##
(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one (diastereomer B)
[0355] Prepared as previously described in Example 62 using the N-Boc-O-TBDPS-protected diastereomer B from Step A of Example 62. MS ESI (+) m/z 388 (M+l) detected; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 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
[0356] ##STR00076##
Synthesis of (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
Step A: Preparation of tert-butyl 3-((S)-3-((S)-2-(tert-butyldiphenylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate
[0357] To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (0.54 g, 1.30 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.64 g, 1.95 mmol) in DMF (10 mL) was 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% Na.sub.2CO.sub.3 (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (40 mL). The combined organics were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:9 to 1:4 ethyl acetate/hexanes) to provide the less polar diastereomer product (180 mg, 19%) as a yellow syrup.
Step B: Preparation of tert-butyl 3-((S)-5-(3-fluorophenyl)-3-((S)-2-hydroxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate
[0358] To a cooled (0 C.) solution of tert-butyl 3-(3-((S)-2-(tert-butyldiphenylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (180 mg, 0.25 mmol) in THF (2.5 mL) was added TBAF (0.40 mL of 1M solution in THF). After stirring at room temperature for 2 hours, the volume was reduced in vacuo and the mixture was diluted with half-saturated NaHCO.sub.3 (30 mL). The mixture was extracted with ethyl acetate (320 mL) and the combined organics were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (95 mg, 79%) as a viscous, yellow syrup.
Step C: Preparation of (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0359] To a solution of tert-butyl 3-((S)-5-(3-fluorophenyl)-3-((S)-2-hydroxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (64 mg, 0.13 mmol) in acetonitrile (1.3 mL) was added Ag.sub.2O (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 was added HCl (0.5 mL of 4 M solution in dioxane). After stirring at 0 C. for 10 minutes and 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; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 7.38 (m, 6H), 7.30 (m, 2H), 7.19 (m, 1H), 4.86 (br q, 1H, J=6.3 Hz), 3.43 (s, 3H), 3.36 (m, 1H), 3.12 (m, 2H), 2.56 (m, 1H), 2.21 (m, 2H), 1.44 (m, 3H).
[0360] Absolute stereochemistry was assigned by examination of the protein:inhibitor co-crystal structure of Eg5 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
[0361] ##STR00077##
(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0362] Prepared as in Example 42 using appropriately substituted reagents. MS (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 7.49-7.29 (m, 8H), 7.20 (m, 1H), 4.77 (br 1, 1H, J=6.3 Hz), 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
[0363] ##STR00078##
(S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethoxypropan-1-one
[0364] Prepared as described in Example 64 using ethyl iodide in place of methyl iodide. MS (+) m/z 416 (M+1) detected; .sup.1H NMR (400 MHz, 10:1 CDCl.sub.3:CD.sub.3OD) 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J=6.3 Hz), 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=6.3 Hz), 1.24 (m, 3H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 67
[0365] ##STR00079##
Synthesis of 2-(3-aminopropyl)-5-(3-fluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
Step A: Preparation of tert-butyl 3-(5-(3-fluorophenyl)-3-(1-carbonyl-3-methylimidazolium iodide)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate
[0366] To 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) was added 1,1-carbonyl diimidazole (234 mg, 1.44 mmol). 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 (210 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to provide the crude imidazole intermediate. To this product was added acetonitrile (3 mL) followed by methyl iodide (854 mg, 6.02 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure to provide 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
[0367] To a solution of tert-butyl 3-(5-(3-fluorophenyl)-3-(1-carbonyl-3-methylimidazolium iodide)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (157 mg, 0.241 mmol) and triethylamine (122 mg, 1.21 mmol) in THF (3 mL) was added N-methoxymethanamine hydrochloride (47 mg, 0.48 mmol). 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 was added HCl (2 mL of 4M in dioxane). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure to provide the final product as the dihydrochloride salt. MS APCI (+) m/z 403 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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, 11H).
[0368] The following examples were prepared as previously described in Example 67 using the appropriate thiohydrazide, ketone, and alkoxyamine or alcohol.
Example 68
[0369] ##STR00080##
2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0370] MS ESI (+) m/z 421 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0371] ##STR00081##
Methyl 2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate
[0372] MS APCI (+) m/z 374 (M+1) detected.
Example 70
[0373] ##STR00082##
Ethyl 2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate
[0374] MS APCI (+) m/z 388 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0375] ##STR00083##
Synthesis of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
Step A: Preparation of 4-azido-1-phenylbutan-1-one
[0376] To a solution of 4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) was added sodium azide (12.8 g, 197 mmol). The solution was warmed to 55 C. and stirred for 16 hours. The cooled mixture was then treated with water (600 mL) and extracted with ether (3200 mL). The combined organics were washed with water (8100 mL) and brine (100 mL) then dried over MgSO.sub.4 and concentrated to provide 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
[0377] To a solution of 2,5-difluorobenzothiohydrazide (1.5 g, 7.97 mmol) in EtOH/dichloromethane (3:1, 16 mL) was 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 another 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 bright yellow syrup.
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-butyldiphenlsilyloxy)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
[0378] To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, 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) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.sub.3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (230 mL) and the combined organic phases were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide 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 the 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 pale yellow oils. Absolute stereochemistry was assigned by examination of a protein:inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
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
[0379] To a 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. was added TBAF (0.31 mL, 1 M, 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.sub.3(20 mL) and extracted with ethyl acetate (320 mL). The combined organics were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, 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.
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
[0380] To a 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) at 0 C. was added methyl iodide (50 L, 0.48 mmol) followed by sodium hydride (10 mg, 60%). After stirring at 0 C. for 30 minutes and room temperature for 3 hours, the mixture was treated with saturated NH.sub.4Cl (20 mL) and extracted with ethyl acetate (320 mL). The combined organic phases were washed with water (610 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to provide the product (40 mg, 94%) as a yellow oil.
