WO2010091164A1 - Inhibitors of glucosylceramide synthase - Google Patents

Inhibitors of glucosylceramide synthase Download PDF

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Publication number
WO2010091164A1
WO2010091164A1 PCT/US2010/023168 US2010023168W WO2010091164A1 WO 2010091164 A1 WO2010091164 A1 WO 2010091164A1 US 2010023168 W US2010023168 W US 2010023168W WO 2010091164 A1 WO2010091164 A1 WO 2010091164A1
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alkyl
compound
nmr
found
formula
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PCT/US2010/023168
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French (fr)
Inventor
Naing Aay
Ron G. Aoyama
Arlyn Arcalas
Wai Ki Vicky Chan
Hongwang Du
Patrick Kearney
Elena S. Koltun
Jason August Nachtigall
Michael Pack
Steven James Richards
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Exelixis, Inc.
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Priority to ARP100100327A priority Critical patent/AR075368A1/en
Priority to TW099103666A priority patent/TW201040149A/en
Publication of WO2010091164A1 publication Critical patent/WO2010091164A1/en

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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of cancer and metabolic diseases.
  • GCS glucosylceramide synthase
  • Glucosylceramide synthase is a pivotal enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylceramide-based glycosphingolipids (GSLs) namely via the pivotal transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramide.
  • GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi, Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking.
  • GSL structures have been shown (see, Yamashita et al, Proc, Nail. Acad. ScL CJSA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some tissues. Ceramide plays a central role in sphingolipid metabolism and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids. Sphingolipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions.
  • sphingolipids and Their regulating enxym.es appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (see, El Alwani et al, Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-263).
  • GCS inhibitors have been proposed for the treatment of a variety of diseases (see, for example, WO2005068426), Such treatments include treatment of glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xe ⁇ iobiotica 2007, 37(3), 298-314), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important,
  • glycolipid storage diseases e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fab
  • SUBSTITUTE SHEET diseases in which excessive glyco lipid synthesis occurs e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • neuronal disorders e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • neuronal disorders e.g., neuronal injury, inflammatory diseases or disorders associated with macrophage recruitment and activation (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity (see, WO 2006053043).
  • overexpression of GCS is implicated in multi-drug resistance and disrupts ceramide-induced apoptosis.
  • ceramide induces apoptosis in acute myeloid leukemia (AML) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-I cells.
  • p-gp P-glycoprotein
  • GCS inhibitors can be useful for treatment of proliferative disorders by inducing apoptosis in diseased cells.
  • the present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I),
  • R 1 , A, L, R 2 , R 3 , and m are as defined hereinbelow.
  • the invention comprises compositions comprising a GCS modulator compound of the invention and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention comprises method for the treatment of a cancer or a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a GCS inhibitor of the invention or a pharmaceutical composition comprising an effective amount of a GCS inhibitor of the invention.
  • the invention comprises GCS modulators.
  • the invention comprises GCS modulators of structural formula (I),
  • R A is independently R ⁇ , Ci-C 6 alkyl, Ci-C 4 haloalkyl, aryl, aryl(Ci-C 4 )alkyl, or -Ci-C 6 alkyl-R A2 , wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R ⁇ is independently halogen, cyano, nitro, -OR A1 , -SR A
  • L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen, methyl, or halomethyl; R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • R , 10 is hydrogen or Ci-C 4 alkyl
  • R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 ) 2 , or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and
  • R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R 13A groups, wherein each R 13A group is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl(C
  • R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 , wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 ,
  • each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; or two R B3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C 3 )alkyl, halogen, or Ci-C 4 haloalkyl; and each R 21 is independently halogen or -R 20 ; one R 2 is hydrogen or methyl optionally substituted with one, two or three halo groups, and the other R 2 is methyl optionally substituted with one, two or three halo groups, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; m is
  • R 1 , A, L, R 2 , R 3 , and m are as defined herein.
  • the compounds of the invention, or their pharmaceutically acceptable salts may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure, and may exist as single stereoisomers, racemates, and mixtures of stereoisomers.
  • the compounds of the invention, or their pharmaceutically acceptable salts, as single stereoisomers, racemates, and mixtures of stereoisomers are all intended to be within the scope of this invention.
  • Embodiment (2) In another embodiment, the compound of Formula (I) is that where each R 2 is independently methyl optionally substituted with one, two, or three halo groups, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1).
  • each R 2 In subembodiment (2-a), each R 2 is methyl, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1).
  • subembodiment (2-b) each R 2 is methyl; and all other groups are as defined in embodiment (1).
  • Embodiment (3) In another embodiment, the compound of Formula (I) is that where both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (2).
  • Embodiment (4) In another embodiment, the compound of Formula (I) is that were A is isopropyl, t-butyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is heteroaryl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3); such as, for example, A is indolyl optionally substituted by one, two, or three R A groups.
  • Embodiment (5) In another embodiment, the compound of Formula (I) is that where A is phenyl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • A is phenyl substituted by two R A groups attached to adjacent carbon atoms, and the two R A groups taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; such as, for example A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5-yl.
  • each R A is independently R ⁇ , Ci-C 6 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(Ci-C 4 )alkyl, or -Ci-C 6 alkyl-R A2 , wherein the aryl(Ci-C 4 )alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R A2 is independently halogen, cyano, nitro, -OR A1 , -SR A1 , -N(R A1 ) 2 , -C(O)R A1 , -S(O)R A1 , -S(O) 2 R A1 , -S(O)N(R A1 ) 2 , -S(O) 2 N(R A1 ) 2 , -C(O)OR A1 ,
  • the compound of Formula (I) is that where when R A is present, each R A is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl, benzyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R A1 , wherein each R A1 is independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-; each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (5).
  • the compound of Formula (I) is that where R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aiyl(C 1 -C 4 )alkyl, or -Ci-C 4 alkyl-R B2 , wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 , -S(O)R B3 , -S(O) 2 R 63 , -S(O)N(R B3 ) 2 , -S(O) 2 N(R B3 ) 2 , -C(O)OR B3 , -C(O)N(R B3 ) 2 , -N(R B3 )C(O)R B3
  • the compound of Formula (I) is that where R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(C r C 4 )alkyl, or -C 1 -C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 ; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments (1) - (6).
  • the compound of Formula (I) is that where R 20 is hydrogen, Ci-C 4 alkyl, -OR B3 , or -N(R B3 ) 2 , wherein each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments (1) - (6).
  • Embodiment (8) In another embodiment, the compound of Formula (I) is that where R 1 is: (i) -N(R 10 XR 11 ), wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -C 1 -C 6 alkyl-N(R 12 ) 2 , or -C 1 -C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one,
  • the compound of Formula (I) is that where R 1 is: (i) -N(R 10 XR 11 ), wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 )2, or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annul
  • R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 ; and R 21 is Ci-C 4 alkyl or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (7).
  • the compound of formula (I) is that of subembodiment (8), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7).
  • the compound of formula (I) is that of subembodiment (8-a), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7).
  • Embodiment (9) In another embodiment, the compound of Formula (I) is that where R 1 is:
  • ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is
  • Embodiment (10) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a):
  • ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; wherein R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 , and R 21 is Ci-C 4 alkyl or Ci-C 4 haloalkyl; (b) the moiety of formula (a) is , wherein t is 1 , 2, or 3, R 20 is hydrogen, Ci-C 4 alkyl, Ci-C 4
  • Embodiment (11) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a), wherein ring B is 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, or l-azabicyclo[2.2.2]oct-3-yl and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (1) - (10).
  • Embodiment (12) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a) wherein said moiety of formula (a) is
  • R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a) wherein ring B is piperazin-1-yl or 1,4-diazepan-l-yl; and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 XR 11 ) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4- methyl- 1,4-diazepan-l-yl, piperazin-1-yl, 4-(l-methylethyl)-piperazin-l-yl, 4-(2- fluoroethyl)piperazin-l-yl, or 4-ethylpiperazin-l-yl; and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (9).
  • Embodiment (13) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a),
  • R 21 , w, and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein ring B is azetidin- 1-yl, pyrrolidin-1-yl, or piperidin-1-yl and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (10).
  • R 1 is -N(R 10 )(R ⁇ ) or 3 -(dimethylamino)azetidin- 1 -yl, 3 -(dimethylamino)pyrrolidin- 1 -yl, 3 -aminoazetidin- 1 -yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3-aminopiperidin-l-yl, 4- aminopiperidin- 1 -yl, 3 -(methylamino)pyrrolidin- 1 -yl, 4-(methylamino)piperidin- 1 -yl, (l-methylethyl)amino-piperidinyl, or 4-hydroxypiperidin-l-yl, and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (9).
  • Embodiment (14) In another embodiment, the compound of Formula (I) is that where L is -[C(R L )2] p -L 1 -[C(R L )2] q -, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (13).
  • the compound of Formula (I) is that where L is -[C(R L )2] p -L 1 -[C(R L )2] q -,wherein/? is 1 or 2; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (1) - (13). [0026] Embodiment (15): In another embodiment, the compound of Formula (I) is that
  • R 1 is a moiety of formula (a) , (a); and ring B, R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (14).
  • Embodiment (16) in another embodiment, is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein said azetidinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • Embodiment (17) in another embodiment, is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8- yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl,
  • Embodiment (18) in another embodiment, the compound of Formula (I) is that where when R 13A is present, each R 13A group is independently halogen, cyano, nitro, C 1 -C 4 alkyl, Ci-C 4 haloalkyl, aryl(Ci-C 4 )alkyl, -OR B1 , -SR B1 , -N(R B1 ) 2 , -C(O)R B1 , -S(O)R B1 , -S(O) 2 R B1 , -S(O)N(R B1 ) 2 , -S(O) 2 N(R B1 ) 2 , -C(O)OR B1 , -C(O)N(R B1 ) 2 , -N(R B1 )C(O)R B1 , -N(R B1 )C(O)OR B1 , -N(R B1 )C(O)OR B1
  • the compound of Formula (I) is that where when R 13A is present, each R 13A group is independently halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl(Ci-C 4 )alkyl, -OR B1 , -SR B1 , or -N(R B1 ) 2 , wherein each R B1 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and all other groups are as defined in any one of embodiments (1) - (14), (16), and (17).
  • Embodiment (19) in another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a), wherein R 11 is -C 1 -C 6 alkyl-N(R 12 ) 2 or -C3-C6 CyClOaUCyI-N(R 12 ) 2 ; and all other groups are as defined in any one of embodiments (I) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is -Ci-C 3 alkyl-N(R 12 ) 2 or -C 3 -C 6 cycloalkyl-N(R 12 ) 2 ; each R 12 is independently hydrogen or -C 1 -C 3 alkyl; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)- 1 -methylethyl,
  • Embodiment (20) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ); and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (6), (9), (14), and (16) - (19).
  • Embodiment (21) In another subembodiment, the compound of Formula (I) is that where each R 3 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 6 cycloalkyl, -OR C1 , -N(R C1 ) 2 , -C(O)R C1 , -S(O)R C1 , -S(O) 2 R 01 , -S(O)N(R C1 ) 2 , -S(O) 2 N(R C1 ) 2 , -C(O)OR C1 , -C(O)N(R C1 ) 2 , -N(R C1 )C(O)R C1 , -N(R C1 )C(O)OR C1 , -N(R C1 )C(O)N(R C1 ) 2 , or -N(R
  • the compound of Formula (I) is that where each R is halogen, C 1 -C 4 alkyl, Ci-C 4 haloalkyl, or -OR , wherein each R is independently hydrogen, Ci-C 4 alkyl, or
  • Ci-C 4 haloalkyl and all other groups are as defined in any one of embodiments (1) - (20).
  • the compound of Formula (I) is that where m is 1, 2, or 3; and R 3 is halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -OR C1 , wherein each R C1 is independently hydrogen,
  • Ci-C 4 alkyl, or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments
  • Embodiment (22) In another embodiment, the compound of Formula (I) is that where w is zero or 1, and R 21 , when present, is Ci-C 4 alkyl or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (15) and (21).
  • Embodiment (23) In another embodiment, the compound of Formula (I) is that where L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 -O-, -CH 2 CH 2 -O-, or
  • Embodiment (24) In another embodiment, the compound of Formula (I) is that where L is Ci -C 3 alkylene; and all other groups are as defined in any one of embodiments (1) -
  • Embodiment (25) In another embodiment, the compound of Formula (I) is that
  • Embodiment (26) In another embodiment, the compound of Formula (I) is that
  • Embodiment (27) In another embodiment, the compound of Formula (I) is that which is a compound listed in Table 1.
  • Embodiment (29) In another embodiment, the compound of Formula (I) is that where m is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (28). [0041] Embodiment (30): In another embodiment, the compound of Formula (I) is that where L is -CH 2 -; and all other groups are as defined in any one of embodiments (1) - (29). [0042] When R 1 is a moiety of formula (a),
  • ring B in the definition of R 1 is (i) a heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or (ii) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl.
  • Ring B refers to the annular atoms which together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring.
  • R 1 is a piperazinyl ring substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • R 1 is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl and the like, wherein the 4 - 10 membered monocyclic heterocyclyl ring is substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • Embodiment (31) In another embodiment, the compound of Formula (I) is that where when R 1 is a moiety of formula (a), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, 8-azabicyclo[3.2.1]octyl, l-azabicyclo[2.2.2]oct-3-yl,
  • ring B is a 7 - 10 membered fused-bicyclic heterocyclyl ring, optionally comprising one, two, or three additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 5 or 6 membered heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • Embodiment (32) In another embodiment, the compound of Formula (I) is that where L is -(CH 2 ) p -L 1 -(CH 2 ) q - , wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31). In subembodiment (32-a), L is -CH 2 O(CH2) q -.
  • L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 -O-, -CH 2 CH 2 -O-, or -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31).
  • Embodiment (33) In another embodiment, the compound of Formula (I) is that where A is
  • each R A is independently halogen, Ci -C 4 alkyl, Ci-C 4 haloalkyl, or -OR A1 , wherein each R A1 is independently hydrogen, Ci-C 4 alkyl, or Ci-C 4 haloalkyl, or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) -(3), (5) - (27), and (29) - (32).
  • the invention also comprises as another embodiment, a pharmaceutical composition
  • a pharmaceutical composition comprising a GCS modulator compound according to any one of the preceding embodiments and a pharmaceutically acceptable excipient, diluent, or carrier.
  • Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also comprises as another embodiment a method for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention (supra).
  • Diseases and disorders mediated by GCS or implicated by GCS include, but are not limited to cancers, and metabolic disorders.
  • the invention also comprises as another embodiment a method for treating cancer, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
  • Examples of metabolic diseases and disorders mediated by GCS or implicated by GCS include but are not limited to, Tay Sachs, Sandhoffs, GMl gangliosidosis, atherosclerosis, polycystic kidney disease, renal hypertrophy, rheumatoid arthritis, Crohn's disease, asthma, sepsis, diabetes mellitus, and obesity; and lysosomal storage diseases such as, for example Fabry diseases, and Gaucher disease.
  • the invention further comprises as another embodiment a method for treating metabolic disorders, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
  • the invention also comprises as another embodiment a method for inducing decreased GCS catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any of the preceding embodiments.
  • the invention also comprises as another embodiment, use of a GCS modulator of any of the preceding embodiments of the invention for the preparation of a medicament for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0061] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
  • Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents.
  • Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s).
  • Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
  • combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • a substituent "R” can reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group can reside on either the 5-membered or the 6- membered ring of the fused ring system.
  • the two "R's" can reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • L is a divalent moiety linking A to the parent structure.
  • particular members defining L may be written, for example, in the form -X-Y- or -Y-X-. Such members are intended to replace the term being defined, in this case L, as written, such that the leading (left) bond is attached to the parent moiety and the ending (right) bond is attached to A.
  • L is of the form -X-Y-
  • the X is bonded to the parent moiety and Y is bonded to A.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound of the invention into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkoxy means the group -OR 0 wherein R 0 is alkyl, as defined herein.
  • alkyl means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined.
  • Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like.
  • (Ci_C 4 )alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl and tert-butyl.
  • Aryl means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic.
  • the valency may be located on any atom of any ring of the aryl group, valency rules permitting.
  • Representative examples include phenyl, naphthyl, indanyl, benzodioxolyl, benzodioxanyl, benzopyranyl, 2,3-dihydro-lH-indolyl
  • (Ci-C 4 )alkyl an aryl moiety attached to a parent structure via a one-to-four carbon alkylene group. Examples include benzyl, phenethyl, and the like.
  • “Bridged-bicyclic heterocyclyl ring” refers to a heterocyclyl ring system in which a valence bond, an atom, or a chain of atoms connects two or more non-adjacent positions of a heterocyclyl ring system. Such a system may contain isolated or conjugated unsaturation, but not aromatic or hetero aromatic rings in its core structure (but may have aromatic substitution
  • Examples of 5 - 10 membered bridged-bicyclic heterocylyl rings include 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3- yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl, and the like.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cycloalkyl radical includes fused bicyclic, bridged bicyclic and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octanyl.
  • fused-bicyclic refers to a bicyclic ring system where two rings have more than one shared atom in their ring structures, where each bond is part of a ring, where each ring is ortho- fused to the other ring; and where no bond is common to more than two rings.
  • a spiro ring system is not a fused-bicyclic by this definition, but fused bicyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms.
  • Halo and halogen mean a fluoro, chloro, bromo or iodo group.
  • Haloalkyl means an alkyl radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted (Ci_ 4 )alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.
  • Haloalkyl includes, for example, halomethyl which means a methyl group substituted by one, two, or three halogen atoms, where each halogen is independently selected.
  • Halomethyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, chlorofluoromethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or polycyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms.
  • the monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic, where the aromatic ring contains at least one heteroatom.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, isoindolyl, benzimidazolyl, benzo furanyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[3,2-c]pyr
  • Heterocyclyl means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example, 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon.
  • the heterocyclyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the heterocyclyl radical includes monocyclic, fused-bicyclic, bridged-bicyclic, and spiro-bicyclic ring systems. Unless otherwise stated, the heterocyclyl may be attached at any annular or bridge carbon or heteroatom which results in the creation of a stable structure.
  • heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, 1
  • substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included.
  • Spiro ring refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
  • a ring atom of a saturated bridged ring system (rings C and C), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto.
  • a representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
  • Stepoisomer means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms.
  • Stepoisomer includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer.
  • the names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.
  • the present invention also includes N-oxidc derivatives of the compounds of the invention. JV-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N ⁇ O), e.g., pyridine iV-oxide, and which possess the desired pharmacological activity.
  • Patient and “subject” for the purposes of the present invention include humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66:1-19 both of which are incorporated herein by reference. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 2-
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Effective amount is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease.
  • the amount of a compound of the invention which constitutes an “effective amount” will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought.
  • the effective amount for a given circumstance can be determined without undue experimentation.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • Boc protected amino acid (1) was coupled with a suitably functionalized amine.
  • the coupling reaction was typically carried out in the presence l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give an amide (2).
  • EDC 3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide
  • HOBt 1-Hydroxybenzotriazole
  • 2-amino-amide (3) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1- dimethylcarboxylic acid.
  • the coupling reaction was typically carried out in the presence of EDC and HOBt to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (4); a compound of formula (I)-
  • R 20 , R 21 , and w are as defined herein.
  • R 20 , R 21 , and w are as defined herein.
  • the resulting carboxylic acid (7) was then coupled with suitably functionalized amines in the presence of 2- (lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU, Applied Biosystems), to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (8), a compound of formula (I). In certain examples, it was followed by the de -protection reaction performed under acidic conditions.
  • R 20 , R 21 , and w are as defined herein.
  • amine (11) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1-dimethylcarboxylic acid.
  • the coupling reaction was typically carried out in the presence of O-(7-Azabenzotriazole-l-yl)-N, N,N'N'- tetramethyluronium hexafluorophosphate (HATU, Novabiochem) to give 2-(2-Aryl carboxamide)-3-Aryl-propanylamide (12), a compound of formula (I).
  • the invention further comprises a method of preparing a compound of formula (I), the method comprising:
  • R 20 , R 21 , and w are as defined herein; with a compound of formula (14), wherein R 2 , R 3 and m are as defined herein, to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof; or (ii) coupling a compound of formula (15),
  • A, L, R 2 , R 3 and m are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (16) wherein -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R x and R Y is R 11 , or R x and R Y and the nitrogen atom to which they are attached form a moiety of formula (a) ,
  • R 20 , R 21 , and w are as defined herein; to provide a compound of formula (I); and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
  • Step 1 (S)-2-amino-3-(lH-indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one:
  • Step 2 (l-(2,4-dichlorophenyl)-N-[(2S)-3-(lH-indol-3-yl)-l-(4-methylpiperazin- l-yl)-l-oxopropan-2-yl]cyclopropanecarboxamide: To a solution of (S)-2-amino-3-(lH- indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one dihydrochloride (690 mg, 1.92 mmol) and Hunig's base (1.64 mL, 9.6 mmol) in dry acetonitrile (10 mL) was added l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Acros, 443 mg, 1.92 mmol).
  • Step 1 l-(4-(trifluoromethyl)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (1 g, 5.4 mmol, AK Scientific) in tetrahydrofuran (10 rnL) at O 0 C was added sodium hydride ( 0.4 g, 16.6 mmol). The reaction mixture was stirred at O 0 C for 5 minutes followed by the addition of 1 ,2-dibromoethane ( 2.6 g, 14.1 mmol) in tetrahydrofuran (1 mL).
  • Step 2 l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid: To l-(4- (trifluoromethyl)phenyl)cyclopropanecarbonitrile (600 mg, 2.8 mmol) was added 20 mL of 3 N NaOH solution and the reaction mixture was heated to reflux for 18 h, then cooled down to room temperature. The resulting solution was acidified with 1 N HCl to pH3, and extracted with 50 mL of EtOAc. The organic layer was dried over magnesium sulfate.
  • Step 3 (S)-2-amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (10 g, 29 mmol, Aldrich) in dichloromethane (100 mL) were added N-methylpiperazine ( 1O g, 100 mmol), 1-hydroxybenzotriazole ( 5 g, 33 mmol), N-methylmorpholine ( 20 mL, 182 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.3g, 38 mmol).
  • N-methylpiperazine 1O g, 100 mmol
  • 1-hydroxybenzotriazole 5 g, 33 mmol
  • N-methylmorpholine 20 m
  • Step 4 N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2- oxoethyl]-l-[4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l-one ( 200 mg, 0.63 mmol) in dichloromethane (5 mL) were added l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid (200 mg, 0.86 mmol), 1-hydroxybenzotriazole ( 250 mg, 1.85 mmol), N-methylmorpholine (1 mL, 9.1 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro
  • N-[(2S)-3-(3-chlorophenyl)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2-yl]-l-(2,4- dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid (PepTech Corp) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • l-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • N-[(lS)-l-[(4-bromophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-bromophenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • S -2-(tert-butoxycarbonylamino)-3-(4-brom
  • N-[(lS)-l-[(4-chlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • Fluka was substituted for (S)-2-(tert-butoxycarbonyla
  • Step 1 (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)propanoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (5 g, 15 mmol, Fluka) in dichloromethane (100 mL) were added 1-hydroxybenzotriazole ( 3 g, 22.5 mmol), N-methylmorpholine ( 16.5 mL, 150 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride ( 4.3g, 22.8 mmol), and Ethyl alcohol ( 13.8 mL, 300 mmol).
  • 1-hydroxybenzotriazole 3 g, 22.5 mmol
  • N-methylmorpholine 16.5 mL, 150 mmol
  • Step 2 (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido) propanoate: To a solution of (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)- propanoate ( 3 g, 11.5 mmol) in dichloromethane (100 niL) were added 1-hydroxybenzotriazole (1.8 g, 13.7 mmol), N-methylmorpholine ( 12.6 mL, 115 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride ( 2.6g, 13.7 mmol), and l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid ( 2.7 g, 11.5 mmol, Acros ).
  • Step 3 (S)-3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido)-propanoic acid: To a solution of (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxamido) propanoate ( 1.5 g, 3.2 mmol) in 10 mL of MeOH was added 20 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours.
  • Step 4 2,4-dichloro-N-alpha- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -N- [2-(dimethylamino)ethyl]-L-phenylalaninamide: To a solution of (S)-3-(2,4-dichlorophenyl)- 2-(l-(2,4-dichlorophenyl)cyclopropane-carboxamido)propanoic acid (70 g, 29 mmol) in dichloromethane (5 mL) were added 1-hydroxybenzotriazole ( 25 mg, 0.19 mmol), N-methylmorpholine ( 0.172 mL, 1.57 mmol), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride ( 36 mg, 0.19 mmol), and N ⁇ N ⁇ dimethylethane-l ⁇ -diamine (16 mg, 0.
  • Step 1 (S)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 niL, 146.2 mmol), 1-methylpiperazine (1.78 niL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol).
  • Step 2 (S)-2-amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l- one hydrochloride: To a solution of (S)-tert-butyl 3 -hydroxy- l-(4-methylpiperazin-l-yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at O 0 C was added sodium hydride (18 mg, 0.77 mmol).
  • reaction mixture was stirred at O 0 C for 5 minutes followed by the addition of 4-chlorobenzyl bromide (157 mg, 0.77 mmol) in tetrahydrofuran (1 mL).
  • the reaction was stirred at O 0 C for 2 h.
  • the reaction was quenched with 5 drops of water and concentrated in vacuo.
  • the concentrated reaction mixture was dissolved in methanol (5 niL), followed by the addition of 4 N HCl in dioxane (3 mL), and the resulting mixture was heated to 65°C for 1 h. Upon cooling the mixture was concentrated in vacuo to give the title compound which was used in the next step without further purification.
  • Step 3 N-[(lS)-l-( ⁇ [(4-chlorophenyl)methyl]oxy ⁇ methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one hydrochloride (0.7 mmol) in dichloromethane (4 mL) was added N-methylmorpholine (0.77 mL, 7 mmol), l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (177 mg, 0.77mmol), l-[3-
  • Step 1 Diethyl 2-acetamido-2-((2,3-dihydrobenzo[6][l,4]dioxin-6-yl)methyl)- malonate: To a freshly prepared solution of sodium ethoxide (sodium 0.6 g, 26 mmol, ethanol 50 mL ) were added 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (2 g, 8.73 mmol) and 2-acetamide-diethylmalonate (1.9 g, 8.75 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2h, and concentrated in vacuo to give the title compound that was submitted to the next step without further purification.
  • sodium ethoxide sodium 0.6 g, 26 mmol, ethanol 50 mL
  • 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (2 g, 8.73
  • Step 2 2-Acetamido-3-(2,3-dihydrobenzo[ ⁇ ] [l,4]dioxin-6-yl)propanoic acid: A solution of diethyl 2-acetamido-2-((2,3-dihydrobenzo[ ⁇ ][l,4]dioxin-6-yl)methyl)malonate (3.17 g, 8.7 mmol) and potassium hydroxide (1.11 g, 27.7 mmol) in water (35 mL) and ethanol (35 mL) was heated to reflux for 2h. The reaction mixture was concentrated in vacuo and the product was submitted to the next step without further purification.
  • Step 3 (S)-2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoic acid: 2-Acetamido-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) was dissolved in a solution of sodium hydroxide (0.42g of NaOH, 50 mL H 2 O) at 37 0 C (39 0 C bath temperature), and the pH was adjusted to 7.5 with the addition of 2N HCl.
  • sodium hydroxide (0.42g of NaOH, 50 mL H 2 O
  • Step 4 (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) in ethanol (25mL) was added thionyl chloride (2.0 mL, 27.4 mmol). The reaction mixture was stirred under reflux conditions (9O 0 C bath temperature) for 2 hours. The resulting solution was concentrated in vacuo and the product was submitted to the next step without further purification.
  • Step 5 (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (300 mg, 1.3 mmol) in acetonitrile (15.0 mL) were added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (250 mg, 1.1 mmol), N,N-diisopropylethylamine (1.5 mL, 9.12 mmol), and HATU ( 400 mg, 1.1 mmol).
  • the reaction mixture was stirred at room temperature for 1 hour.
  • the resulting solution was concentrated in vacuo, dissolved in dichloromethane (35 mL), and extracted with water (10 mL) 2 times. The layers were separated and the organic layer was concentrated in vacuo.
  • the product was purified by column chromatography (silica-gel, EtOAc, Hexanes), resulting in 350 mg (68.8%) of the title compound.
  • Step 6 (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydro- benzo[b] [l,4]dioxin-6-yl)propanoic acid: To a solution of (S)-ethyl 2-amino-3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (350 mg, 0.75 mmol) in 15 mL of MeOH was added 15 mL of 2 N NaOH solution and the reaction mixture was stirred at room temperature for 18 hours.
  • Step 7 N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N'2'- ⁇ [l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl ⁇ -3-(2,3-dihydro-l,4-benzodioxin-6-yl)-L-alaninamide: To a solution of (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydrobenzo[b][l,4]dioxin- 6-yl)-propanoic acid (320 mg, 0.73 mmol) in acetonitrile (15.0 mL) were added (S)-quinuclidin- 3-amine (250 mg, 1.9 mmol), N,N-diisopropylethylamine (1.0 mL, 6.0 mmol), and HATU ( 400 mg
  • Step 1 l-(4-(trifluoromethoxy)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (15g, 74.6 mmol) in THF (450 mL) was added NaH (100%, 9.0 g, 375 mmol) at 0 0 C. The reaction was stirred at room temperature for 30 min and 15 mL of dibromoethane (15 mL, 174 mmol) was added. The reaction was stirred at room temperature for 48 h and quenched by addition of 10OmL of water.
  • Step 2 l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid: To a solution of NaOH (35 g, 795 mmol) in 400 mL of water was added l-(4-(trifluoromethoxy)- phenyl)cyclopropanecarbonitrile (14.9 g, 65.0 mmol). The reaction mixture was heated to 12O 0 C for 48 h. The resulting solution was cooled down to 0 0 C and acidified to pH 3 via addition of concentrated HCl. The resulting precipitate was filtered, washed with water, and dried.
  • Step 3 (S)-ethyl 2-amino-3-(4-bromophenyl)propanoate: To a solution of Boc-L- 4-bromophenylalanine (30.Og, 87.16 mmol, Chem-Impex) in ethanol (450 mL) were added thionyl chloride (8.0 mL, 109.67 mmol).
  • Step 4 (S)-ethyl 3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)- cyclopropanecarboxamido)propanoate: To a solution of (S)-ethyl 2-amino-3-(4- bromophenyl)propanoate (11.5 g, 42.26 mmol) in acetonitrile (150.0 mL) were added l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (10.4 g, 42.26 mmol), N 5 N- diisopropylethylamine (13.9 mL, 84.52 mmol), and HATU ( 19.3 g, 50.71 mmol).
  • Step 5 (S)-3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)cyclopropane- carboxamido)propanoic acid: To a solution of (S)-ethyl 3-(4-bromophenyl)-2-(l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxamido)propanoate (17.4 g, 34.8 mmol) in 300 mL of MeOH was added 100 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours.
  • Step 6 N-(azetidin-3-ylmethyl)-4-bromo-Nalpha-[(l- ⁇ 4-[(trifluoromethyl)oxy]- phenyl ⁇ cyclopropyl)carbonyl]-L-phenylalaninamide: To a solution of (S)-3-(4- bromophenyl)-2-( 1 -(4-(trifluoromethoxy)phenyl)cyclopropane-carboxamido)propanoic acid (100 mg, 0.2 mmol) in acetonitrile (5.0 mL) were added tert-butyl 3-(aminomethyl)azetidine-l- carboxylate (Oakwood, 40.0 mg, 0.2 mmol), N,N-diisopropyl-ethylamine (1.1 niL, 6.1 mmol), and HATU ( 76 mg, 0.2 mmol).
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl]-l-[4-[(trifluoromethyl)oxy]phenyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 6, wherein tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for tert-butyl 3-(aminomethyl)azetidine-l -carboxylate (Oakwood).
  • N- ⁇ (lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2- oxoethyl ⁇ -l-(2,4-dichlorophenyl)cyclopropanecarboxamide 1 H NMR (400MHz, CD 3 OD): 8.50 (s, IH), 7.50-7.38 (m, 3H), 7.28-7.23 (m, IH), 7.17-7.08 (m, IH), 5.20-5.10 (m, IH), 4.10- 3.80 (m, 2H), 4.60-3.45 (m, IH), 3.18-3.02 (m, 2H), 2.98-2.83 (s, IH), 1.85-1.60 (m, 4H), 1.55- 1.37 (m, 5H), 1.13-1.00 (m, 2H).
  • N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -N-[2-(dimethylamino)ethyl]- N-methyl-5-phenyl-L-norvalinamide 1 H NMR (400MHz, CD 3 OD): 8.41 (s, IH), 7.56 (s, IH), 7.43 (d, IH), 7.39 (d, IH), 7.27-7.14 (m, 5H), 4.68 (dd, IH), 3.85-3.80 (m, IH), 3.45-3.38 (m, IH), 3.17-3.11 (m, IH), 3.05 (s, 3H), 2.78 (s, 6H), 2.63-2.55 (m, 3H), 1.75-1.43 (m, 6H), 1.22- 1.05 (m, 2H).
  • N-(3-aminocyclohexyl)-2,4-dichloro-Nalpha- ⁇ [l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl ⁇ -L-phenylalaninamide 1 H NMR (400MHz, CD 3 OD): 8.52 (s, IH), 7.50-7.38 (m, 4H), 7.23-7.15 (m, 2H), 4.82-4.75 (m, IH), 3.67-3.58 (m, IH), 2.20-2.13 (m, IH), 2.02-1.83 (m, 3H), 1.77-1.40 (m, 5H), 1.25-1.00 (m, 3H).