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
[0381] To a 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 cone. HCl (57 L, 0.69 mmol) followed by 10% Pd/C (10 mg, wet, Degussa type). After stirring under a H.sub.2 balloon for 1 hour, the mixture was filtered and concentrated under reduced pressure. The colorless glass was triturated with diethyl ether and filtered to provide the di-HCl salt product as a white solid (89 mg, 79%). MS ESI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz). Absolute stereochemistry assigned by examination of a protein:inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 72
[0382] ##STR00084##
(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0383] Prepared as previously described 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 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=6 Hz), 1.44 (m, 2H), 1.34 (m, 1H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 73
[0384] ##STR00085##
Synthesis of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one
[0385] To a 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) was added 1N HCl/MeOH (0.5 mL) followed by 10% Pd/C (10 mg, wet, Degussa type). After stirring under a H.sub.2 balloon for 1 hour, the mixture was filtered and concentrated under reduced pressure. The colorless glass was triturated with diethyl ether and filtered to provide the di-HCl salt product as a white solid (54 mg, 66%). MS ESI (+) m/z 406 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (m, 1H), 7.47 (m, 2H), 7.39 (t, 2H, J=7 Hz), 7.32 (t, 1H, J=7 Hz), 7.15 (m, 2H), 4.89 (q, 1H, J=6 Hz), 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=6.7 Hz), 1.48 (d, 3H, J=6.7 Hz). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 74
[0386] ##STR00086##
tert-Butyl 2-((S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-yloxy)acetate
[0387] Prepared as previously described in Example 71 using tert-butyl 2-bromoacetate in place of methyl iodide. MS ESI (+) m/z 520 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (m, 1H), 7.46 (d, 2H, J=8 Hz), 7.34 (m, 2H), 7.27 (m, 1H), 7.13 (m, 2H), 4.93 (q, 1H, J=6 Hz), 4.18 (d, 1H, J=16 Hz), 3.96 (d, 1H, J=16 Hz), 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 was assigned by inference from (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
[0388] ##STR00087##
(R)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0389] Prepared as previously described in Example 71 using (R)-2-(t-butyldiphenylsilyloxy)propanoic acid in place of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid. MS ESI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (m, 1H), 7.46 (d, 2H, J=7 Hz), 7.37 (t, 2H, J=8 Hz), 7.30 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.71 (q, 1H, J=6 Hz), 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=6 Hz), 1.45 (m, 1H). Stereochemistry was assigned by comparison to (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)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 76
[0390] ##STR00088##
(R)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0391] Prepared as previously described 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (m, 1H), 7.44 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=8 Hz), 7.29 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.68 (q, 1H, J=6 Hz), 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=6 Hz). Stereochemistry was assigned by comparison to (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)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 77
[0392] ##STR00089##
(S)-1-((S)-5-(2,5-difluorophenyl)-2-(3-(dimethylamino)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0393] Prepared as previously described in Example 47 using (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one in place 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.56 (m, 1H), 7.49 (d, 2H, J=7 Hz), 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=7 Hz).
Example 78
[0394] ##STR00090##
Synthesis 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
Step A: Preparation of tert-butyl 3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate
[0395] To 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 (50 mg, 0.12 mmol) in THF (2 mL) was added Boc-anhydride (31 mg, 0.14 mmol). After warming slowly 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 provide the product as a colorless oil (62 mg, 100%).
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
[0396] To a cooled (0 C.) solution of tert-butyl 3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (62 mg, 0.12 mmol) in DMF (2 mL) was added methyl iodide (37 L, 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 NH.sub.4Cl (20 mL) and extracted with ethyl acetate (320 mL). The combined organics were washed with water (520 mL) and brine (20 mL), and then dried over Na.sub.2SO.sub.4. 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 was 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.sub.3 (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (210 mL). The combined organics were washed with NaHCO.sub.3 (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to provide a yellow oil. The oil was 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 provide the di-HCl product as a yellow solid (31 mg, 51%). MS ESI (+) m/z 434 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6 Hz), 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=6 Hz).
Example 79
[0397] ##STR00091##
Synthesis of (S)-1-((S)-1-(3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylamino)-1-oxopropan-2-ylamino)-1-oxopropan-2-ylamine
[0398] To 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) was added PyBOP (52.8 mg, 0.102 mmol) followed by DIEA (44 L, 0.25 mmol). After stirring at room temperature for 64 hours, the mixture was partitioned between saturated NaHCO.sub.3(20 mL) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organics were washed with water (510 mL), brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The orange residue was chromatographed (0-3% MeOH in DCM) to provide the Boc-protected product as a colorless glass (30 mg, 89%). To a cooled (0 C.) solution of this product in DCM (2 mL) was added TFA (0.5 mL). After stirring for 5 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO.sub.3 (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 Na.sub.2SO.sub.4, and concentrated under reduced pressure to provide the product as a colorless glass (25 mg, 98%). MS ESI (+) m/z 562 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.79 (br, 1H), 7.50 (m, 1H), 7.42 (d, 2H, J=8 Hz), 7.36 (t, 2H, J=7 Hz), 7.30 (t, 1H, J=7 Hz), 7.13 (m, 2H), 7.04 (t, 1H, J=5 Hz), 4.65 (q, 1H, J=6 Hz), 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=7 Hz), 1.34 (d, 3H, J=7 Hz), 1.26 (m, 3H).
Example 80
[0399] ##STR00092##
Synthesis 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
[0400] 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) was added triethylamine (50.4 L, 0.362 mmol) followed by pivaloyl chloride (45 L, 0.362 mmol). After warming slowly to room temperature and stirring for 16 hours, the mixture was partitioned between DCM (10 mL) and saturated NaHCO.sub.3 (10 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organics were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, 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-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one
[0401] To a solution of 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one (100 mg, 0.225 mmol) in MeOH (3 mL) was added 1N HCl/MeOH (1 mL) followed by 10% Pd/C (40 mg, wet, Degussa type). After stirring under a H.sub.2 balloon for 3 hours, the mixture was filtered and concentrated under reduced pressure to provide the product as a white foam. MS ESI (+) m/z 418 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (m, 1H), 7.43 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=7 Hz), 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
[0402] ##STR00093##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (Enantiomer A)
[0403] Prepared as previously described in Example 80 using isobutyryl chloride in place of pivaloyl chloride. The 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one enantiomers were separated on a chiral column (Chiralcel OJ-H 25010 mm) eluting with 1:1 EtOH/hexanes to provide the more polar enantiomer A and the less polar enantiomer B. Reduction of the azide group of enantiomer A provided the final product. MS ESI (+) m/z 404 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (m, 1H), 7.45 (d, 2H, J=8 Hz), 7.35 (t, 2H, J=7 Hz), 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=11 Hz, 6 Hz).