  • N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -5-phenyl-N-[(3R)-piperidin- 3-yl]-L-norvalinamide 1 H NMR (400MHz, CD 3 OD): 8.45 (s, IH), 7.55-7.38 (m, 3H), 7.28- 7.20 (m, 2H), 7.17-7.08 (m, 3H), 4.37-4.32 (t, IH), 3.93-3.84 (m, IH), 3.30-3.25 (m, IH), 2.97- 2.93 (m, IH), 2.78-2.73 (m, IH), 2.62-2.47 (m, 2H), 2.02-1.85 (m, 2H), 1.80-1.62 (m, 3H), 1.58- 1.42 (m, 6H), 1.19-1.04 (m, 2H).
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l- ⁇ [4-(trifluoromethyl)- phenyl]methyl ⁇ ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for l-Boc-3-(aminomethyl)azetidine .
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l- ⁇ [4-(trifluoromethyl)- phenyl]methyl ⁇ ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for
  • Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl
  • N-piperidin-4-yl-l-(biphenyl-4-ylmethyl)-2-oxoethyl]-l-(2,4-dichlorophenyl)- cyclopropane carboxamide 1 H NMR (400MHz, CD 3 OD): 8.57 (s, IH), 7.60 (d, 2H), 7.52 (d,
  • N-piperidin-4-yl-Nalpha- [(1- ⁇ 4- [(trifluoromethyl)oxy] phenyl ⁇ cyclopropyl)- carbonyl]-L-phenylalaninamide 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 8.07 (d, IH), 7.41 - 7.25
  • N-piperidin-4-yl-4-(trifluoromethyl)-Nalpha-[(l- ⁇ 4-[(trifluoromethyl)oxy]- phenylJcyclopropyOcarbonylj-L-phenylalaninamide 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 8.13
  • Step 1 (S)-l-tert-buty ⁇ 2-methyl aziridine-l,2-dicarboxylate: To a solution of (S)-methyl aziridine-2-carboxylate (prepared according to Tetrahedron Asymmetry, 2002, 13(11), 1129-1134) (1.0 g, 9.89 mmol) in acetonitrile (20 mL) was added boc-anhydride (2.37 g, 10.88 mmol). The reaction mixture was stirred at room temperature for 2 h after which solvent was removed under reduced pressure, resulting in 1.86 g of the title compound that was used in the next step without further purification.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
  • Step 2 (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (S)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous chloroform (16 mL), followed by addition of (l-methylcyclopropyl)methanol (1.2, 14.9 mmol) and 0.04 mL (0.25 mmol) of a 7 M boron trifluoride diethyl etherate (Aldrich). The reaction mixture was stirred at room temperature for 24 hours and quenched with a few drops of methanol.
  • Step 3 (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate: (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate (800 mg, 2.8 mmol) was dissolved in anhydrous diethyl ether (6 mL) and 4 M HCl/dioxane (14mL, 55.7 mmol, Aldrich) was added. The reaction mixture was stirred for 4 hours at room temperature and the solvent was removed in vacuo.
  • Step 5 (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l- methyl-cyclopropyl)methoxy)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropanecarboxamido)-3-((l-methylcyclopropyl)methoxy)propanoate (850 mg, 2.1 mmol) in 10 mL of THF was added 8.5 mL of IN LiOH solution (8.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours.
  • Step 1 (S)-methyl 2-(f ⁇ rt-butoxycarbonylamino)-4-methylpent-4-enoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-4-methylpent-4-enoic acid (Alfa Aesar, 1.0 g, 4.4 mmol) in anhydrous acetonitrile (20 mL) was added potassium carbonate (1.8 g, 13.1 mmol) and methyl iodide (0.81 mL, 13.1 mmol).
  • Step 2 (S)-methyl 2-amino-3-(l-methylcyclopropyl)propanoate: To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-methylpent-4-enoate (300 mg, 1.2 mmol) in anhydrous dichloromethane (12 mL) under nitrogen atmosphere was added dimethylzinc (3 mL of a 2 M toluene solution, 6.2 mmol), followed by addition of diiodomethane (0.5 mL, 6.2 mmol). The reaction mixture was stirred overnight at room temperature. The resulting solution was extracted with saturated ammonium chloride (30 mL), and water (10 mL).
  • Step 3 (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(l- methyl-cyclopropyl)propanoate: To a solution of (S)-methyl 2-amino-3-(l- methylcyclopropyl)propanoate (187 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 5.5 mmol) in dry acetonitrile (5 mL) was added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Acros, 250 mg, 1.1 mmol), followed by HATU (Applied Biosystems, 450 mg, 1.2 mmol).
  • Step 4 (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxyamido)-3-(l- methylcyclopropyl)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropane-carboxamido)-3-(l-methylcyclopropyl)propanoate (350 mg, 0.9 mmol) in 5 mL of THF was added 1.9 mL of IN LiOH solution (1.9 mmol), and the reaction mixture was stirred at room temperature for 2 hours.
  • Step 5 N-l-azabicyclo[2.2.2]oct-3-yl-N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl ⁇ -3-(l-methylcyclopropyl)-L-alaninamide: To a solution of (S)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxyamido)-3-(l-methylcyclopropyl)propanoic acid (300 mg, 0.8 mmol) and N,N-diisopropylethylamine (00.4 mL, 2.6 mmol) in acetonitrile (4 mL) was added quinuclidin-3 -amine (Sigma-Aldrich, 117 mg, 0.9 mmol), followed by HATU (Applied Biosystems, 350 mg, 0.9 mmol).
  • Glucosylceramide synthase (GCS) activity was measured as the amount of UDP-glucose consumed during the synthase-catalyzed reaction by using the enzyme UDP-glucose dehydrogenase to create NADH from UDP-glucose and then quantitatively converting low fluorescence resazurin to high fluorescence resorufm with diaphorase and the NADH that is formed by the dehydrogenase.
  • the synthase-catalyzed reaction transferred glucose from UDP-glucose to C6-ceramide to give UDP and glucosylceramide as products; the assay measured the disappearance of the UDP-glucose substrate.

Abstract

The present invention comprises glucosylceramide synthase (GCS) modulators of following structural formula (I); wherein R1, A, L, R2, R3, and m are defined herein, as well as N-oxides of them and pharmaceutically acceptable salts thereof, and methods of making said compounds. The invention further comprises compositions comprising the compounds, N-oxides, and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which GCS is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is implicated.

Description

INHIBITORS OF GLUCOSYLCBRAMIDE SYNTHASE
BACKGROUND OF THE INVENTION Field of the Invention
[0001] The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of cancer and metabolic diseases.
Summary of the Related Art
(0002] Glucosylceramide synthase (GCS) is a pivotal enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylceramide-based glycosphingolipids (GSLs) namely via the pivotal transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramide. GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi, Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking. Synthesis of GSL structures has been shown (see, Yamashita et al, Proc, Nail. Acad. ScL CJSA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some tissues. Ceramide plays a central role in sphingolipid metabolism and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids. Sphingolipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions. In particular, sphingolipids and Their regulating enxym.es appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (see, El Alwani et al, Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-263).
[0003] GCS inhibitors have been proposed for the treatment of a variety of diseases (see, for example, WO2005068426), Such treatments include treatment of glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xeγiobiotica 2007, 37(3), 298-314), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important,
1 SUBSTITUTE SHEET diseases in which excessive glyco lipid synthesis occurs (e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy), neuronal disorders, neuronal injury, inflammatory diseases or disorders associated with macrophage recruitment and activation (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity (see, WO 2006053043). [0004] In particular, it has been shown that overexpression of GCS is implicated in multi-drug resistance and disrupts ceramide-induced apoptosis. For example, Turzanski et al., {Experimental Hematology 2005, 33(1), 62-72) have shown that ceramide induces apoptosis in acute myeloid leukemia (AML) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-I cells. Thus, GCS inhibitors can be useful for treatment of proliferative disorders by inducing apoptosis in diseased cells.
SUMMARY OF THE INVENTION
[0005] In light of the preceding diseases that can be affected by GCS inhibitors, there is a need in the art for new inhibitors. Towards this end, novel compounds have been identified that are useful in inhibiting GCS's catalytic activity and are useful for the treatment of cancer and metabolic disease.
[0006] The present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I),
Figure imgf000003_0001
and optionally pharmaceutically acceptable salts thereof, wherein R1, A, L, R2, R3, and m are as defined hereinbelow.
[0007] In another aspect, the invention comprises compositions comprising a GCS modulator compound of the invention and a pharmaceutically acceptable carrier, diluent, or excipient. [0008] In another aspect, the invention comprises method for the treatment of a cancer or a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a GCS inhibitor of the invention or a pharmaceutical composition comprising an effective amount of a GCS inhibitor of the invention. DETAILED DESCRIPTION OF THE INVENTION
[0009] In a first aspect, the invention comprises GCS modulators. As embodiment (1), the invention comprises GCS modulators of structural formula (I),
Figure imgf000004_0001
(I) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein A is isopropyl, t-butyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups, wherein each RA is independently R^, Ci-C6 alkyl, Ci-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C6 alkyl-RA2, wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each R^ is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3;
L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen, methyl, or halomethyl; R1 is -N(R10XR11) or a moiety of formula (a),
wherein
R , 10 is hydrogen or Ci-C4 alkyl; R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and
R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, cyano, nitro, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; w is 0, 1, 2, or 3; ring B in the definition of R1 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms;
R20 is -RB2, hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3,
-S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3,
-C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or
-N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and each R21 is independently halogen or -R20; one R2 is hydrogen or methyl optionally substituted with one, two or three halo groups, and the other R2 is methyl optionally substituted with one, two or three halo groups, or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; m is 1, 2, 3, 4 or 5; and each R3 is independently halogen, cyano, nitro, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, -ORC1, -N(RC1)2, -C(O)RC1, -S(O)RC1, -S(O)2R01, -S(O)N(RC1)2, -S(O)2N(RC1)2, -C(O)ORC1, -C(O)N(RC1)2, -N(RC1)C(O)RC1, -N(RC1)C(O)ORC1, -N(RC1)C(O)N(RC1)2, or -N(RC1)S(O)2RC1, wherein each RC1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl, or two R taken together with the ring atoms to which they are attached form an aryl, heteroaryl, a monocyclic cycloalkyl, or a heterocyclyl, each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl. [0010] The present invention further comprises GCS modulators of structural formula (IV),
R1 H
A-L °
(IV) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein E is -C(O)-; R is
Figure imgf000007_0001
, and R1, A, L, R2, R3, and m are as defined herein.
[0011] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure, and may exist as single stereoisomers, racemates, and mixtures of stereoisomers. The compounds of the invention, or their pharmaceutically acceptable salts, as single stereoisomers, racemates, and mixtures of stereoisomers are all intended to be within the scope of this invention. [0012] The invention also comprises each of the following embodiments: [0013] Embodiment (2): In another embodiment, the compound of Formula (I) is that where each R2 is independently methyl optionally substituted with one, two, or three halo groups, or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1). In subembodiment (2-a), each R2 is methyl, or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1). In subembodiment (2-b), each R2 is methyl; and all other groups are as defined in embodiment (1). [0014] Embodiment (3): In another embodiment, the compound of Formula (I) is that where both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (2).
[0015] Embodiment (4): In another embodiment, the compound of Formula (I) is that were A is isopropyl, t-butyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-a), the compound of Formula (I) is that where A is C3-Cs cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-b), A is C3-Cs cycloalkyl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-c), A is C3-Cs cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-d), A is C3-Cs cycloalkyl or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-e), A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3). In subembodiment (4-f), A is heteroaryl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3); such as, for example, A is indolyl optionally substituted by one, two, or three RA groups.
[0016] Embodiment (5): In another embodiment, the compound of Formula (I) is that where A is phenyl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-a), A is phenyl substituted by two RA groups attached to adjacent carbon atoms, and the two RA groups taken together, form -O-(G)y_O-; wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; such as, for example A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5-yl. [0017] Embodiment (6): In another embodiment, the compound of Formula (I) is that where when RA is present, each RA is independently R^, Ci-C6 alkyl, C1-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C6 alkyl-RA2, wherein the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (5). In subembodiment (6-a), the compound of Formula (I) is that where when RA is present, each RA is independently halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, benzyl, -ORA1, -N(RA1)2, or -C(O)RA1, wherein each RA1 is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-; each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (5).
[0018] Embodiment (7): In another embodiment, the compound of Formula (I) is that where R20 is -RB2, hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aiyl(C1-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3, -S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3, -C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or -N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments (1) - (6). In subembodiment (7-a), the compound of Formula (I) is that where R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(CrC4)alkyl, or -C1-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments (1) - (6). In subembodiment (7-b), the compound of Formula (I) is that where R20 is hydrogen, Ci-C4 alkyl, -ORB3, or -N(RB3)2, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments (1) - (6).
[0019] Embodiment (8): In another embodiment, the compound of Formula (I) is that where R1 is: (i) -N(R10XR11), wherein R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -C1-C6 alkyl-N(R12)2, or -C1-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups; or R1 is (ii) a moiety of formula (a),
Figure imgf000010_0001
and all other groups are as defined in any one of embodiments (1) - (7). In subembodiment (8-a), the compound of Formula (I) is that where R1 is: (i) -N(R10XR11), wherein R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and R13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl is optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, or-N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000010_0002
R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2; and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (7). In subembodiment (8-b), the compound of formula (I) is that of subembodiment (8), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7). In subembodiment (8-c), the compound of formula (I) is that of subembodiment (8-a), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7). [0020] Embodiment (9): In another embodiment, the compound of Formula (I) is that where R1 is:
(i) -N(R10XR11X wherein R10 is hydrogen or methyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000011_0001
wherein ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is
Figure imgf000011_0003
wherein t is 1, 2, or 3; and r is 0, 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (8).
[0021] Embodiment (10): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10)(Rπ) or a moiety of formula (a):
Figure imgf000011_0002
wherein
(a) ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; wherein R20 is hydrogen, -ORB3, -N(RB3)2, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2, and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl; (b) the moiety of formula (a) is
Figure imgf000012_0001
, wherein t is 1 , 2, or 3, R20 is hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein RB2 is -ORB3 or -N(RB3)2, and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl; or
(c) the moiety of formula (a) is
Figure imgf000012_0002
, wherein r is 0, 1, 2, or 3, R20 is -N(RB3)2 or -Ci-C4 alkyl-N(RB3)2; and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (9).
[0022] Embodiment (11): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000012_0003
wherein ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; and R10, R11, w, R20, R21, and all other groups are as defined in any one of embodiments (I) - (IO). In subembodiment (11-a), R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein ring B is 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, or l-azabicyclo[2.2.2]oct-3-yl and R10, R11, w, R20, R21, and all other groups are as defined in any one of embodiments (1) - (10). [0023] Embodiment (12): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a) wherein said moiety of formula (a) is
Figure imgf000012_0004
, wherein t is 1, 2, or 3; and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (10). In subembodiment (12-a), R1 is -N(R10)(Rπ) or a moiety of formula (a) wherein ring B is piperazin-1-yl or 1,4-diazepan-l-yl; and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (I) - (IO). In subembodiment (12-b), R1 is -N(R10XR11) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4- methyl- 1,4-diazepan-l-yl, piperazin-1-yl, 4-(l-methylethyl)-piperazin-l-yl, 4-(2- fluoroethyl)piperazin-l-yl, or 4-ethylpiperazin-l-yl; and R10, R11, and all other groups are as defined in any one of embodiments (1) - (9).
[0024] Embodiment (13): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR1 J) or a moiety of formula (a),
wherein said moiety of formula (a) is
Figure imgf000013_0001
, wherein r is 0, 1, 2, or 3; and R10, R11, R20,
R21, w, and all other groups are as defined in any one of embodiments (I) - (IO). In subembodiment (13-a), R1 is -N(R10XR11) or a moiety of formula (a), wherein ring B is azetidin- 1-yl, pyrrolidin-1-yl, or piperidin-1-yl and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (10). In subembodiment (13-b), R1 is -N(R10)(Rπ) or 3 -(dimethylamino)azetidin- 1 -yl, 3 -(dimethylamino)pyrrolidin- 1 -yl, 3 -aminoazetidin- 1 -yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3-aminopiperidin-l-yl, 4- aminopiperidin- 1 -yl, 3 -(methylamino)pyrrolidin- 1 -yl, 4-(methylamino)piperidin- 1 -yl, (l-methylethyl)amino-piperidinyl, or 4-hydroxypiperidin-l-yl, and R10, R11, and all other groups are as defined in any one of embodiments (1) - (9).
[0025] Embodiment (14): In another embodiment, the compound of Formula (I) is that where L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (13). In subembodiment (14-a), the compound of Formula (I) is that where L is -[C(RL)2]p-L1-[C(RL)2]q-,wherein/? is 1 or 2; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (1) - (13). [0026] Embodiment (15): In another embodiment, the compound of Formula (I) is that
where R1 is a moiety of formula (a) ,
Figure imgf000014_0001
(a); and ring B, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (14).