Example 82
[0404] ##STR00094##
1-(2-(3-aminopropyl)-5-(2, 5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (Enantiomer B)
[0405] Prepared as in Example 81 using the less polar enantiomer B. MS ESI (+) m/z 404 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (m, 1H), 7.45 (d, 2H, J=8 Hz), 7.35 (t, 2H, J=8 Hz), 7.28 (m, 11H), 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=7 Hz, 13 Hz).
Example 83
[0406] ##STR00095##
Synthesis of(S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
Step A: Preparation of 2-(methoxymethoxy)-1-phenylethanone
[0407] To a cooled (0 C.) solution of 2-hydroxyacetophenone (1.0 g, 7.3 mmol) in DMF (50 mL) was added lithium hydride (74 mg, 95%, 8.8 mmol). After stirring for 30 minutes, MOM-Cl (0.73 mL, 9.5 mmol) was added slowly via syringe and the mixture was allowed to warm slowly to room temperature and was stirred for 16 hours. The reaction mixture was treated with saturated NH.sub.4Cl (100 mL) and extracted with ethyl acetate (350 mL). The combined organics were washed with water (650 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The brown residue was chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide 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
[0408] To a solution of 2-(methoxymethoxy)-1-phenylethanone (0.60 g, 3.33 mmol) in EtOH/DCM (3:1, 12 mL) was 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%).
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
[0409] To a solution of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.70 g, 2.14 mmol) in DMF (20 mL) was 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 L, 2.85 mmol). After stirring at room temperature for 16 hours, the mixture was treated with saturated NaHCO.sub.3 (50 mL) and extracted with ethyl acetate (330 mL). The combined organics were washed with water (630 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The yellow residue was chromatographed (19:1 to 9:1 hexanes/ethyl acetate) to afford the less polar diastereomer (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, 12%), and the more polar diastereomer (S)-2-(tert-butyldiphenylsilyloxy)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxy-methoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (146 mg of a 1:1 mixture with starting material) as yellow oils. Absolute stereochemistry was assigned by inference from (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-((methoxy-methoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one
[0410] To 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) was 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 (230 mL). The combined organics were washed with NaHCO.sub.3 (30 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The pale yellow residue was chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide the product as a white solid (0.045 g, 64%).
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
[0411] To 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 was added methyl iodide (100 L, 1.6 mmol) followed by sodium hydride (10 mg). After slowly warming to room temperature and stirring for 16 hours, the mixture was treated with saturated NH.sub.4Cl (10 mL) and extracted with ethyl acetate (210 mL). The combined organics were washed with water (610 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The pale yellow residue was chromatographed (4:1 to 2:1 hexanes/ethyl acetate) to provide the product as a pale yellow oil (0.040 g, 86%). MS ESI (+) m/z 437 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=10 Hz), 4.71 (q, 1H, J=7 Hz), 4.59 (d, 1H, J=10 Hz), 3.43 (s, 3H), 3.39 (s, 3H), 1.48 (d, 3H, J=7 Hz). Stereochemistry was assigned by inference from (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 84
[0412] ##STR00096##
(S)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0413] Prepared as previously described 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=10 Hz), 3.41 (s, 3H), 3.35 (s, 3H), 1.47 (d, 3H, J=7 Hz). Stereochemistry was assigned by inference from (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 85
[0414] ##STR00097##
Synthesis of (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0415] To a solution of (S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (16 mg, 0.037 mmol) in MeOH (2 mL) was added HCl (300 L of 6 M solution). After stirring at 50 C. for 5 hours, the mixture was cooled to room temperature and partitioned between saturated NaHCO.sub.3(20 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (210 mL). The combined organics were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The pale yellow residue was chromatographed (9:1 to 2:1 hexanes/ethyl acetate) to provide the product as a colorless gum (4.2 mg, 29%). MS ESI (+) m/z 393 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (m, 1H), 7.37 (m, 5H), 7.13 (m, 2H), 4.74 (m, 2H), 4.48 (d, 1H, J=11 Hz), 4.19 (d, 1H, J=10 Hz), 3.44 (s, 3H), 1.59 (m, 3H). Absolute stereochemistry was assigned by examination of a protein:inhibitor co-crystal structure of Eg5 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
[0416] ##STR00098##
Synthesis of 1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one
Step A: Preparation of N-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide
[0417] To a solution of 5-chloro-2-methylbenzohydrazide (2.70 g, 14.62 mmol) prepared as in Example 1, Step B, in toluene (100 mL) was added 4-azido-1-phenylbutan-1-one (3.04 g, 16.1 mmol) prepared as in Example 70, Step A, followed by p-toluenesulfonic acid monohydrate (0.28 g, 1.46 mmol). The reaction was heated to reflux and stirred under a Dean-Stark trap for 16 hours. The cooled mixture was diluted with EtOAc (300 mL) and washed with NaHCO.sub.3 (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was triturated with ether and filtered to afford the product (3.09 g, 59%) as a tan solid.
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
[0418] To a solution of N-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloyl chloride (70 L, 0.56 mmol). After stirring at room temperature for 16 hours the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (310 mL). The combined organic phases were washed successively with 10% NaHSO.sub.4 (210 mL), NaHCO.sub.3 (10 mL) and brine (10 mL) then dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%) as a colorless oil.
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
[0419] To a 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) was added PtO.sub.2 (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 concentrated. The residue was purified by flash column chromatography (CH.sub.2Cl.sub.2 to 3% MeOH/CH.sub.2Cl.sub.2 to 10%) to afford the di-HCl product which was triturated with hexanes and filtered to afford a white solid (18 mg, 26%). MS ESI (+) m/z 414 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.74 (s, 1H), 7.54 (d, 2H, J=7 Hz), 7.33 (m, 4H), 7.22 (d, 1H, J=9 Hz), 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).