[0027] Embodiment (16): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (14). In sub-embodiment (16-a), the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is R13, wherein R13 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein said azetidinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
[0028] Embodiment (17): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (14). In subembodiment (17-a) , the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is R13, wherein R13 is 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8- yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept-2-yl are optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
[0029] Embodiment (18): In another embodiment, the compound of Formula (I) is that where when R13A is present, each R13A group is independently halogen, cyano, nitro, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, C1-C4 alkyl, Ci -C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and all other groups are as defined in any one of embodiments (1) - (14), (16), and (17). In subembodiment (18-a), the compound of Formula (I) is that where when R13A is present, each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, or -N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and all other groups are as defined in any one of embodiments (1) - (14), (16), and (17).
[0030] Embodiment (19): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR1 J) or a moiety of formula (a), wherein R11 is -C1-C6 alkyl-N(R12)2 or -C3-C6 CyClOaUCyI-N(R12)2; and all other groups are as defined in any one of embodiments (I) - (14). In subembodiment (19-a), the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is -Ci-C3 alkyl-N(R12)2 or -C3-C6 cycloalkyl-N(R12)2; each R12 is independently hydrogen or -C1-C3 alkyl; and all other groups are as defined in any one of embodiments (1) - (14). In subembodiment (19-b), the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)- 1 -methylethyl,
2-(ethylamino)ethyl, 2-(diethylamino)ethyl, 2-(diethylamino)-l -methylethyl, 3-aminopropyl, 3 -(methylamino)propyl, 3 -(dimethylamino)propyl, 3 -(ethylamino)propyl,
3-(diethylamino)propyl, 2-amino-2-methylpropyl, 3-(dimethylamino)-2,2-dimethylpropyl, 3-(diethylamino)-2,2-dimethylpropyl, 2-aminocyclohexyl, 3-aminocyclohexyl, or 4-aminocyclohexyl; and all other groups are as defined in any one of embodiments (1) - (14). [0031] Embodiment (20): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11); and R10, R11, and all other groups are as defined in any one of embodiments (1) - (6), (9), (14), and (16) - (19).
[0032] Embodiment (21): In another subembodiment, the compound of Formula (I) is that where each R3 is independently halogen, cyano, nitro, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, -ORC1, -N(RC1)2, -C(O)RC1, -S(O)RC1, -S(O)2R01, -S(O)N(RC1)2, -S(O)2N(RC1)2, -C(O)ORC1, -C(O)N(RC1)2, -N(RC1)C(O)RC1, -N(RC1)C(O)ORC1, -N(RC1)C(O)N(RC1)2, or -N(RC1)S(O)2RC1, wherein each RC1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two R3 taken together with the ring atoms to which they are attached form an aryl, heteroaryl, a monocyclic cycloalkyl, or a heterocyclyl, each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or C1-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (20). In subembodiment (21 -a), the compound of Formula (I) is that where each R is halogen, C1-C4 alkyl, Ci-C4 haloalkyl, or -OR , wherein each R is independently hydrogen, Ci-C4 alkyl, or
Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (20). In subembodiment (21-b), the compound of Formula (I) is that where m is 1, 2, or 3; and R3 is halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, or -ORC1, wherein each RC1 is independently hydrogen,
Ci-C4 alkyl, or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments
(I) - (20).
[0033] Embodiment (22): In another embodiment, the compound of Formula (I) is that where w is zero or 1, and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (15) and (21).
[0034] Embodiment (23): In another embodiment, the compound of Formula (I) is that where L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH2-O-, -CH2CH2-O-, or
-CH2-O-CH2-; and all other groups are as defined in any one of embodiments (1) - (22).
[0035] Embodiment (24): In another embodiment, the compound of Formula (I) is that where L is Ci -C3 alkylene; and all other groups are as defined in any one of embodiments (1) -
(23).
[0036] Embodiment (25): In another embodiment, the compound of Formula (I) is that
which is a compound of formula (Ia),
Figure imgf000016_0001
(Ia) ; and all other groups are as defined in any one of embodiments (1) - (24).
[0037] Embodiment (26): In another embodiment, the compound of Formula (I) is that
which is a compound of formula (Ib),
Figure imgf000016_0002
(Ib); and all other groups are as defined in any one of embodiments (1) - (24).
[0038] Embodiment (27): In another embodiment, the compound of Formula (I) is that which is a compound listed in Table 1. [0039] Embodiment (28): In another embodiment, the compound of Formula (I) is that where A is C3-C8 cycloalkyl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (3) and (6) - (27).
[0040] Embodiment (29): In another embodiment, the compound of Formula (I) is that where m is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (28). [0041] Embodiment (30): In another embodiment, the compound of Formula (I) is that where L is -CH2-; and all other groups are as defined in any one of embodiments (1) - (29). [0042] When R1 is a moiety of formula (a),
Figure imgf000017_0001
(a)
"ring B in the definition of R1" is (i) a heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or (ii) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl. "Ring B" refers to the annular atoms which together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring. Thus, when ring B is, for example, piperazinyl, R1 is a piperazinyl ring substituted with R20 and (R21)w, wherein R20, R21, and w are as defined herein. Similarly, when ring B is a 4 - 10 membered monocyclic heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, R1 is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl and the like, wherein the 4 - 10 membered monocyclic heterocyclyl ring is substituted with R20 and (R21)w, wherein R20, R21, and w are as defined herein. [0043] Embodiment (31): In another embodiment, the compound of Formula (I) is that where when R1 is a moiety of formula (a), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, 8-azabicyclo[3.2.1]octyl, l-azabicyclo[2.2.2]oct-3-yl,
3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, l-azabicyclo[2.2.2]octyl,
2,6-diazaspiro[3,3]heptyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, or 1,7- diazaspiro[4.4]nonyl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-a), ring B is a 7 - 10 membered fused-bicyclic heterocyclyl ring, optionally comprising one, two, or three additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-b), ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-c), ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-d), ring B is a 5 or 6 membered heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-e), ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30). In subembodiment (31-f), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
[0044] Embodiment (32): In another embodiment, the compound of Formula (I) is that where L is -(CH2)p-L1-(CH2)q- , wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31). In subembodiment (32-a), L is -CH2O(CH2)q-. In subembodiment (31-b), L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-O-, -CH2CH2-O-, or -CH2-O-CH2-; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31).
[0045] Embodiment (33): In another embodiment, the compound of Formula (I) is that where A is
Figure imgf000019_0001
and each RA is independently halogen, Ci -C4 alkyl, Ci-C4 haloalkyl, or -ORA1, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-; wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) -(3), (5) - (27), and (29) - (32).
[0046] The invention also comprises as another embodiment, a pharmaceutical composition comprising a GCS modulator compound according to any one of the preceding embodiments and a pharmaceutically acceptable excipient, diluent, or carrier. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
[0047] The invention also comprises as another embodiment a method for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention (supra). [0048] Diseases and disorders mediated by GCS or implicated by GCS include, but are not limited to cancers, and metabolic disorders. Examples of cancers which may be modulated by a compound or composition of the invention include, but are not limited to, cancers in which glycolipid synthesis is abnormal, for example, breast cancer, renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinal cancer, pancreas and prostrate cancer. Thus, the invention also comprises as another embodiment a method for treating cancer, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
[0049] Examples of metabolic diseases and disorders mediated by GCS or implicated by GCS include but are not limited to, Tay Sachs, Sandhoffs, GMl gangliosidosis, atherosclerosis, polycystic kidney disease, renal hypertrophy, rheumatoid arthritis, Crohn's disease, asthma, sepsis, diabetes mellitus, and obesity; and lysosomal storage diseases such as, for example Fabry diseases, and Gaucher disease. Thus, the invention further comprises as another embodiment a method for treating metabolic disorders, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
[0050] The invention also comprises as another embodiment a method for inducing decreased GCS catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any of the preceding embodiments. [0051] The invention also comprises as another embodiment, use of a GCS modulator of any of the preceding embodiments of the invention for the preparation of a medicament for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment.
Pharmaceutical Formulations and Dosage Forms
[0052] Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[0053] The compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
[0054] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0055] If desired, a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
[0056] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. [0057] Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. [0058] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated. [0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.
[0060] Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0061] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[0062] Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[0063] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[0064] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
[0065] Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[0066] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about
75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
[0067] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack
Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
[0068] The compounds of this disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
[0069] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents. Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s). Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents. [0070] If formulated as a fixed dose, such combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
Definitions
[0071] Terms used herein may be preceded and/or followed by a single dash, "-", or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, Ci-Cβalkoxycarbonyloxy and
-OC(O)OC i-Cβalkyl indicate the same functionality.
[0072] If a group "R" is depicted as "floating" on a ring system, as for example in the formula:
Figure imgf000025_0001
then, unless otherwise defined, a substituent "R" can reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
[0073] If a group "R" is depicted as floating on a heterocyclic ring system, as for example in the formulae:
Figure imgf000025_0002
then, unless otherwise defined, a substituent "R" can reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, "X" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the "R" group can reside on either the 5-membered or the 6- membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two "R's" can reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
[0074] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the formula:
Figure imgf000025_0003
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" can reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon).
[0075] Certain variables used herein are indicated as divalent linking moieties, for example, L is a divalent moiety linking A to the parent structure. For such divalent variables, particular members defining L may be written, for example, in the form -X-Y- or -Y-X-. Such members are intended to replace the term being defined, in this case L, as written, such that the leading (left) bond is attached to the parent moiety and the ending (right) bond is attached to A. For example, if L is of the form -X-Y-, the X is bonded to the parent moiety and Y is bonded to A. [0076] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound of the invention into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents. [0077] "Alkoxy" means the group -OR0 wherein R0 is alkyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like. [0078] "Alkyl" means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. (Ci_C4)alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl and tert-butyl.
[0079] "Aryl" means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms. The monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic. The polycyclic aryl radical includes fused, bridged, and spiro ring systems. Any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic aryl radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, benzodioxolyl, benzodioxanyl, benzopyranyl, 2,3-dihydro-lH-indolyl
(including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yl, and the like), phthalimidyl, and the like.
[0080] "(Ci-C4)alkyl" an aryl moiety attached to a parent structure via a one-to-four carbon alkylene group. Examples include benzyl, phenethyl, and the like.
[0081] "Bridged-bicyclic heterocyclyl ring" refers to a heterocyclyl ring system in which a valence bond, an atom, or a chain of atoms connects two or more non-adjacent positions of a heterocyclyl ring system. Such a system may contain isolated or conjugated unsaturation, but not aromatic or hetero aromatic rings in its core structure (but may have aromatic substitution
thereon), such as
Figure imgf000027_0001
wherein x is an integer of
1 to 3; and y is an integer of 1 to 3. Examples of 5 - 10 membered bridged-bicyclic heterocylyl rings include 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3- yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl, and the like.
[0082] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms. The cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The cycloalkyl radical includes fused bicyclic, bridged bicyclic and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octanyl. [0083] "Fused-bicyclic" refers to a bicyclic ring system where two rings have more than one shared atom in their ring structures, where each bond is part of a ring, where each ring is ortho- fused to the other ring; and where no bond is common to more than two rings. A spiro ring system is not a fused-bicyclic by this definition, but fused bicyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms.
[0084] "Halo" and "halogen" mean a fluoro, chloro, bromo or iodo group. [0085] "Haloalkyl" means an alkyl radical, as defined herein, substituted with one or more halo atoms. For example, halo-substituted (Ci_4)alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like. Haloalkyl includes, for example, halomethyl which means a methyl group substituted by one, two, or three halogen atoms, where each halogen is independently selected. Halomethyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, chlorofluoromethyl, and the like. [0086] "Heteroaryl" means a monovalent monocyclic or polycyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms. The monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic, where the aromatic ring contains at least one heteroatom. The polycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Unless stated otherwise, Any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic heteroaryl radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, isoindolyl, benzimidazolyl, benzo furanyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl, pyrrolo[3,2-c]pyridin-7-yl, and the like), thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the TV-oxide derivatives thereof. [0087] "Heterocyclyl" means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example, 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. The heterocyclyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring. The heterocyclyl radical includes monocyclic, fused-bicyclic, bridged-bicyclic, and spiro-bicyclic ring systems. Unless otherwise stated, the heterocyclyl may be attached at any annular or bridge carbon or heteroatom which results in the creation of a stable structure. More specifically the term heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2,3,3a,7a-tetrahydro-lH-isoindolyl, and tetrahydropyranyl, and the TV-oxide derivatives thereof. [0088] The term "optionally substituted" means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more substituents, only sterically practical and/or synthetically feasible compounds are meant to be included.
[0089] "Spiro ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
Figure imgf000029_0001
a ring atom of a saturated bridged ring system (rings C and C), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto. A representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl. [0090] "Stereoisomer" means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms. "Stereoisomer" includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer. The names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof. [0091] The present invention also includes N-oxidc derivatives of the compounds of the invention. JV-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N→O), e.g., pyridine iV-oxide, and which possess the desired pharmacological activity.
[0092] "Patient" and "subject" for the purposes of the present invention include humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
[0093] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66:1-19 both of which are incorporated herein by reference. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it. [0094] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid and the like.
[0095] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[0096] "Effective amount" is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease. The amount of a compound of the invention which constitutes an "effective amount" will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought. The effective amount for a given circumstance can be determined without undue experimentation. [0097] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapeutically active ingredients and the severity of the disease for which the therapeutic effect is sought may be necessary, and will be ascertainable with routine experimentation.
Synthesis [0098] The following abbreviations and acronyms are used herein,
BnNH2 Benzylamine
BOC t-butoxycarbonyl
BOC-anhydride di(t-butyl) dicarbonate
BzI benzyl
CHAPS 3 -[(3 -cholamidopropyl)dimethylammonio] - 1 -propanesulfonate
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIEA diisopropyl(ethyl)amine
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DOPC dioleoyl phosphatidylcholine
EDC 1 - [3 -(dimethylamino)propyl] -3 -ethylcarbodiimide methiodide
Et3N triethylamine
Et2O diethyl ether
EtOH ethanol
EtOAc Ethyl acetate
HATU Λ/,Λ/,Λf',Λf '-tetramethyl-0-(7-azabenzotriazol- 1 -yl)uronium hexafluorophosphate
HEPES 4-(2-hydroxy ethyl)- 1 -piperazineethanesulfonic acid
HOBt 1 -hydroxybenzotriazole
MeBnBr 3-methylbenzyl bromide
MeCN Acetonitrile
MeOH methanol
MsCl Methylsulfonyl chloride
NADH Nicotinamide adenine dinucleotide
NMM N-methylmorpholine
THF tetrahydrofuran
UDP-glucose Uridine diphosphate glucose
COMPOUND SYNTHESIS: [0099] The following examples serve to provide further appreciation of the invention, but are not meant in any way to restrict the effective scope of the invention.
[00100] Compounds of the invention were synthesized by the synthetic route outlined in Scheme 1, starting with commercially available suitably functionalized Boc amino acid derivatives (1) or other Boc protected amino acid. Thus, Boc protected amino acid (1) was coupled with a suitably functionalized amine. The coupling reaction was typically carried out in the presence l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give an amide (2). The resulting amide (2) was then converted to a corresponding 2-amino-amide (3) by the de- protection reaction performed under acidic conditions. Subsequently, 2-amino-amide (3) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1- dimethylcarboxylic acid. The coupling reaction was typically carried out in the presence of EDC and HOBt to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (4); a compound of formula (I)-
Scheme 1.
Figure imgf000033_0001
(1) (2) (3)
Figure imgf000033_0002
(4)
(3) wherein L, A, R > 2 , R , and m are defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a) ,
Figure imgf000033_0003
wherein R20, R21, and w are as defined herein.
[00101] Alternatively, the synthesis was carried out as outlined on Scheme 2. Suitably functionalized Boc protected amino acid derivatives (1) were converted to a corresponding amino-ester hydrochloride (5) by de-protection-esterification reaction performed under acidic conditions.
Scheme 2.
Figure imgf000034_0001
(1) (5) (6)
Figure imgf000034_0002
(7) W wherein L, A, R2, R3, and m are defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a) ,
Figure imgf000034_0003
wherein R20, R21, and w are as defined herein.
[00102] The subsequent coupling reaction with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1-dimethylcarboxylic acid was typically carried out in the presence of 2-(lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU, Applied Biosystems) to give an intermediate (6). Hydrolysis of ester (6) was typically carried out under Basic conditions. The resulting carboxylic acid (7) was then coupled with suitably functionalized amines in the presence of 2- (lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU, Applied Biosystems), to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (8), a compound of formula (I). In certain examples, it was followed by the de -protection reaction performed under acidic conditions.
[00103] Compounds of the invention were alternatively synthesized by the synthetic route outlined in Scheme 3. Thus, commercially available hydroxysuccinimide esters (9) were coupled with a suitably functionalized amines, followed by the de -protection reaction carried under acidic conditions to give an amine (11). Scheme 3.
Figure imgf000035_0001
(9) (10) (11 ) (12) wherein L, RA, R2, R3, and m are defined herein, n is 0, 1, 2, or 3, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a) ,
Figure imgf000035_0002
wherein R20, R21, and w are as defined herein.
[00104] Subsequently, amine (11) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1-dimethylcarboxylic acid. The coupling reaction was typically carried out in the presence of O-(7-Azabenzotriazole-l-yl)-N, N,N'N'- tetramethyluronium hexafluorophosphate (HATU, Novabiochem) to give 2-(2-Aryl carboxamide)-3-Aryl-propanylamide (12), a compound of formula (I).
[00105] Thus, the invention further comprises a method of preparing a compound of formula (I), the method comprising:
(i) coupling a compound of formula (13),
Figure imgf000036_0001
(13) (14) (D wherein A and L are as defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a) ,
Figure imgf000036_0002
wherein R20, R21, and w are as defined herein; with a compound of formula (14), wherein R2, R3 and m are as defined herein, to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof; or (ii) coupling a compound of formula (15),
Figure imgf000036_0003
wherein A, L, R2, R3 and m are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (16) wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a) ,
Figure imgf000036_0004
wherein R20, R21, and w are as defined herein; to provide a compound of formula (I); and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
Example 1 l-(2,4-dichlorophenyl)-N-[(2S)-3-(lH-indol-3-yl)-l-(4-methylpiperazin-l-yl)-l-oxopropan-
2-yl] cyclopropanecarboxamide
Figure imgf000037_0001
[00106] Step 1: (S)-2-amino-3-(lH-indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one:
(S)-2,5-dioxopyrrolidin-l-yl 2-(tert-butoxycarbonylamino)-3-(lH-indol-3-yl)propanoate
(Advanced Chemtech, 803 mg, 2 mmol) was dissolved into dry acetonitrile (10 mL). N-methylpiperazine (233 μL, 2.1 mmol) was added and the solution stirred for two hours. A complete reaction was indicated by LCMS analysis. A 4N solution of hydrochloric acid in dioxane (2 mL) was added and the solution stirred overnight. A precipitate was formed that was filtered off and washed with acetonitrile. LCMS analysis of the solid indicated it to be (S)-2- amino-3-(lH-indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one, presumably as the dihydrochloride salt. After drying under vacuum, 690 mg of the title compound was obtained (1.92 mmol of the mono hydrochloride salt). This material was used in the next step without further purification.
[00107] Step 2: (l-(2,4-dichlorophenyl)-N-[(2S)-3-(lH-indol-3-yl)-l-(4-methylpiperazin- l-yl)-l-oxopropan-2-yl]cyclopropanecarboxamide: To a solution of (S)-2-amino-3-(lH- indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one dihydrochloride (690 mg, 1.92 mmol) and Hunig's base (1.64 mL, 9.6 mmol) in dry acetonitrile (10 mL) was added l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Acros, 443 mg, 1.92 mmol). HATU (Applied Biosystems, 802 mg, 2.11 mmol) was added and the reaction solution stirred overnight. The product was isolated by reverse-phase preparative HPLC (aqueous ammonium acetate buffer solution, pH ~ 4-5, acetonitrile; 20-70% eluant gradient). Pure product containing fractions were collected, combined, concentrated and lyophilized to obtain (l-(2,4-dichlorophenyl)-N-[(2S)-3- ( 1 H-indol-3 -yl)- 1 -(4-methylpiperazin- 1 -yl)- 1 -oxopropan^-yljcyclopropanecarboxamide (466 mg). NMR (400MHz, DMSO-d6): δ 10.84 (s, IH), 7.61 (d, IH), 7.41(d, IH), 7.35 (m, 2H), 7.31 (d, IH), 7.04 (t, IH), 7.01 (d, IH), 6.85 (t, IH), 6.68 (d, IH), 5.93 (dd, IH), 3.25 (bs, 3H), 3.08 (b, IH), 2.95 (m, 2H), 2.17 (b, IH), 2.09 (b, IH), 2.05 (s, 3H), 1.94 (b, IH), 1.70 (b, IH), 1.45 (b, 2H), 0.97 (m, 2H); MS (EI) for C26H28Cl2N4O2, found 499.00(MH+). [00108] The following compounds were made in a manner analogous to Example 1. [00109] l-(2,4-dichlorophenyl)-N-[(lS)-2-[3-(dimethylamino)azetidin-l-yl]-l-(lH-indol- 3-ylmethyl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 10.87 (d, IH), 7.60 (dd, IH), 7.46 (dd, IH), 7.42 - 7.36 (m, 2H), 7.33 (dd, IH), 7.03 (m, 3H), 6.60 (dd, IH), 4.57 - 4.39 (m, IH), 3.96 (t, IH), 3.80 (m, IH), 3.69 - 3.51 (m, 2H), 3.38 (m, IH), 2.98 - 2.91 (m, 2H), 1.98 (s, 3H), 1.90 (s, 3H), 1.48 (m, 2H), 1.12 - 0.85 (m, 2H). MS (EI) for C26H28Cl2N4O2, found 500.4 (MH+).
[00110] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-L-tryptophanamide: 1H NMR (400MHz, DMSO-d6): δ 10.81 (s, IH), 7.72 (t, IH), 7.58 (d, IH), 7.43 (d, IH), 7.36 (dd, IH), 7.31 (d, 2H), 7.10 - 7.01 (m, IH), 7.01 - 6.90 (m, 2H), 6.40 (d, IH), 4.45 (dd, IH), 3.20 - 2.84 (m, 4H), 2.18 (t, 2H), 2.11 (s, 6H), 1.43 (d, 2H), 0.99 (d, 2H). MS (EI) for C25H28Cl2N4O2, found 488.4 (MH+).
[00111] l-(2,4-dichlorophenyl)-N-[(lS)-l-(lH-indol-3-ylmethyl)-2-(4-methyl-l,4- diazepan-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, IH), 7.62 (d, IH), 7.44 (dd, IH), 7.39 (d, 2H), 7.32 (d, IH), 7.07 - 6.93 (m, 3H), 6.70 (dd, IH), 4.94 (dt, IH), 3.32 - 3.27 (m, 2H), 3.19 (dd, IH), 3.07 - 2.82 (m, 2H), 2.41 - 2.15 (m, 3H), 2.09 (d, 4H), 2.03 - 1.92 (m, IH), 1.61 (s, IH), 1.47 (s, 3H), 1.00 (d, 2H). MS (EI) for C27H30Cl2N4O2, found 514.5 (MH+).
[00112] l-(2,4-dichlorophenyl)-N-[(lS)-l-(lH-indol-3-ylmethyl)-2-oxo-2-piperazin-l- ylethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, IH), 8.24 (s, IH), 7.63 (d, IH), 7.44 (d, IH), 7.41 - 7.34 (m, 2H), 7.32 (d, IH), 7.05 (dd, IH), 7.02 (d, IH), 6.97 (dd, IH), 6.72 (d, IH), 4.94 (dd, IH), 3.27 (d, J = 3.9Hz, 3H), 3.11 (s, IH), 3.02 - 2.87 (m, 2H), 2.67 - 2.52 (m, IH), 2.46 (s, IH), 2.23 (s, IH), 1.55 - 1.40 (m, 2H), 1.07 - 0.93 (m, 2H). MS (EI) for C25H26Cl2N4O2, found 486.4 (MH+).
[00113] l-(2,4-dichlorophenyl)-N-[(lS)-l-(lH-indol-3-ylmethyl)-2-morpholin-4-yl-2- oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 10.87 (s, IH), 7.66 - 7.62 (m, IH), 7.44 (d, IH), 7.39 (d, 2H), 7.33 (d, IH), 7.11 - 7.02 (m, 2H), 7.02 - 6.93 (m, IH), 6.74 (d, IH), 5.03 - 4.81 (m, IH), 3.33 - 3.20 (m, 5H), 3.12 (m, 2H), 3.02 - 2.92 (m, 2H), 2.90 - 2.78 (m, IH), 1.57 - 1.39 (m, 2H), 1.01 (m, 2H). MS (EI) for C25H25Cl2N3O3, found 487.4 (MH+).
[00114] l-(2,4-dichlorophenyl)-N-[(lS)-2-{4-[3-(dimethylamino)propyl]piperazin-l-yl}-l- (lH-indol-S-ylmethylJ-l-oxoethyllcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 10.86 (s, IH), 7.65 - 7.60 (m, IH), 7.42 (dd, IH), 7.39 - 7.37 (m, 2H), 7.32 (d, IH), 7.05 (dd, IH), 7.01 (d, IH), 6.99 - 6.94 (m, IH), 6.68 (d, IH), 4.94 (q, IH), 3.26 (s, 4H), 2.95 (qd, 2H), 2.23 (dd, 2H), 2.16 (s, 2H), 2.15 (s, 6H), 2.10 (d, 2H), 1.96 (d, IH), 1.70 (d, IH), 1.53 - 1.41 (m, 4H), 1.01 (d, 2H). MS (EI) for C30H37 Q2N5O2, found 571.6 (MH+). [00115] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(l-methylpiperidin-4- yl)-L-tryptophanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, IH), 7.55 - 7.51 (m, IH), 7.40 (dd, IH), 7.33 - 7.36 (m, 2H), 7.32 (d, IH), 7.05 (dd, IH), 7.01 (d, IH), 6.99 - 6.94 (m, IH), 6.68 (d, IH), 4.94 (q, IH), 3.60 (m, IH), 3.11 (m, 2H), 2.48 (m, 4H), 2.23 (s, 3H), 2.19 (m, 2H), 2.26 (m, 2H), 1.21 (m, 2H), 1.18 (m, 2H). MS (EI) for C27H30Cl2N4O2, found 514.5 (MH+). [00116] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[3-(dimethylamino)- propyl]-L-tryptophanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.79 (d, IH), 7.88 - 7.80 (m, IH), 7.55 (t, IH), 7.42 (d, IH), 7.35 (dd, IH), 7.33 - 7.27 (m, 2H), 7.03 (ddd, IH), 6.94 (ddd, IH), 6.89 (d, IH), 6.34 (t, J = 13.1 Hz, IH), 4.48 - 4.33 (m, IH), 2.99 - 2.88 (m, 4H), 2.20 (t, 2H), 2.14 (s, 6H), 1.49 -1.36 (m, 4H), 1.02 - 0.90 (m, 2H). MS (EI) for C26H30Cl2N4O2, found 502.5 (MH+).
[00117] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-tryptophanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, IH), 7.88 (d, IH), 7.57 (s, IH), 7.42 (d, IH), 7.32 (m, 3H), 7.02 (t, IH), 6.94 (m, 2H), 6.38 (d, IH), 4.50 (m, IH), 3.55 (m, IH), 2.93 (m, 3H), 2.63 (m, 4H), 2.21 (m, IH), 1.68-1.41 (m, 6H), 1.26 (m, IH), 0.97 (m, 2H). MS (EI) for C28H30Cl2N4O2, found 526(MH+). [00118] l-(4-chlorophenyl)-N-[(lS)-l-(lH-indol-3-ylmethyl)-2-(4-methylpiperazin-l-yl)- 2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, IH), 7.38 (d, IH), 7.32 (m, 3H), 7.20 (m, 2H), 7.04 (t, IH), 6.96 (m, 2H), 6.58 (d, IH), 4.91 (m, IH), 3.26 (s, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.10-1.69 (m, 4H), 2.02 (s, 3H), 1.32 (m, 2H), 0.95 (m, 2H). MS (EI) for C26H29ClN4O2, found 466(MH+). [00119] N-[(lS)-l-(lH-indol-3-ylmethyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l-[4- (methyloxy)phenyl]cyclopropanecarboxamide: 1U NMR (400 MHz, DMSO-d6): δ 10.88 (s, IH), 7.38 (d, IH), 7.31 (d, IH), 7.14 (d, 2H), 7.04 (t, IH), 6.96 (m, 2H), 6.83 (d, 2H), 6.40 (d, IH), 4.93 (m, IH), 3.73 (s, 3H), 3.23 (s, 2H), 3.13 (m, 2H), 2.93 (m, 2H), 2.11-1.61 (m, 4H), 2.00 (s, 3H), 1.31 (m, 2H), 0.89 (m, 2H). MS (EI) for C27H32N4O3, found 461(MH+).
Example 2
N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l-[4- (trifluoromethyljphenyljcyclopropanecarboxamide
Figure imgf000040_0001
Figure imgf000040_0002
[00120] Step 1: l-(4-(trifluoromethyl)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (1 g, 5.4 mmol, AK Scientific) in tetrahydrofuran (10 rnL) at O0C was added sodium hydride ( 0.4 g, 16.6 mmol). The reaction mixture was stirred at O0C for 5 minutes followed by the addition of 1 ,2-dibromoethane ( 2.6 g, 14.1 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 0 0C for 2 h and 16 h at room temperature, followed by addition of 1 mL of water, and concentration under reduced pressure. The resulting slurry was dissolved in 100 mL of Ethyl Acetate, and extracted with 10 mL of water. The organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in 600 mg (52.6%) of l-(4-(trifluoromethyl)phenyl)cyclopropanecarbonitrile which was used in the next step without further purification. MS (EI) for CnH8F3N, found 212 (MH+).
[00121] Step 2: l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid: To l-(4- (trifluoromethyl)phenyl)cyclopropanecarbonitrile (600 mg, 2.8 mmol) was added 20 mL of 3 N NaOH solution and the reaction mixture was heated to reflux for 18 h, then cooled down to room temperature. The resulting solution was acidified with 1 N HCl to pH3, and extracted with 50 mL of EtOAc. The organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in 400 mg (62%) of l-(4-(trifluoromethyl)phenyl)- cyclopropanecarboxylic acid which was used in the next step without further purification. MS (EI) for CnH9F3O2, found 231 (MH+).
[00122] Step 3: (S)-2-amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (10 g, 29 mmol, Aldrich) in dichloromethane (100 mL) were added N-methylpiperazine ( 1O g, 100 mmol), 1-hydroxybenzotriazole ( 5 g, 33 mmol), N-methylmorpholine ( 20 mL, 182 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.3g, 38 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (2 X 250 mL) and saturated sodium bicarbonate solution (2 X 250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol (100 mL) followed by the addition of 4 N HCl in dioxane (100 mL, Aldrich). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give 11.5g (100%) of (S)-2-amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l-one which was used in the next step without further purification. MS (EI) for C14H19CI2N3O, found 316.3 (MH+).
[00123] Step 4: N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2- oxoethyl]-l-[4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l-one ( 200 mg, 0.63 mmol) in dichloromethane (5 mL) were added l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid (200 mg, 0.86 mmol), 1-hydroxybenzotriazole ( 250 mg, 1.85 mmol), N-methylmorpholine (1 mL, 9.1 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (300 mg, 1.56 mmol). The reaction was stirred at room temperature for 18 hours. The organic solution was extracted with water (2 X 250 mL) and saturated sodium bicarbonate solution (2 X 250 mL), dried with magnesium sulfate, filtered and concentrated in vacuo. The product was then purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM formic acid buffer) to give 24 mg of the title compound. 1H NMR (400MHz, CDCl3): δ 7.65 (d, 2H), 7.50 (d, 2H), 7.36 (d, IH), 7.15 (dd, IH), 7.95 (d, 1 H), 6.09 (d, 1 H), 5.22 (dd, IH), 3.57 (m, IH), 3.48 (m, 2H), 3.30 (m, IH), 2.96 (m, 1H),2.87 (m, IH), 2.34 (m, 3H), 2.24 (s, 3H), 2.06 (m, IH), 1.52 (m, 2H), 1.04 (m, 2H); MS (EI) for C25H26Cl2F3N3O2, found 529.2 (MH+).