[0420] The following examples were prepared using the appropriately substituted benzohydrazides, ketones and acid chlorides:
Example 87
[0421] ##STR00099##
(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(phenyl)methanone dihydrochloride
[0422] MS ESI (+) m/z 421.9 (M+l) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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 (brs, 2H), 2.63 (m, 1H), 1.86 (m, 2H).
Example 88
[0423] ##STR00100##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0424] MS ESI (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0425] ##STR00101##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-methylbutan-1-one dihydrochloride
[0426] MS ESI (+) m/z 402 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.59 (d, 2H, J=8 Hz), 7.51 (m, 1H), 7.34 (m, 3H), 7.15 (t, 2H, J=8 Hz), 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=7 Hz).
Example 90
[0427] ##STR00102##
1-(2-(3-aminopropyl)-5-(5-chloro-2-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride
[0428] MS ESI (+) m/z 404.4 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.77 (m, 1H), 7.57 (m, 2H), 7.41 (m, 1H), 7.35 (m, 3H), 7.13 (t, 1H, J=9), 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=7 Hz), 1.07 (d, 3H, J=7 Hz).
Example 91
[0429] ##STR00103##
1-(2-(3-aminopropyl)-5-(2-chloro-5-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride
[0430] MS ESI (+) m/z 404 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.09 (d, 3H, J=7 Hz).
Example 92
[0431] ##STR00104##
1-(2-(3-aminopropyl)-5-(2,5-dichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride
[0432] MS ESI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (d, 1H, J=2 Hz), 7.57 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=8 Hz), 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=7 Hz), 1.09 (d, 3H, J=7 Hz).
Example 93
[0433] ##STR00105##
(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(cyclopropyl)methanone dihydrochloride
[0434] MS ESI (+) m/z 386 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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), 1.05 (m, 1H), 0.98 (m, 1H), 0.87 (m, 2H).
Example 94
[0435] ##STR00106##
1-(2-(3-aminopropyl)-5-(2-chloro-5-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0436] MS ESI (+) m/z 418 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0437] ##STR00107##
1-(2-(3-aminopropyl)-5-(2,5-dichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0438] MS ESI (+) m/z 435 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.77 (d, 1H, J=2 Hz), 7.55 (d, 2H, J=6), 7.40 (d, 1H, J=9 Hz), 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
[0439] ##STR00108##
1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride
[0440] MS ESI (+) m/z 400 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.07 (d, 3H, J=7 Hz).
Example 97
[0441] ##STR00109##
1-(2-(3-aminopropyl)-5-(2-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0442] MS ESI (+) m/z 452 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0443] ##STR00110##
1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0444] MS ESI (+) m/z 372 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.53 (m, 3H), 7.46 (d, 1H, J=6 Hz), 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
[0445] ##STR00111##
1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0446] MS ESI (+) m/z 372 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (d, 1H, J=3 Hz), 7.53 (d, 2H, J=6 Hz), 7.48 (d, 1H, J=5 Hz), 7.33 (m, 4H), 3.24 (m, 1H), 2.99 (brs, 2H), 2.48 (m, 1H), 1.73 (m, 2H), 1.33 (s, 9H).
Example 100
[0447] ##STR00112##
1-(2-(3-aminopropyl)-5-(5-chlorothiophen-2-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one
[0448] MS ESI (+) m/z 406 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0449] ##STR00113##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(4-fluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0450] MS ESI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (m, 2H), 7.45 (m, 1H), 7.15 (m, 2H), 7.02 (m, 2H), 3.19 (m, 1H), 2.97 (brs, 2H), 2.48 (m, 1H), 1.70 (m, 2H), 1.34 (s, 9H).
Example 102
[0451] ##STR00114##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-p-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0452] MS ESI (+) m/z 416 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0453] ##STR00115##
1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0454] MS ESI (+) m/z 436 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0455] ##STR00116##
1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0456] MS ESI (+) m/z 480 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0457] ##STR00117##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,4-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0458] MS ESI (+) m/z 429.9 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0459] ##STR00118##
1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)-5-(2,5-difluorophenyl)-3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0460] MS ESI (+) m/z 458 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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 (brs, 2H), 2.52 (m, 1H), 1.78 (m, 2H), 1.35 (s, 9H), 1.24 (s, 9H).
Example 107
[0461] ##STR00119##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0462] MS ESI (+) m/z 416 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.44 (m, 1H), 7.32 (d, 2H, J=9 Hz), 7.22 (t, 1H, J=7 Hz), 7.13 (m, 3H), 3.25 (m, 1H), 3.04 (brs, 2H), 2.50 (m, 1H), 2.33 (s, 3H), 1.78 (m, 2H), 1.33 (s, 9H).
Example 108
[0463] ##STR00120##
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,5-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one dihydrochloride
[0464] MS ESI (+) m/z 429.9 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0465] ##STR00121##
Synthesis of N-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl)propyl)isobutyramide
[0466] To a solution of 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride, prepared as in the above examples, (50 mg, 0.11 mmol) in anhydrous CH.sub.2Cl.sub.2 (1 mL) was added DIEA (95 L, 0.54 mmol) followed by isobutyryl chloride (17 L, 0.16 mmol). After stirring at room temperature for 16 hours the mixture was treated with 1N HCl (10 mL) and extracted with CH.sub.2Cl.sub.2 (210 mL). The combined organic phases were washed with brine (10 mL) then dried over Na.sub.2SO.sub.4 and concentrated. The residue was chromatographed (4:1 to 2:1 hexanes/EtOAc) to afford the product (31 mg, 62%) as a colorless gum. MS ESI (+) m/z 458.1 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0467] ##STR00122##
N-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl)propyl)methanesulfonamide
[0468] Prepared as in Example 109 using methanesulfonyl chloride in place of isobutyryl chloride. MS ESI (+) m/z 466.1 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=6.8 Hz), 1.15 (d, 3H, J=6.8 Hz).
Example 111
[0469] ##STR00123##
Synthesis of (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one
Step A: Preparation of (S)-2-methoxypropanoic anhydride
[0470] To a solution of (S)-2-methoxy propanoic acid (0.25 g, 4.80 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added EDCI (0.46 g, 2.38 mmol). After stirring at room temperature for 1 hour, hexanes were added and the mixture filtered to obtain the product (0.24 g, 53%).
Step B: Preparation of (2S)-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one
[0471] 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) was added (S)-2-methoxypropanoic anhydride from the previous step (277 mg, 1.46 mmol). After stirring at reflux for 48 hours the crude mixture was chromatographed (CH.sub.2Cl.sub.2 to 2.5% MeOH/CH.sub.2Cl.sub.2) to afford the product (81 mg, 65%) as a clear oil.
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
[0472] (2S)-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (50 mg, 0.11 mmol) was reduced as in Example 86, Step C, to afford the product (32 mg, 68%) as a colorless oil. MS ESI (+) m/z 404 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 4.52 (q, 0.5H, J=7 Hz), 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=7 Hz), 1.27 (d, 1.5H, J=7 Hz). 1:1 mixture of diastereomers.
Example 112
[0473] ##STR00124##
(S)-1-((S)-2-(3 aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxybutan-1-one
[0474] Prepared as 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz, 4 Hz), 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=8 Hz). Stereochemistry was assigned by comparison to (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
[0475] ##STR00125##
(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxybutan-1-one
[0476] Prepared as 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; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz). Stereochemistry was assigned by comparison to (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
[0477] ##STR00126##
(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
[0478] Prepared as in Example 71 using 2-(tert-butyldiphenylsilyloxy)-3-methylbutanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. Product obtained as a 2:1 mixture of diastereomers. MS APCI (+) m/z 448 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=5 Hz), 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=7 Hz), 0.99 (m, 3H), 0.82 (d, 2.15H, J=7 Hz).
Example 115
[0479] ##STR00127##
(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
[0480] Prepared as in Example 71 using 2-(tert-butyldiphenylsilyloxy)-3-methylbutanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 448 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (m, 3H), 7.35 (m, 2H), 7.28 (m, 1H), 7.12 (m, 2H), 4.45 (d, 1H, J=4 Hz), 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=7 Hz), 0.99 (d, 3H, J=7 Hz). Stereochemistry was assigned by comparison to (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
[0481] ##STR00128##
(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxybutan-1-one
[0482] Prepared as in Example 73. MS APCI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (m, 3H), 7.38 (m, 2H), 7.32 (m, 1H), 7.14 (m, 2H), 4.78 (dd, 1H, J=7 Hz, 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=7 Hz). Stereochemistry was assigned by comparison to (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
[0483] ##STR00129##
(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxybutan-1-one
[0484] Prepared as in Example 73. MS APCI (+) m/z 420 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz, 3 Hz), 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=7 Hz). Stereochemistry was assigned by comparison to (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
[0485] ##STR00130##
(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
[0486] Prepared as in Example 73. Product obtained as a 2:1 mixture of diastereomers. MS APCI (+) m/z 434 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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=7 Hz), 1.12 (m, 3H), 0.87 (d, 1.4H, J=7 Hz), 0.66 (d, 1.6H, J=6 Hz).
Example 119
[0487] ##STR00131##
(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one
[0488] Prepared as in Example 73. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl.sub.3) 7.46 (m, 3H), 7.34 (app t, 2H, J=8 Hz), 7.26 (m, 1H), 7.11 (m, 2H), 4.65 (d, 1H, J=3 Hz), 3.24 (m, 1H), 2.98 (t, 2H, J=6 Hz), 2.64 (m, 1H), 2.28 (m, 1H), 2.12 (m, 1H), 1.66 (m, 1H), 1.08 (d, 3H, J=7 Hz), 0.86 (d, 3H, J=7 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Example 120
[0489] ##STR00132##
2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (Enantiomer A)
[0490] Prepared as previously described in Example 68. The tert-butyl 3-(5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate enantiomers were separated on a chiral column (Chiralcel ODH 25020 mm) eluting with 2% EtOH/hexanes to provide the less polar enantiomer A and the more polar enantiomer B. Boc-deprotection of enantiomer A provided the final product. MS ESI (+) m/z 421 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0491] ##STR00133##
2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (Enantiomer B)
[0492] Prepared as in Example 120 using the more polar enantiomer, B. MS ESI (+) m/z 421 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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
[0493] ##STR00134##
Synthesis of 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
Step A: Preparation of (2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-imidazol-1-yl)methanone
[0494] To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.492 g, 1.37 mmol) in THF (8 mL) was added 1,1-carbonyl diimidazole (0.266 g, 1.64 mmol). 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 Na.sub.2SO.sub.4 and concentrated to provide the crude product.
Step B: Preparation of (2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(3-methylimidazolium iodide-1-yl)methanone
[0495] To a solution of (2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-imidazol-1-yl)methanone (0.621 g, 1.37 mmol) in acetonitrile (5 mL) was added iodomethane (0.972 g, 6.85 mmol). After stirring in a sealed flask for 24 hours, the mixture was concentrated to provide the crude product.
Step C: Preparation of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0496] To a solution of (2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(3-methylimidazolium iodide-1-yl)methanone (0.112 g, 0.188 mmol) and O-(tert-buty)hydroxylamine hydrochloride (0.047 g, 0.376 mmol) in dichloromethane (3 mL) was 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%).
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
[0497] To a cooled (0 C.) solution of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.061 g, 0.13 mmol) and iodomethane (0.18 g, 1.3 mmol) in DMF (4 mL) was added sodium hydride (0.006 g, 0.26 mmol). 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 NH.sub.4Cl (5 mL). The organic layer was washed with water (25 mL), dried and concentrated under reduced pressure to provide the crude product.
Step E: Preparation of 2-(3-aminopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0498] To a solution of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.032 g, 0.065 mmol) and platinum oxide (15 mg) in methanol (3 mL) was added HCl (5.3 M solution in dioxane, 0.05 mL). After stirring under a hydrogen balloon for 1 hour, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product.