[00124] The following compounds were made in a manner analogous to Example 2. [00125] N-[(lS)-l-[(2-chlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(2-chlorophenyl)propanoic acid (PepTech Corp) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.60 (d, IH), 7.43-7.33 (m, 3H), 7.24-7.17 (m, 3H), 6.87 (d, IH), 5.02 (m, IH), 3.44-3.27 (m, 4H), 2.96-2.84 (m, 2H), 2.23-2.10 (m, 7H), 1.37 (m, IH), 1.23 (m, IH), 0.92 (m, 2H); MS (EI) for C24H26Cl3N3O2, found 495.85 (MH+). [00126] l-(2,4-dichlorophenyl)-N-[(lS)-l-{[4-(methyloxy)phenyl]methyl}-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): 58.15, (s, IH), 7.65 (s, IH), 7.43 (s, IH), 6.96 (d, 2H), 6.78 (d, 2H), 6.66 (d, IH), 4.85 (m, IH), 3.72, (s, 3H), 3.32 (m, 4H), 2.76 (m, 2H), 2.20 (m, 2H), 2.13 (s, 3H), 2.05 (m, 2H), 1.42 (m, 2H), 1.01 (m, 2H). MS (EI) for C25H29Q2N3O3: 491.3 (MH+). [00127] N-[(2S)-3-(3-chlorophenyl)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2-yl]-l-(2,4- dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid (PepTech Corp) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.59 (d, IH), 7.39(m, 2H), 7.27 (m, 2H), 7.14 (bs, IH), 7.06 (m, IH), 6.89 (d, IH), 4.88 (m, IH), 3.41 (m, 2H), 3.35 (m, 2H), 2.80 (m, 2H), 2.17 (m, 4H), 2.12 (s, 3H), 1.35 (m, 2H), 0.95 (m, 2H); MS (EI) for C24H26Cl3N3O2, found 495.04 (MH+). [00128] 2-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]-2-methylpropanamide was synthesized in a manner similar to Example 2, wherein iodomethane was substituted for 1,2-dibromoethane, and 2-(2,4- dichlorophenyl)acetonitrile (Aldrich) was substituted for 2-(4-
(trifluoromethyl)phenyl)acetonitrile. 1H NMR (400MHz, CDCl3): δ 7.26 (m, 3H), 7.26 (d, IH), 7.10 (m, IH), 6.96 (d, IH), 5.98 (d, IH), 5.19 (m, IH), 3.62 (m, IH), 3.48 (m, IH), 3.38 (m, IH), 3.17 (m, IH), 3.01 (m, IH), 2.83 (m, IH), 2.30 (m, 2H), 2.20 (s, 3H), 2.01(m, 2H), 1.46 (d, 6H). MS (EI) for C24H27C4N3O2: 532.5 (MH+).
[00129] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(3,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-ylj^-oxoethyljcyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(3,4- dichlorophenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert- butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.61 (d, IH), 7.50 (m, IH), 7.45-7.39 (m, 2H), 7.37 (d, IH), 7.12 (dd, IH), 6.97 (d, IH), 4.93-4.87 (m, IH), 3.46-3.38 (m, 4H), 2.88-2.76 (m, 2H), 2.26-2.15 (m, 7H), 1.41 (m, IH), 1.28 (m, IH), 0.97 (m, 2H); MS (EI) for C24H25Cl4N3O2, found 530.31 (MH+).
[00130] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(4-fluorophenyl)methyl]-2-(4-methylpiperazin- l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 8.17 (s, IH), 7.63 (s, IH), 7.43 (s, IH), 7.08 (m, 4H), 6.81 (d, IH), 4.59 (m, IH), 3.34 (m, 4H), 2.81 (m, 2H), 2.19 (m, 2H), 2.14 (s, 3H), 2.09 (m, 2H), 1.38 (m, 2H), 0.97 (m, 2H); MS (EI) for C24H26Cl2FN3O2, found 479.2 (MH+).
[00131] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, D4-MeOD): δ 7.51 (d, IH), 7.48-7.35 (m, 3H), 7.35 (dd, IH), 7.15 (d, IH), 5.18 (t, IH), 3.78- 3.63 (m, 2H), 3.58-3.44 (m, 2H), 3.05 (dd, IH), 2.96 (dd, IH), 2.78-2.55 (m, 4H), 1.58-1.43 (m, 2H), 1.13-1.10 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 530 (MH+).
[00132] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethyl- amino)ethyl]-L-phenylalaninamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-bromophenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, N^N1- dimethylethane-l,2-diamine (Aldrich) was substituted for N-methylpiperazine, and l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 8.19(s, IH), 7.81 (t, IH), 7.59 (s, IH), 7.39 (m, 4H), 7.01 (d, 2H), 4.42 (m, 2H), 3.11 (m, 2H), 2.80 (m, 2H), 2.24 (m, 2H), 2.14 (s, 6H), 1.37 (m, 2H), 0.95 (m, 2H); MS (EI) for C23H26BrCi2N3O2, found 528.6 (MH+).
[00133] l-(2,4-dichlorophenyl)-N-[(lS)-l-{[4-(ethyloxy)phenyl]methyl}-2-(4-methyl- piperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-ethoxyphenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 8.24 (s, IH), 7.70 (s, IH), 7.17 (m, 4H), 6.92 (m, 2H), 4.91 (m, IH), 4.09 (m, 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 7H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H); MS (EI) for C26H3iCl2N3O3, found 504.5 (MH+).
[00134] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(2,4-dimethylphenyl)methyl] -2-(4-methyl- piperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dimethylphenyl)propanoic acid (PepTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)- propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-de): δ 8.24 (s, IH), 7.73 (s, IH), 7.20 (m, 3H), 7.04 (m, 3H), 4.91 (m, IH), 4.09 (m, 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 8H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H). MS (EI) for C26H3ICl2N3O2, found 488.5 (MH+). [00135] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-l-(naphthalen-2- ylmethyl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(naphthalen-2-yl)propanoic acid (Aldrich) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.84- 7.78 (m, 3H), 7.58-7.43 (m, 3H), 7.39-7.25 (m, 4H), 5.19-5.10 (m, IH), 3.62-3.37 (m, 4H), 3.05 (m, 2H), 2.57-2.40 (m, 2H), 2.35-2.23 (m, IH), 2.18 (s, 3H), 1.83-1.77 (m, IH), 1.60-1.50 (m, 2H), 1.16 (m, IH), 1.00 (m, IH); MS (EI) for C28H29Cl2N3O2, found 511 (MH+). [00136] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(4-methylphenyl)methyl] -2-(4-methyl- piperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-methylphenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.64 (t, IH), 7.42 (d, 2H), 7.03 (d, 2H), 6.94 (d, 2H), 6.69 (d, IH), 4.87 (m, IH), 3.42-3.25 (m, 4H), 2.82-2.70 (m, 2H), 2.25 (s, 3H), 2.20-2.13 (m, 7H), 1.42 (m, 2H), 0.97 (m, 2H); MS (EI) for C25H29Cl2N3O2, found 475.44 (MH+).
[00137] N-[(lS)-l-[(4-bromophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-bromophenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.63 (s, IH), 7.43 (m, 4H), 7.05 (d, 2H), 6.86 (d, IH), 4.90 (m, IH), 3.46-3.33 (m, 4H), 2.86-2.73 (m, 2H), 2.24-2.10 (m, 7H), 1.44-1.34 (m, 2H), 1.01-0.96 (m, 2H); MS (EI) for C24H26BrCl2N3O2, found 540.31 (MH+).
[00138] l-(3,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein l-(3,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-dg): δ 7.60 (d, IH), 7.55 (d, IH), 7.48 (d, 2H), 7.36 (m, IH), 7.23 (d, 2H), 7.19 (d, IH), 4.98 (m, IH), 3.45 (m, 2H), 2.94 (m, 2H), 2.1h (m, 7H), 1.22 (m, IH), 1.10 (m, IH), 0.97 (m, 2H); MS (EI) for C24H25Cl4N3O2, found 529.80 (MH+).
[00139] N-[(lS)-l-[(4-chlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 7.63 (s, IH), 7.40 (s, 2H), 7.26 (d, 2H), 7.09 (d, 2H), 6.83 (d, IH), 4.87 (m, IH), 3.46-3.25 (m, 4H), 2.86- 2.73 (m, 2H), 2.19-2.02 (m, 7H), 1.42-1.29 (m, 2H), 0.98-0.89 (m, 2H); MS (EI) for C24H26Cl3N3O2, found 495.84 (MH+).
[00140] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(2-fluorophenyl)methyl] -2-(4-methylpiperazin- l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(2-fluorophenyl)propanoic acid (Synthetech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and 1- (2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 8.14 (s, IH), 7.60 (d, IH), 7.39 (m, 2H), 7.24 (m, IH), 7.06 (m, 2H), 6.78 (d, IH), 4.94 (m, IH), 3.56 (m, 4H), 2.86 (m, 2H), 2.22 (m, 3H), 2.12 (m, 4H), 1.30 (m, 2H), 0.93 (m, 2H); MS (EI) for C24H26Cl2FN3O2, found 478.4 (MH+).
[00141] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[4- (trifluoromethyl)phenyl] methyl} ethyl] cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4- (trifluoromethyl)phenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonyl- amino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropane- carboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)- cyclopropanecarboxylic acid. 1H NMR (400MHz, DMSO-d6): δ 8.18 (s, IH), 7.61 (d, 3H), 7.41 (s, IH), 7.33 (d, 2H), 6.95 (d, 2H), 4.96( m, IH), 3.40 (m, 4H), 2.93 (m, 2H), 2.17 (m, 2H), 2.13 (s, IH), 2.06 (m, 2H), 1.41 (m, 2H), 1.29 (m, 2H); MS (EI) for C25H26Q2F3N3O2, found 529.5 (MH+). [00142] l-(2,4-dichlorophenyl)-N-[2-(4-methylpiperazin-l-yl)-2-oxo-l-(phenylmethyl)- ethyl]cyclopropane-carboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.51 (d, IH), 7.48-7.35 (m, 3H), 7.35 (dd, IH), 7.15 (d, IH), 5.18 (t, IH), 3.78-3.63 (m, 2H), 3.58-3.44 (m, 2H), 3.05 (dd, IH), 2.96 (dd, IH), 2.78-2.55 (m, 4H), 1.58-1.43 (m, 2H), 1.13-1.10 (m, 2H). MS (EI) for C24H27Cl2N3O2, found 460.402 (MH+).
[00143] l-(2,6-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl] cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.52 (d, IH), 7.48 (m, 2H), 7.39-7.25 (m, 3H), 7.05 (d, IH), 5.04 (m, IH), ), 3.47 (m, 4H), 2.93 (3, 2H), 2.27-2.21 (m, 4H), 2.15 (s, 3H), 1.59 (m, 2H), 1.06 (m, 2H); MS (EI) for C24H25Cl4N3O2, found 529.23 (MH+).
[00144] l-(2,4-dichlorophenyl)-N-{(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-[(3,4,5- trifluorophenyl)methyl] ethyl} cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-dβ): δ 7.57 (d, IH), 7.39 (m, IH), 7.26 (m, IH), 6.88 (m, 2H), 4.89 (q, IH), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H), 0.95 (m, 2H). MS (EI) for C24H24Cl2F3N3O2, found 515.4 (MH+).
[00145] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(3,4-difluorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 8.17 (s, IH), 7.60 (d, IH), 7.42 (dt, 2H), 7.30 (dt, IH), 7.17 (ddd, IH), 6.94 (d, J = 8.2Hz, 2H), 4.94 - 4.80 (m, IH), 3.40 (dd, 4H), 2.81 (qd, 2H), 2.55 - 2.47 (m, IH), 2.20 (t, 4H), 1.51 - 1.21 (m, 2H), 1.02 - 0.90 (m, 2H). MS (EI) for C24H25Cl2F2N3O2, found 497.4 (MH+). [00146] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(4-hydroxyphenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl] cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 9.23 (s, IH), 7.64 (dd, IH), 7.50 - 7.36 (m, 2H), 6.84 (d, 2H), 6.76 - 6.53 (m, 3H), 4.83 (q, IH), 3.31 (m, 4H), 2.69 (m, 2H), 2.16 (m, 3H), 2.13 (s, 3H), 2.09 - 1.98 (m, IH), 1.53 - 1.29 (m, 2H), 1.00 (m, 2H). MS (EI) for C24H27Cl2N3O3, found 477.4 (MH+).
[00147] N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- [3-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, CDCl3): δ 7.51 (m, 4H), 7.35 (s, IH), 7.16 (d, IH), 6.92 (d, IH), 7.03 (d, IH), 6.04 (d, IH), 5.22 (d, IH), 3.46 (m, 4H), 2.99 (dd, IH), 2.84 (dd, IH), 2.37 (m, 2H), 2.31 (s, 3H), 2.14 (m, 2H), 1.52 (m, 2H), 1.05 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 528.4 (MH+). [00148] l-(2-chlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methyl- piperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.54 (m, IH), 7.48-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.21 (d, IH), 6.65 (d, IH), 5.03 (q, IH), 3.47-3.43 (m, 2H), 3.37 (m, 2H), 2.95-2.84 (m, 2H), 2.27-2.15 (m, 2H), 2.13 (s, 3H), 2.07-2.03 (m, IH), 1.86 (s, IH), 1.42-1.38 (m, IH), 1.26-1.22 (m, IH), 0.99-0.91 (m, 2H); MS (EI) for C24H26Cl3N3O2, found 495.92 (MH+).
[00149] N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (4-fluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.54 (d, IH), 7.39-7.36 (m, IH), 7.34-7.30 (m, 2H), 7.20-7.16 (m, 3H), 6.74 (d, IH), 5.03-4.97 (m, IH), 3.48- 3.30 (m, 4H), 2.98-2.93 (m, IH), 2.88-2.83 (m, IH), 2.22-2.17 (m, 3H), 2.13 (s, 4H), 1.24-1.21 (m, IH), 1.12-1.09 (m, IH), 0.91 (d, 2H); MS (EI) for C24H26Cl2FN3O2, found 478.03 (MH+). [00150] N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- [2-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.74-7.68 (m, 2H), 7.59-7.53 (m, 3H), 7.35-7.34 (m, IH), 7.20 (d, IH), 6.51 (d, IH), 5.04-4.99 (m, IH), 3.44-3.34 (m, 4H), 2.92-2.82 (m, 2H), 2.25-2.17 (m, 2H), 2.12 (s, 4H), 2.08-2.03 (m, IH), 1.88 (s, IH), 1.40-1.38 (m, IH), 1.04 (s, 2H); MS (EI) for C25H26Cl2F3N3O2, found 528.17 (MH+).
[00151] N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-difluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.54 (d, IH), 7.42-7.35 (m, 2H), 7.28-7.20 (m, 2H), 7.11-7.06 (m, IH), 7.00 (d, IH), 5.02-4.96 (m, IH), 3.47-3.33 (m, 4H), 2.98-2.84 (m, 2H), 2.25-2.17 (m, 3H), 2.14 (s, 4H), 1.32-1.28 (m, IH), 1.16- 1.13 (m, IH), 0.93 (d, 2H); MS (EI) for C24H25Cl2F2N3O2, found 496.04 (MH+). [00152] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N~2~ {[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-5-phenyl-L-norvalinamide: 1U NMR (400MHz, CD3OD): 7.58 (s, IH), 7.49 (dd, IH), 7.40-7.37 (m, IH), 7.28-7.21 (m, 2H), 7.17-7.10 (m, 3H), 4.40-4.36 (m, IH), 4.05-4.00 (m, IH), 3.57-3.54 (m, IH), 3.22-3.05 (m, 4H), 2.80 (dd, IH), 2.65-2.52 (m, 2H), 2.05-2.02 (m, IH), 2.00-1.83 (m, 3H), 1.80-1.64 (m, 3H), 1.60-1.53 (m, 5H), 1.20-1.14 (m, IH), 1.08-1.00 (m, IH). MS (EI) for C28H33Cl2N3O2, found 514.18 (MH+).
[00153] 4-bromo-N-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanyl-N-[2- (dimethylamino)ethyl]-L-prolinamide: 1U NMR (400MHz, CD3OD): 8.50 (s, IH), 7.53-7.38 (m, 4H), 7.08-7.00 (m, 2H), 4.82 (t, IH), 4.23 (dd, IH), 3.82-3.78 (m, IH), 3.76-3.64 (m, IH), 3.62-3.52 (m, IH), 3.40-3.30 (m, IH), 3.20-3.00 (m, 3H), 2.85-2.80 (m, IH), 2.78 (s, 6H), 2.23- 2.09 (m, 2H), 2.00-1.90 (m, 2H), 1.60-1.50 (m, 2H), 1.10-1.03 (m, 2H). MS (EI) for C28H33BrCl2N4O2, found 624.66 (MH+).
Example 3
2,4-dichloro-N-alpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (dimethylamino)ethyl]-L-phenylalaninamide
Figure imgf000049_0001
[00154] Step 1: (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)propanoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (5 g, 15 mmol, Fluka) in dichloromethane (100 mL) were added 1-hydroxybenzotriazole ( 3 g, 22.5 mmol), N-methylmorpholine ( 16.5 mL, 150 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride ( 4.3g, 22.8 mmol), and Ethyl alcohol ( 13.8 mL, 300 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (25 mL), saturated sodium bicarbonate solution (25 mL), and IN HCl solution (25 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol (25 mL) followed by the addition of 4 N HCl in dioxane (25 mL, Aldrich). The reaction was stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo to give 3.Og (60%) of the title compound which was used in the next step without further purification. MS (EI) for CI IHI3CI2NO2, found 263.16 (MH+).
[00155] Step 2: (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido) propanoate: To a solution of (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)- propanoate ( 3 g, 11.5 mmol) in dichloromethane (100 niL) were added 1-hydroxybenzotriazole (1.8 g, 13.7 mmol), N-methylmorpholine ( 12.6 mL, 115 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride ( 2.6g, 13.7 mmol), and l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid ( 2.7 g, 11.5 mmol, Acros ). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (25 mL), saturated sodium bicarbonate solution (25 mL), and IN HCl solution (25 mL). The layers were separated and the organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo to give 1.5g (50%) of the title compound which was used in the next step without further purification. MS (EI) for C11H19CI4NO3, found 476.5 (MH+). [00156] Step 3: (S)-3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido)-propanoic acid: To a solution of (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxamido) propanoate ( 1.5 g, 3.2 mmol) in 10 mL of MeOH was added 20 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours. The resulting solution was concentrated down under reduced pressure, acidified with 1 N HCl to pH=3, and extracted with 100 mL of EtOAc. The organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in 1.2 g (80%) of the title compound which was used in the next step without further purification. MS (EI) for Ci9Hi5Cl4NO3, found 448.5 (MH+).
[00157] Step 4: 2,4-dichloro-N-alpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N- [2-(dimethylamino)ethyl]-L-phenylalaninamide: To a solution of (S)-3-(2,4-dichlorophenyl)- 2-(l-(2,4-dichlorophenyl)cyclopropane-carboxamido)propanoic acid (70 g, 29 mmol) in dichloromethane (5 mL) were added 1-hydroxybenzotriazole ( 25 mg, 0.19 mmol), N-methylmorpholine ( 0.172 mL, 1.57 mmol), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride ( 36 mg, 0.19 mmol), and N^N^dimethylethane-l^-diamine (16 mg, 0.19 mmol, TCI America). The reaction was stirred at room temperature for 18 hours. The resulting solution was washed with water (25 mL), and saturated sodium bicarbonate solution (25 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was then purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM formic acid buffer) to give 41 mg of the title compound. 1H NMR (400MHz, DMSO-d6): δ 7.59 (m, IH), 7.50 (d, IH), 7.42 (m, 2H), 7.33 (dd, IH), 7.16 (d, IH), 6.73 (d, IH), 4.52 (m, IH), 3.09 (m, 3H), 2.84 (m, IH), 2.27 (t, 2H), 2.16 (s, 6H), 1.37 (m, 2H), 0.95 (m, 2H); MS (EI) for C23H25Cl4N3O2, found 517.3 (MH+). [00158] The following compounds were made in a manner analogous to Example 3. [00159] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (dimethylamino)ethyl]-N-methyl-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein N1,N1,N2-trimethylethane-l,2-diamine (Aldrich) was substituted for N1,N1-dimethylethane-l,2-diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 8.18 (s, IH), 7.58 (d, IH), 7.51 (dd, IH), 7.42 (m, 2H), 7.33 (m, IH), 7.23 (m, IH), 4.99 (m, IH), 3.40 (m, IH), 3.23 (m, IH), 2.95 (s, 3H), 2.86 (m, 2H), 2.27 (m, 2H), 2.13 (s, 6H), 1.37 (m, IH), 1.14 (m, IH), 0.96 (m, IH), 0.89 (m, IH); MS (EI) for C24H27 Ci4N3O2, found 532.4 (MH+). [00160] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(l- methylpiperidin-4-yl)-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein l-methylpiperidin-4-amine (TCI) was substituted for N^N^dimethylethane-l^- diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 8.21 (s, IH), 7.61 (s, IH), 7.50 (d, IH), 7.45-7.40 (m, 2H), 7.33 (dd, IH), 7.15 (d, IH), 6.58 (d, IH), 4.53-4.47 (m, IH), 3.45-3.41 (m, IH), 3.00-2.95 (m, IH), 2.88-2.82 (m, IH), 2.67 (m, 2H), 2.15 (s, 3H), 1.97 (m, 2H), 1.62 (m, 2H), 1.41-1.24 (m, 4H), 0.96 (m, 2H); MS (EI) for C25H27Cl4N3O2, found 544.33 (MH+). [00161] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2- pyrrolidin-l-ylethyl)-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein 2-(pyrrolidin-l-yl)ethanamine (Fluka) was substituted for N^N^dimethylethane-l^- diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 9.18 (s, IH), 7.69 (t, IH), 7.57 (d, IH), 7.50 (d, IH), 7.42 (m, 2H), 7.32 (dd, IH), 7.16 (d, IH), 4.53 (m, IH), 3.15 (m, 2H), 3.03 (m, IH), 2.85 (m, IH), 2.48 (m, 6H), 1.69 (m, 4H), 1.36 (m, 2H), 0.95 (m, 2H); MS (EI) for C25H27Ci4N3O2, found 544.5 (MH+).
[00162] 2,4-dichloro-Nalpha- { [ l-(2,4-dichlorophenyl)cyclopropyl] carbonyl}-N-methyl-N- (l-methylpyrrolidin-3-yl)-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein l-methylpyrrolidin-3-amine (Matrix Scientific) was substituted for N^N1- dimethylethane-l,2-diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 9.18 (s, IH), 7.69 (t, IH), 7.57 (d, IH), 7.50 (d, IH), 7.42 (m, 2H), 7.32 (dd, IH), 7.16 (d, IH), 4.53 (m, IH), 3.15 (m, 2H), 3.03 (m, IH), 2.85 (m, IH), 2.48 (m, 6H), 1.69 (m, 4H), 1.36 (m, 2H), 0.95 (m, 2H); MS (EI) for C25H27Ci4N3O2, found 544.5 (MH+). [00163] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-
(l-methylpiperidin-4-yl)-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein N,l-dimethylpiperidin-4-amine (Matrix Scientific) was substituted for N1,N1-dimethylethane-l,2-diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 7.60 (m, IH), 7.56 (dd, IH), 7.41 (m, 2H), 7.34 (m, IH), 7.21 (m, IH), 4.95 (m, IH), 4.07 (m, IH), 2.88 (m, 2H), 2.75 (s, 3H), 4.47 (m, 4H), 2.12 (s, 3H), 1.86 (m,2H), 1.68 (m,2H), 1.26(m,2H), 0.92 (m,2H); MS (EI) for C26H29Ci4N3O2, found 558.3 (MH+).
[00164] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(3R)-3- (dimethylamino)-pyrrolidin-l-yl]-2-oxoethyl}cyclopropanecarboxamide was synthesized in a manner similar to Example 3, wherein (R)-N ,N-dimethylpyrrolidin-3 -amine (Aldrich) was substituted for N^-dimethylethane-l^-diamine (Aldrich). 1U NMR (400MHz, DMSO-d6): δ 7.59 (s, IH), 7.52 (t, IH), 7.41 (m, 2H), 7.36-7.32 (m, IH), 7.21 (m, IH), 6.96-6.86 (m, IH), 4.79-4.72 (m, IH), 3.54-3.49 (m, IH), 3.44-3.41 (m, 2H), 3.15-3.10 (m, IH), 2.98-2.86 (m, 3H), 2.08 (d, 6H), 2.02-1.93 (m, IH), 1.64-1.49 (m, IH), 1.39-1.35 (m, IH), 1.23-1.18 (m, IH), 0.93 (m, 2H); MS (EI) for C25H27Cl4N3O2, found 544.32 (MH+).
[00165] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(3S)-3- (dimethylamino)-pyrrolidin-l-yl]-2-oxoethyl}cyclopropanecarboxamide was synthesized in a manner similar to Example 3, wherein (S)-N ,N-dimethylpyrrolidin-3 -amine (Aldrich) was substituted for N^-dimethylethane-l^-diamine (Aldrich). 1U NMR (400MHz, DMSO-d6): δ 7.59 (s, IH), 7.52 (t, IH), 7.41 (m, 2H), 7.35-7.32 (m, IH), 7.22-7.19 (m, IH), 6.88 (t, IH), 4.82- 4.74 (m, IH), 3.80-3.69 (m, IH), 3.48-3.45 (m, IH), 3.29-3.23 (m, IH), 3.19-3.12 (m, IH), 2.98- 2.87 (m, 3H), 2.10 (d, 6H), 2.04-1.93 (m, IH), 1.68-1.48 (m, IH), 1.40-1.36 (m, IH), 1.24-1.17 (m, IH), 0.93 (m, 2H); MS (EI) for C25H27Cl4N3O2, found 544.33 (MH+). [00166] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (dimethylamino)-l-methylethyl]-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein N^N^dimethylpropane-l^-diamine (Matrix) was substituted for N^N1- dimethylethane-l,2-diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 7.60 (s, IH), 7.54 (m, 3H), 7.32 (m, IH), 7.19 (m, IH), 4.51 (m, IH), 3.74 (m, IH), 3.06 (m, IH), 2.87 (m, IH), 2.10 (m, 8H), 1.39 (m, IH), 1.25 (m, IH), 1.00 (d, 2H), 0.94 (m, 3H); MS (EI) for C24H27Cl4N3O2, found 531.3 (MH+). [00167] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[l- (phenylmethyl)-piperidin-4-yl]-L-phenylalaninamide was synthesized in a manner similar to Example 3, wherein l-benzylpiperidin-4-amine (Aldrich) was substituted for N^N1- dimethylethane-l,2-diamine (Aldrich). 1H NMR (400MHz, DMSO-d6): δ 7.60 (m, 2H), 7.50 (d, IH), 7.42 (m, 2H), 7.24 (m, 6H), 7.14 (d, IH), 4.49 (m, IH), 3.42 (m, 3H), 2.90 (m, 2H), 2.66 (m, 2H), 1.95 (m, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 1.27 (m, 2H), 0.96 (m, 2H); MS (EI) for C31H31C14N3O2, found 620.6 (MH+).
[00168] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 7.88-7.75 (m, 3H), 7.57-7.43 (m, 3H), 7.40-7.33 (m, 2H), 7.30-7.24 (m, IH), 5.18-5.07 (m, IH), 3.82-3.40 (m, 2H), 3.08-3.00 (m, 2H), 2.55-2.35 (m, 2H), 2.28-2.20 (m, IH), 2.17 (s, 3H), 1.80- 1.70 (m, IH), 1.60-1.48 (m, 2H), 1.17-1.09 (m, IH), 1.06-0.98 (m, IH). MS (EI) for C28H29Cl2N3O2, found 510 (MH+).
[00169] l-(2,4-dichlorophenyl)-N-[(lR)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 7.51 (d, IH), 7.47-7.41 (m, 2H), 7.39-7.35 (m, IH), 7.29-7.23 (m, IH), 7.26 (dd, IH), 7.17-7.13 (d, IH), 5.15 (dd, IH), 3.78-3.60 (m, 2H), 3.60-3.43 (m, 2H), 3.05-2.95 (m, 2H), 2.78-2.60 (m, 3H), 2.58-2.43 (m, 4H), 1.57-1.42 (m, 2H), 1.18-1.01 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 529.68 (MH+).
[00170] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l- (phenylmethyl)ethyl]-cyclo propanecarboxamide: 1H NMR (400MHz, DMSO-d6): 7.51 (s, IH), 7.44-7.34 (m, 2H), 7.30-7.20 (m, 3H), 7.13-7.08 (m, IH), 6.57 (d, IH), 5.09-5.00 (m, IH), 3.64-3.48 (m, 3H), 2.88 (d, 2H), 2.65-2.47 (m, 3H), 2.23-2.15 (m, IH), 1.63-1.52 (m, 2H), 1.18- 1.04 (m, 2H). MS (EI) for C24H27Cl2N3O2, found 461.90 (MH+).
[00171] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-l-(naphthalen-l- ylmethyl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.18 (d, IH), 7.85 (d, IH), 7.80 (d, 2H), 7.60-7.45 (m, 3H), 7.43-7.35 (m, 3H), 7.27 (d, IH), 6.63 (d, IH), 5.25-5.21 (m, IH), 3.58-3.38 (m, 2H), 3.25-3.05 (m, 3H), 2.78-2.65 (m, IH), 2.42-2.37 (m, IH), 2.18-2.01 (m, 4H), 1.97-1.88 (m, IH), 1.65-1.55 (m, 2H), 1.24-1.04 (m, 3H). MS (EI) for C28H29Cl2N3O2, found 509.90 (MH+). [00172] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(8aR)- hexahydropyrrolo-[l,2-a]pyrazin-2(lH)-yl]-2-oxoethyl}cyclopropanecarboxamide:
1H NMR (400MHz, CD3OD): 8.23 (s, IH), 7.53-7.38 (m, 4H), 7.28-7.12 (m, 2H), 5.22-5.13 (m, IH), 4.25 (ddd, 2H), 3.45-3.38 (m, IH), 3.21-3.05 (m, 2H), 3.03-2.78 (m, 4H), 2.58-2.40 (m, 2H), 2.35-2.08 (m, IH), 2.00-1.84 (m, 3H), 1.55-1.43 (m, 3H), 1.13-1.00 (m, 2H). MS (EI) for C26H27Cl4N3O2, found 555.88 (MH+).
[00173] N-l-azabicyclo[2.2.2]oct-3-yl-2,4-dichloro-Nalpha-{[l-(2,4- dichlorophenyl)cyclopropyl]-carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.55 (s, IH), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H), 4.63-4.59 (m, IH), 4.08-3.98 (m, IH), 3.57- 3.46 (m, IH), 3.20-3.00 (m, 6H), 2.85-2.65 (m, IH), 1.97-1.82 (m, 3H), 1.78-1.44 (m, 4H), 1.18- 1.00 (m, 2H). MS (EI) for C26H27Cl4N3O2, found 556.13 (MH+).
[00174] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (diethylamino)-ethyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.24 - 8.02 (m, IH), 7.58 (dd, IH), 7.50 (d, IH), 7.42 (t, IH), 7.40 (s, IH), 7.32 (dd, IH), 7.16 (d, IH), 6.72 (d, IH), 4.52 (td, , IH), 3.11 (td, 2H), 3.02 (ddd, 3H), 2.85 (dd, IH), 2.44 (d, 2H), 2.38 (td, 2H), 1.37 (dd, IH), 1.32 - 1.23 (m, IH), 0.94 (dt, 8H). MS (EI) for C25H29Cl4N3O2, found 546.3 (MH+).
[00175] 2,4-dichloro-Nalpha- { [ l-(2,4-dichlorophenyl)cyclopropyl] carbonyl}-N- [2-(l- methylpyrrolidin-2-yl)ethyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): 8.22 (s, IH), 7.76 (q, IH), 7.62 - 7.54 (m, IH), 7.50 (d, IH), 7.44 - 7.41 (m, 2H), 7.32 (dd, IH), 7.16 (d, IH), 6.64 (dd, IH), 4.50 (tdd, IH), 3.09 - 2.92 (m, 4H), 2.85 (ddd, IH), 2.19 (d, , 3H), 2.13 - 1.96 (m, 2H), 1.93 - 1.77 (m, IH), 1.72 - 1.52 (m, 3H), 1.41 - 1.20 (m, 4H), 1.00 - 0.87 (m, 2H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+).
[00176] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2- piperidin-l-ylethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, IH), 7.63 - 7.54 (m, 2H), 7.50 (d, IH), 7.47 - 7.36 (m, 2H), 7.32 (dd, IH), 7.16 (d, IH), 6.72 (d, IH), 4.52 (td, IH), 3.20 - 2.99 (m, 3H), 2.85 (dd, IH), 2.37 - 2.21 (m, 6H), 1.52 - 1.42 (m, 4H), 1.42 - 1.25 (m, 4H), 1.00 - 0.90 (m, 2H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+). [00177] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[3- (dimethylamino)-propyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.22 (s, IH), 7.76 (t, IH), 7.61 - 7.55 (m, IH), 7.50 (d, IH), 7.42 (s, IH), 7.32 (dd, IH), 7.16 (d, IH), 6.66 (d, IH), 4.50 (td, IH), 3.13 - 2.93 (m, 3H), 2.86 (dd, IH), 2.23 (t, 2H), 2.17 (s, 6H), 1.55 - 1.42 (m, 2H), 1.41 - 1.25 (m, 2H), 0.96 (t, 2H). MS (EI) for C24H27Cl4N3O2, found 532.3 (MH+).
[00178] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(l- ethylpiperidin-3-yl)-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 7.60 (dd, IH), 7.50 (d, IH), 7.48 - 7.42 (m, 2H), 7.40 (dd, IH), 7.33 (dd, IH), 7.15 (d, IH), 6.71 (d, IH), 4.51 (td, IH), 3.02 (dd, IH), 2.90 - 2.80 (m, IH), 2.37 - 2.20 (m, 3H), 1.56 (d, 2H), 1.38 (dd, 2H), 1.29 - 1.07 (m, 2H), 1.03 - 0.87 (m, 6H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+). [00179] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[l- (phenylmethyl)pyrrolidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.16 (s, IH), 7.79 (t, IH), 7.60 - 7.57 (m, IH), 7.51 - 7.48 (m, IH), 7.43 (dddd, 2H), 7.32 - 7.26 (m, 4H), 7.25 - 7.20 (m, IH), 7.12 (dd, IH), 6.60 (d, IH), 4.50 (td, IH), 4.13 - 4.00 (m, IH),
3.54 (d, 2H), 3.02 - 2.78 (m, 2H), 2.64 - 2.50 (m, 2H), 2.38 - 2.25 (m, IH), 2.21 - 1.99 (m, 2H),
1.55 - 1.34 (m, 2H), 1.25 (dd, IH), 1.03 - 0.89 (m, 2H). MS (EI) for C30H29Cl4N3O2, found 606.4 (MH+).