Step F: Preparation of 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
[0499] 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, 0.05 mmol) was added TFA (2 mL). After stirring for 18 hours, the mixture was concentrated and chromatographed (10:1:0.2 dichloromethane/methanol/30% NH.sub.4OH) to provide the product (0.01 g, 49%). MS ESI (+) m/z 407 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) 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).
[0500] The following compounds are prepared by using the procedures described above, utilizing the appropriately substituted reagents.
##STR00135##
TABLE-US-00001 R.sup.1 Name
##STR00186##
TABLE-US-00002 Ar.sup.2 R.sup.1 Name 4- (S)-1- (2S)1-(2-(3-aminopropyl)-5-(2,5- methylphenyl methoxy- difluorophenyl)-2-p-tolyl-1,3,4-oxadiazol- ethyl 3(2H)-yl)-2-methoxypropan-1-one 4- (S)-1- 1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5- chlorophenyl methoxy- (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- ethyl yl)-2,2-dimethylpropan-1-one 4- (S)-1- 1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5- bromophenyl methoxy- (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- ethyl yl)-2-methoxypropan-1-one 4-t- (S)-1- 1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)- butylphenyl methoxy- 5-(2,5-difluorophenyl)-1,3,4-oxadiazol- ethyl 3(2H)-yl)-2-methoxypropan-1-one 3,4- (S)-1- 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- dimethyl- methoxy- 2-(3,4-dimethylphenyl)-1,3,4-oxadiazol- phenyl ethyl 3(2H)-yl)-2,2-dimethylpropan-1-one 3- (S)-1- 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- methylphenyl methoxy- 2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- ethyl methoxypropan-1-one 3,5- (S)-1- 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- dimethyl- methoxy- 2-(3,5-dimethylphenyl)-1,3,4-oxadiazol- phenyl ethyl 3(2H)-yl)-2-methoxypropan-1-one 2- t-butyl 1-(2-(3-aminopropyl)-2-(2-chlorophenyl)-5- chlorophenyl (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one 2- t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- ethylphenyl 2-(2-ethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2,2-dimethylpropan-1-one 3- t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- nitrophenyl 2-(3-nitrophenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2,2-dimethylpropan-1-one 3- t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- hydroxy- 2-(3-hydroxyphenyl)-1,3,4-oxadiazol-3(2H)- phenyl yl)-2,2-dimethylpropan-1-one 3- t-butyl 1-(2-(3-aminophenyl)-2-(3-aminopropyl)-5- aminophenyl (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one 3- t-butyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- carboxy- 3-pivaloyl-2,3-dihydro-1,3,4-oxadiazol-2- phenyl yl)benzoic acid 3- t-butyl 4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- cyanophenyl 3-pivaloyl-2,3-dihydro-1,3,4-oxadiazol-2- yl)benzonitrile 3,4- t-butyl 1-(2-(3-aminopropyl)-2-(3,4-dichlorophenyl)- dichloro- 5-(2,5-difluorophenyl)-1,3,4-oxadiazol- phenyl 3(2H)-yl)-2,2-dimethylpropan-1-one 3- t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- fluorophenyl 2-(3-fluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one 3- t-butyl 1-(2-(3-aminopropyl)-2-(3-chlorophenyl)-5- chlorophenyl (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one 4- (S) (2S)-1-(243-aminopropyl)-5-(2,5- fluorophenyl methoxy- difluorophenyl)-2-(4-fluorophenyl)-1,3,4- ethyl oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 3- (S)-2- (2S)-1-(2-(3-aminopropyl)-5-(2,5- fluorophenyl methoxy- difluorophenyl)-2-(3-fluorophenyl)-1,3,4- ethyl oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 2- (S)-2- (2S)-1-(2-(3-aminopropyl)-2-(2- chlorophenyl methoxy- chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4- ethyl oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 3- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- methyl- 2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- phenyl methylpropan-1-one 3- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- ethylphenyl 2-(3-ethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methylpropan-1-one 3-pyridyl iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- 2-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one 5- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- methyl- 2-(5-methylthiophen-2-yl)-1,3,4-oxadiazol- thiophen- 3(2H)-yl)-2-methylpropan-1-one 2-yl 1-methyl-1H- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- imidazol- 2-(1-methyl-1H-imidazol-2-yl)-1,3,4- 2-yl) oxadiazol-3(2H)-yl)-2-methylpropan-1-one 2- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- methyl- 2-(2-methylthiazol-4-yl)-1,3,4-oxadiazol- thiazol- 3(2H)-yl)-2-methylpropan-1-one 4-yl 2-methyl- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- phenyl 2-o-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one 2-pyridyl iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- 2-(pyridin-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one 2-(1H- iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- imidazol- 2-(1H-imidazol-4-yl)-1,3,4-oxadiazol-3(2H)- 4-yl)- yl)-2-methylpropan-1-one 3-amino-1H- iso-Propyl 1-(2-(3-amino-1H-pyrazol-5-yl)-2-(3- pyrazol- aminopropyl)-5-(2,5-difluorophenyl)-1,3,4- 5-yl oxadiazol-3(2H)-yl)-2-methylpropan-1-one
##STR00187##
TABLE-US-00003 NR.sup.2R.sup.3 Ar.sup.1 Name NH.sub.2 2-fluorophenyl 1-(2-(3-aminopropyl)-5-(2-fluorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one NH.sub.2 2-chlorophenyl 1-(2-(3-aminopropyl)-5-(2-chlorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one NHAlaAla 2,5- difluorophenyl NHC(O)CH.sub.2).sub.2NMe.sub.2 2,5- N-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2- difluorophenyl phenyl-2,3-dihydro-1,3,4-oxadiazol-2- yl)propyl)-3-(dimethylamino)propanamide
##STR00191##
TABLE-US-00004 R.sup.1 Ar.sup.1 Name t-butyl 2-fluorophenyl 1-(2-(3-aminopropyl)-5-(2-fluorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl 2-chlorophenyl 1-(2-(3-aminopropyl)-5-(2-chlorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl 3-fluorophenyl 1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl 3-chlorophenyl 1-(2-(3-aminopropyl)-5-(3-chlorophenyl)-2- phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl 2-fluoro-5- 1-(2-(3-aminopropyl)-5-(5-chloro-2- chlorophenyl fluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 2-chloro-5- 1-(2-(3-aminopropyl)-5-(2-chloro-5- methylphenyl methylphenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 2-trifluoro 1-(2-(3-aminopropyl)-5-(5-fluoro-2- methyl-5- (trifluoromethyl)phenyl)-2-phenyl-1,3,4- fluorophenyl oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1- one (S)-2- 2-chloro-5- (2S)-1-(2-(3-aminopropyl)-5-(2-chloro-5- methoxyethyl fluorophenyl fluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 2,5- (2S)-1-(2-(3-aminopropyl)-5-(2,5- methoxyethyl dichlorophenyl dichlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 2-chlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2- methoxyethyl chlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 2-fluorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2- methoxyethyl fluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 3-chlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(3- methoxyethyl chlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 3-fluorophenyl (2S)-1-(2-(3-aminopropyl)-5-(3- methoxyethyl fluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 2-fluoro-5- (2S)-1-(2-(3-aminopropyl)-5-(2-fluoro-5- methoxyethyl methoxyphenyl methoxyphenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 2,3- (2S)-1-(2-(3-aminopropyl)-5-(2,3- methoxyethyl dichlorophenyl dichlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 3,4- (2S)-1-(2-(3-aminopropyl)-5-(3,4- methoxyethyl dichlorophenyl dichlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- 3,5- (2S)-1-(2-(3-aminopropyl)-5-(3,5- methoxyethyl dichlorophenyl dichlorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one (S)-2- thiophen-2-yl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5- methoxyethyl (thiophen-2-yl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methoxypropan-1-one (S)-2- thiophen-3-yl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5- methoxyethyl (thiophen-3-yl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methoxypropan-1-one (S)-2- 5- (2S)-1-(2-(3-aminopropyl)-5-(5- methoxyethyl chlorothiophen- chlorothiophen-2-yl)-2-phenyl-1,3,4- 2-yl oxadiazol-3(2H)-yl)-2-methoxypropan-1- one (S)-2- 2-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5- methoxyethyl (pyridin-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one (S)-2- 3-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5- methoxyethyl (pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one (S)-2- 4-chloropyridin- (2S)-1-(2-(3-aminopropyl)-5-(4- methoxyethyl 3-yl chloropyridin-3-yl)-2-phenyl-1,3,4- oxadiazol-3(2H)-yl)-2-methoxypropan-1- one (S)-2- 3-chloropyridin- (2S)-1-(2-(3-aminopropyl)-5-(3- methoxyethyl 2-yl chloropyridin-2-yl)-2-phenyl-1,3,4- oxadiazol-3(2H)-yl)-2-methoxypropan-1- one acetyl 2,5- 1-(2-(3-aminopropyl)-5-(2,5- difluorophenyl difluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)ethanone t-butyl 2-fluoro-5- 1-(2-(3-aminopropyl)-5-(2-fluoro-5- methoxyphenyl methoxyphenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 3,6- 1-(2-(3-aminopropyl)-5-(3,6- difluoropyridin- difluoropyridin-2-yl)-2-phenyl-1,3,4- 2-yl oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1- one t-butyl 4-fluoropyridin- 1-(2-(3-aminopropyl)-5-(4-fluoropyridin-3- 3-yl yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one
##STR00192##
TABLE-US-00005 R.sup.1 Name
##STR00243##
TABLE-US-00006 R.sup.4 R.sup.5 NR.sup.2R.sup.3 Name H H NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H Me NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me Et NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethyl-N-methyl- 2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Et Et NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N,N-diethyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H Et NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethyl-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide H 3-pyridyl NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-N- (pyridin-3-yl)-1,3,4-thiadiazole- 3(2H)-carboxamide H cyclopropyl NH.sub.2 2-(3-aminopropyl)-N-cyclopropyl- 5-(2,5-difluorophenyl)-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide Me 2-pyridyl NH.sub.2 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methyl-2- phenyl-N-(pyridin-2-yl)-1,3,4- thiadiazole-3(2H)-carboxamide H
##STR00264##
TABLE-US-00007 R.sup.4 R.sup.5 n Y Name H OH 2 OH 5-(2,5-difluorophenyl)-N-hydroxy-2- (2-hydroxyethyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H OH 3 OH 5-(2,5-difluorophenyl)-N-hydroxy-2- (3-hydroxypropyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H OH 2 OP(O)(OH).sub.2 2-(5-(2,5-difluorophenyl)-3- (hydroxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate H OH 3 OP(O)(OH).sub.2 3-(5-(2,5-difluorophenyl)-3- (hydroxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me OH 1 OH 5-(2,5-difluorophenyl)-N-hydroxy-2- (hydroxymethyl)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide Me OH 2 OH 5-(2,5-difluorophenyl)-N-hydroxy-2- (2-hydroxyethyl)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide Me OH 3 OH 5-(2,5-difluorophenyl)-N-hydroxy-2- (3-hydroxypropyl)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OH 1 OP(O)(OH).sub.2 (5-(2,5-difluorophenyl)-3- (hydroxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)methyl dihydrogen phosphate Me OH 2 OP(O)(OH).sub.2 2-(5-(2,5-difluorophenyl)-3- (hydroxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)ethyl dihydrogen phosphate Me OH 3 OP(O)(OH).sub.2 3-(5-(2,5-difluorophenyl)-3- (hydroxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propyl dihydrogen phosphate H OMe 1 OH 5-(2,5-difluorophenyl)-2- (hydroxymethyl)-N-methoxy-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OMe 2 OH 5-(2,5-difluorophenyl)-2-(2- hydroxyethyl)-N-methoxy-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide H OMe 3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-methoxy-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OMe 1 OP(O)(OH).sub.2 (5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)methyl dihydrogen phosphate H OMe 2 OP(O)(OH).sub.2 2-(5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate H OMe 3 OP(O)(OH).sub.2 3-(5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me OMe 1 OH 5-(2,5-difluorophenyl)-2- (hydroxymethyl)-N-methoxy-N- methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me OMe 2 OH 5-(2,5-difluorophenyl)-2-(2- hydroxyethyl)-N-methoxy-N-methyl- 2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OMe 3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-methoxy-N- methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me OMe 4 OH 5-(2,5-difluorophenyl)-2-(4- hydroxybutyl)-N-methoxy-N-methyl- 2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OMe 1 OP(O)(OH).sub.2 (5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)methyl dihydrogen phosphate Me OMe 2 OP(O)(OH).sub.2 2-(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)ethyl dihydrogen phosphate Me OMe 3 OP(O)(OH).sub.2 3-(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propyl dihydrogen phosphate Me OMe 4 OP(O)(OH).sub.2 4-(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)butyl dihydrogen phosphate H OEt 3 OH 5-(2,5-difluorophenyl)-N-ethoxy-2- (3-hydroxypropyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H OEt 3 OP(O)(OH).sub.2 3-(5-(2,5-difluorophenyl)-3- (ethoxycarbamoyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate H
##STR00291##
TABLE-US-00008 Ar.sup.2 Name 4-fluorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (4-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 4-methylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- p-tolyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan- 1-one 4-chlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5- (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 4-bromophenyl (2S)-1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5- (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 4-t-butylphenyl (2S)-1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)-5- (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3,4-dimethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (3,4-dimethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-methylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- m-tolyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan- 1-one 3,5-dimethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (3,5-dimethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 2-chlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(2-chlorophenyl)-5- (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 2-ethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (2-ethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-nitrophenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (3-nitrophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-hydroxyphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (3-hydroxyphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-aminophenyl (2S)-1-(2-(3-aminophenyl)-2-(3-aminopropyl)-5-(2,5- difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-carboxyphenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-((S)- 2-methoxypropanoyl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)benzoic acid 3-cyanophenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-((S)- 2-methoxypropanoyl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)benzonitrile 3,4- (2S)-1-(2-(3-aminopropyl)-2-(3,4-dichlorophenyl)-5- dichlorophenyl (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-chlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(3-chlorophenyl)-5- (2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-ethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (3-ethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 3-pyridyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (pyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 2-pyridyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- (pyridin-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one 5-methylthiophen- (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- 2-yl (5-methylthiophen-2-yl)-1,3,4-thiadiazol-3(2H)-yl)- 2-methoxypropan-1-one 1-methyl-1H- (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- imidazol-2-yl (1-methyl-1H-imidazol-2-yl)-1,3,4-thiadiazol-3(2H)- yl)-2-methoxypropan-1-one 5-methylthiazol- (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2- 2-yl (5-methylthiazol-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one
##STR00292##
TABLE-US-00009 R Ar.sup.1 Name
##STR00324##
TABLE-US-00010 X R.sup.1 NR.sup.2R.sup.3 Name S (S)-2- methoxyethyl
Example 123
[0501] The activity of the compounds of the present invention may be determined by the following procedure. The assays were conducted at 30 C. in a Costar 3695 (96-well, polystyrene, -area, clear) plate in a final volume of 50 L. Hydrolysis of ATP was monitored in a system that coupled the product ADP to the oxidation of NADH using pyruvate kinase and lactate dehydrogenase. Assay mixtures contained the following: 20 mM K.sup.+Pipes, pH 7.0, 0.01% Triton X-100, 2% DMSO, 25 mM KCl, 2 mM MgCl.sub.2, 1 mM DTT, 25 M ATP, 1 mM phospho(enol)pyruvate, 200 M NADH, 7.9 U/mL pyruvate kinase, 9 U/mL lactate dehydrogenase, 0.25 M bovine microtubules, 20 M paclitaxel and 20 nM Eg5. The concentration of inhibitor was typically varied over the range of 10-200,000 nM. The reaction was monitored kinetically in an absorbance-based plate reader for a period of 10 minutes. Velocities were estimated from linear fits to the progress curves and were expressed as POC (percent of uninhibited control wells). IC.sub.50's were estimated from the POC data using a standard 4-parameter logistical model and compared to a control inhibitor run in each plate. In this assay, compounds of the invention exhibited an IC.sub.50 of less than 50 M.
Example 124
[0502] The ability of the compounds of the present invention to inhibit cellular viability may be determined by the following procedure. Cells from a variety of established tumor cell lines, e.g., HeLa, were plated in Costar 3904 96-well plates, in growth medium for the cell line (for HeLa:DMEM high glucose, L-glutamine, 20 mM Hepes, 10% FBS), at a density that allowed for logarithmic growth over the 72 hour period of the assay (HeLa: 1000 cells/well), and incubated at 37 C., 5% CO.sub.2 overnight. The following day, one-tenth volume of a 10 concentration of compounds was added to the wells in an 11-point dilution series. The dilution series was composed of an initial 1:2 dilution in DMSO, followed by a 1:20 dilution in growth medium, for a final DMSO concentration on cells of 0.5%. Control wells were treated with 0.5% DMSO. The typical range of dilution was 2.5 M to 1 nM, which was expanded to 50 M to 50 M depending on the potency of the compound. Once compound was added to the cells, plates were incubated as above. After 72 hour incubation, 20 L resazurin solution (Cell Titer Blue, Promega G8081) was added to all wells and the plates incubated for an additional 2 hours. Viable cells convert resazurin to resorufin, a fluorescent end product. The plate was read on a fluorescent plate reader at 560 nm excitation/590 nm emission. The fluorescent signal of the control wells was defined as 100% and the percent of control signal for each well of a dilution series for the compound was defined as: (fluorescent signal of treated well)(average fluorescent signal of the control well).sup.1100. The EC.sub.50 for inhibition of viability was determined from the inflection point of a standard 4-parameter logistical curve fitted to the values obtained. In this assay, the compounds of the invention exhibited an EC.sub.50 of less than 50 M.
[0503] The foregoing description is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be resorted to falling within the scope of the invention as defined by the claims that follow.
[0504] The words comprise, comprising, include, including, and includes when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.
[0505] The foregoing description is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be resorted to falling within the scope of the invention as defined by the claims that follow.
[0506] The words comprise, comprising, include, including, and includes when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.