[00180] N-[(lS)-l-[(4-acetylphenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 7.83 - 7.78 (m, 2H), 7.60 (t, IH), 7.40 (d, 2H), 7.21 (d, 2H), 6.87 (t, IH), 4.93 (dd, IH), 3.47 - 3.27 (m, 4H), 2.88 (ddd, , 2H), 2.54 (s, 3H), 2.19 (s, 3H), 2.12 (s, 4H), 1.35 (m, 2H), 0.99 - 0.91 (m, 2H). MS (EI) for C26H29Cl2N3O3, found 503.4 (MH+).
[00181] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[l-(phenyl- methyl)-1H-imidazol-5-yl] methyl} ethyl] cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.14 (s, IH), 7.60 - 7.57 (m, IH), 7.52 (d, IH), 7.41 - 7.35 (m, 2H), 7.35 - 7.28 (m, 2H), 7.23 - 7.18 (m, 2H), 6.95 (d, IH), 6.74 (d, IH), 5.09 (s, 2H), 4.82 (q, IH), 3.33 (d, 4H), 2.72 - 2.54 (m, 2H), 2.29 - 1.91 (m, 7H), 1.46 - 1.28 (m, 2H), 1.06 - 0.83 (m, 2H). MS (EI) for C28H3ICl2N5O2, found 541.5 (MH+).
[00182] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(2-methylphenyl)methyl] -2-(4- methylpiperazin-l-yl)-2-oxoethyl] cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- de): δ 8.13 (s, IH), 7.63 (dd, IH), 7.44 - 7.37 (m, 2H), 7.11 - 7.01 (m, 3H), 6.96 (d, IH), 6.77 (d, IH), 4.92 (q IH), 3.40 - 3.19 (m, 3H), 3.00 - 2.88 (m, IH), 2.82 - 2.74 (m, 2H), 2.22 (s, 3H), 2.13 (ddd, 3H), 2.07 (s, 3H), 1.82 - 1.72 (m, IH), 1.44 - 1.31 (m, 2H), 1.03 - 0.90 (m, 2H). MS (EI) for C25H29Cl2N3O2, found 475.4 (MH+).
[00183] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(3-methylphenyl)methyl] -2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.61 (dd, IH), 7.45 - 7.34 (m, 2H), 7.09 (t, IH), 6.97 (d, IH), 6.84 (d, 2H), 6.72 (d, IH), 4.86 (q, J = 6.6 Hz, IH), 3.45 - 3.21 (m, 4H), 2.75 (qd, 2H), 2.23 (s, 3H), 2.17 (dd, J = 14.6, 5.2 Hz, 2H), 2.12 (s, 3H), 2.06 - 1.97 (m, IH), 1.40 (d, J = 3.3 Hz, 2H), 1.02 - 0.91 (m, 2H). MS (EI) for C25H29Cl2N3O2, found 475.4 (MH+).
[00184] l-(2,4-dichlorophenyl)-N- [(I S)-I- [(3-fluorophenyl)methyl]-2-(4-methylpiperazin- l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1U NMR (400MHz, DMSO-d6): δ 7.57 (d, IH), 7.39 (m, 2H), 7.26 (m, IH), 6.91 (m, IH), 6.88 (m, 2H), 4.89 (q, IH), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H), 0.95 (m, 2H). MS (EI) for C24H26Cl2FN3O2, found 479.4 (MH+).
[00185] N-[(lS)-l-[(4-cyanophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.6 (d, IH), 7.37-7.42 (m, 2H), 7.23 (m, IH), 7.04-7.11 (m, 3H), 6.78 (d, IH), 4.94 (dd, IH), 3.31-3.41 (m, 4H), 2.87 (dd, IH), 2.79 (dd, IH), 2.18 (m, 3H), 2.12 (m, 2H), 1.39 (m, IH), 1.27 (m, IH), 0.94 (m, 2H). MS (EI) for C25H26Cl2N4O2, found 486.4 (MH+). [00186] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[4-(l- methylethyl)-piperazin-l-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.60 (dd, IH), 7.52 (d, IH), 7.48 - 7.36 (m, 2H), 7.34 (dd, IH), 7.20 (d, IH), 6.92 (d, IH), 5.08 - 4.93 (m, IH), 3.31 - 3.23 (m, 2H), 2.96 - 2.83 (m, 2H), 2.70 - 2.54 (m, IH), 2.33 (d, 2H), 2.22 (dd, IH), 2.15 - 2.05 (m, IH), 1.47 - 1.33 (m, IH), 1.20 (dd, IH), 1.00 - 0.80 (m, 10H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+).
[00187] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[3- (trifluoromethyljphenyljmethyljethyljcyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.57 (d, IH), 7.53 (d, IH), 7.47 (d, IH), 7.43 (t, 2H), 7.39 (dd, IH), 7.33 (d, IH), 6.94 (d, IH), 4.98 - 4.86 (m, IH), 3.36 (d, 4H), 2.97 - 2.85 (m, 2H), 2.20 (d, 3H), 2.14 (s, 4H), 1.48 - 1.33 (m, IH), 1.25 (dd, IH), 1.00 - 0.87 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 529.4 (MH+). [00188] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[2- (trifluoromethyl)-phenyl]methyl}ethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.63 (d, IH), 7.61 - 7.54 (m, 2H), 7.45 - 7.39 (m, 3H), 7.39 - 7.33 (m, IH), 7.02 (d, IH), 4.99 - 4.94 (m, IH), 3.38 (dd, 3H), 3.20 (dd, IH), 3.05 - 2.79 (m, 2H), 2.29 - 2.17 (m, 3H), 2.13 (s, 3H), 2.00 (dd, IH), 1.45 - 1.25 (m, IH), 1.22 - 1.06 (m, IH), 0.99 - 0.82 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 529.4 (MH+).
[00189] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-(pyridin-2- ylmethyl)ethyl]cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 8.32 (m, IH), 8.15 (s, IH), 7.70 - 7.54 (m, IH), 7.49 - 7.36 (m, 2H), 7.22 - 7.07 (m, 3H), 5.07 (dd, IH), 3.55 - 3.24 (m, 4H), 2.96 (dd, IH), 2.85 (dd, IH), 2.30 - 2.16 (m, 4H), 2.14 (s, 3H), 1.48 - 1.26 (m, 2H), 1.07 - 0.82 (m, 2H). MS (EI) for C23H26Cl2N4O2, found 462.4 (MH+). [00190] N-[(lS)-l-(cyclohexylmethyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l-(2,4- dichloro-phenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.70 - 7.57 (m, IH), 7.51 - 7.30 (m, 2H), 6.73 (d, IH), 4.74 (dd, IH), 3.49 - 3.24 (m, 4H), 2.34 - 2.17 (m, 4H), 2.16 (s, 3H), 1.72 (d, IH), 1.65 - 1.34 (m, 6H), 1.31 (t, 2H), 1.24 - 1.01 (m, 5H), 0.97 - 0.87 (m, IH), 0.87 - 0.63 (m, 2H). MS (EI) for C24H33Cl2N3O2, found 467.4 (MH+). [00191] 3,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (dimethylamino)ethyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 7.86 (t, J = 5.5Hz, IH), 7.58 - 7.55 (m, IH), 7.49 - 7.45 (m, IH), 7.44 - 7.38 (m, 2H), 7.31 (d, IH), 7.08 (dd, IH), 6.65 (d, IH), 4.45 (td, IH), 3.22 - 3.01 (m, 2H), 2.83 (ddd, J = 22.5, 13.5, 6.9Hz, 2H), 2.48 (dt, 2H), 2.27 (q, 2H), 2.16 (s, 6H), 1.40 - 1.31 (m, 2H), 1.04 - 0.87 (m, 2H). MS (EI) for C23H25C14N3O2, found 518.3 (MH+).
[00192] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-4-(trifluoromethyl)-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 7.86 (t, IH), 7.60 - 7.53 (m, 3H), 7.44 - 7.36 (m, 2H), 7.28 (d, 2H), 6.61 (d, IH), 4.50 (td, IH), 3.22 - 3.01 (m, 2H), 2.92 (ddd, 2H), 2.48 (dt, 2H), 2.28 (dd, 2H), 2.17 (s, 6H), 1.40 - 1.28 (m, 2H), 1.01 - 0.88 (m, 2H). MS (EI) for C24H26Cl2F3N3O2, found 517.4 (MH+). [00193] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[3- (dimethylamino)-propyl]-N-methyl-L-phenylalaninamide: IH NMR (400 MHz, DMSO-d6): δ 7.61 - 7.56 (m, IH), 7.51 (d, IH), 7.42 - 7.40 (m, 2H), 7.33 (dt, , IH), 7.22 (dd, IH), 6.81 (dd, IH), 5.03 (dtd, IH), 3.46 - 3.29 (m, 2H), 3.25 - 3.14 (m, 2H), 2.99 - 2.89 (m, 3H), 2.89 - 2.79 (m, IH), 2.74 (s, IH), 2.10 (t, IH), 2.07 (d, 6H), 1.59 (s, IH), 1.53 - 1.44 (m, IH), 1.37 (d, IH), 1.23 - 1.10 (m, IH), 1.00 - 0.84 (m, 2H). MS (EI) for C25H29Cl4N3O2, found 546.3 (MH+). [00194] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[3- (dimethylamino)-2,2-dimethylpropyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO- d6): δ 7.60 - 7.54 (m, 2H), 7.51 (d, IH), 7.44 (dd, IH), 7.40 - 7.31 (m, 2H), 7.18 (d, IH), 6.74 (d, IH), 4.57 (td, IH), 3.04 - 2.92 (m, 2H), 2.91 - 2.80 (m, 2H), 2.18 (s, 6H), 2.01 (s, 2H), 1.33 (tt, 2H), 1.04 - 0.88 (m, 2H), 0.74 (d, 6H). MS (EI) for C26H31Cl4N3O2, found 560.4 (MH+). [00195] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(l- methylpiperidin-2-yl)methyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 7.58 (dd, IH), 7.52 - 7.49 (m, IH), 7.44 (ddd, IH), 7.39 (dd, 2H), 7.33 (dd, IH), 7.20 - 7.08 (m, IH), 6.78 (dd, IH), 4.54 (dd, IH), 3.11 - 2.82 (m, 3H), 2.75 (d, IH), 2.14 (d, 3H), 1.98 (t, IH), 1.87 (s, IH), 1.62 (s, IH), 1.49 (s, IH), 1.39 (d, 3H), 1.27 (d, IH), 1.13 (dt, 2H), 0.95 (s, 2H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+).
[00196] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2- pyrrolidin-l-ylpropyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 7.61 (dd, IH), 7.53 (d, IH), 7.51 - 7.46 (m, IH), 7.45 (dd, IH), 7.41 (d, IH), 7.35 (dd, IH), 7.19 (dd, IH), 6.78 (dd, IH), 4.56 (dd, IH), 3.29 - 3.13 (m, 2H), 3.11 - 2.98 (m, 2H), 2.97 - 2.85 (m, 2H), 2.38 (td, 2H), 1.68 (d, 4H), 1.34 (dd, 2H), 0.95 (d, 2H), 0.91 (d, 2H). MS (EI) for C26H29Cl4N3O2, found 558.3 (MH+).
[00197] l-(2,4-dichlorophenyl)-N-[(lS)-l-[(3,5-dichlorophenyl)methyl]-2-(4- ethylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 7.62 (d, IH), 7.54 (d, IH), 7.43 (m, 2H), 7.36 (dd, IH), 7.23 (d, IH), 6.95 (d, IH), 5.05 - 4.99 (m, IH), 3.53 - 3.40 (m, 4H), 2.97 - 2.85 (m, 2H), 2.31 - 2.26 (m, 4H), 2.20 (m, IH), 2.12 (m, IH), 1.40 (m, IH), 1.21 (m, IH), 0.99 - 0.91 (m, 5H). MS (EI) for C25H27Cl4N3O2, found 544.3 (MH+).
[00198] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(3,5-dichlorophenyl)methyl]-2-[4-(2- hydroxyethyl)-piperazin-l-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.60 (d, IH), 7.52 (d, IH), 7.47 - 7.37 (m, 2H), 7.34 (dd, IH), 7.21 (d, IH), 6.93 (d, IH), 4.99 (m, IH), 3.46 (t, 2H), 3.44 - 3.24 (m, 4H), 3.01 - 2.78 (m, 2H), 2.43 - 2.11 (m, 6H), 1.49 - 1.29 (m, IH), 1.30 - 1.04 (m, IH), 1.04 - 0.81 (m, 2H). MS (EI) for C25H27Cl4N3O3, found 560.3 (MH+). [00199] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(3,5-dichlorophenyl)methyl]-2-[4-(2- fluoroethyljpiperazin-l-ylj-l-oxoethyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 7.55 (d, IH), 7.47 (d, IH), 7.36 (dd, 2H), 7.29 (dt, IH), 7.20 - 7.12 (m, IH), 6.89 (t, IH), 4.95 (td, IH), 4.52 (t, IH), 4.40 (t, IH), 3.32 (t, 4H), 2.85 (ddd, 2H), 2.56 (t, IH), 2.49 (t, IH), 2.41 - 2.11 (m, 4H), 1.38 - 1.29 (m, IH), 1.18 - 1.07 (m, IH), 0.94 - 0.80 (m, 2H). MS (EI) for C25H26Cl4FN3O2, found 562.3 (MH+).
[00200] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (dimethylamino)-ethyl]-N-methyl-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, IH), 7.60 (dt, IH), 7.46 - 7.34 (m, 4H), 7.08 - 6.98 (m, 2H), 4.84 (dd, IH), 3.45 (dt, IH), 3.25 - 3.08 (m, IH), 2.93 (s, 2H), 2.85 - 2.70 (m, 3H), 2.37 - 2.20 (m, 2H), 2.21 - 2.08 (m, 6H), 1.43 - 1.29 (m, 2H), 1.03 - 0.88 (m, 2H). MS (EI) for C24H28BrCl2N3O2, found 542.3 (MH+).
[00201] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-N-methyl-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, IH), 7.57 (d, 2H), 7.46 (d, IH), 7.34 (d, IH), 7.08 - 6.98 (m, 2H), 4.86 (dd, IH), 3.40 (dt, IH), 3.25 - 3.08 (m, IH), 2.93 (s, 2H), 2.85 - 2.70 (m, 3H), 2.37 - 2.20 (m, 2H), 2.21 - 2.08 (m, 6H), 1.43 - 1.29 (m, 2H), 1.03 - 0.88 (m, 2H). MS (EI) for C25H28Cl2F3N3O2, found 531.4 (MH+).
[00202] N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl]- N-methyl-L-leucinamide: 1H NMR (400MHz, DMSO-d6): δ 7.44 (m, IH), 7.36 (m, IH), 7.28 (m, IH), 5.96-5.85 (m, IH), 4.94 (m, IH), ), 3.58-3.42 (m, 2H), 3.28 (m, IH), 3.06-2.90 (m, 4H), 2.50-2.41 (m, 2H), 2.29-2.25 (m, 6H), 1.79 (m, IH), 1.31 (m, 2H), 1.09 (m, IH), 0.96 (m 4H), 0.87 (d, 3H); MS (EI) for C2iH3iCl2N3O2, found 428.14 (MH+).
[00203] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N- [(3R)-l-methylpyrrolidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.48- 7.38 (m, 4H), 7.22 (d, IH), 7.17 (d, IH), 4.57-4.55 (m, IH), 3.35 (s, 3H), 3.20-3.02 (m, 5H), 2.98 (dd, IH), 2.97 (s, 3H), 2.57-2.45 (m, IH), 2.14-2.01 (m, IH), 1.77-1.63 (m, IH), 1.58-1.43 (m, 2H), 1.19-1.14 (m, IH), 1.05-0.98 (m, IH). MS (EI) for C25H27Cl4N3O2, found 544.10 (MH+). [00204] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N- [l-(phenylmethyl)piperidin-4-yl]-L-phenylalaninamide: 1U NMR (400MHz, CD3OD): 7.50- 7.29 (m, 9H), 7.24-7.21 (m, IH), 7.17-7.12 (m, IH), 5.20-5.18 (m, IH), 3.80-3.70 (m, 2H), 3.18- 2.95 (m, 4H), 2.82 (d, 3H), 2.39-2.08 (m, 2H), 1.95-1.65 (m, 2H), 1.60-1.40 (m, 2H), 1.13-1.00
(m, 2H). MS (EI) for C32H33Cl4N3O2, found 634.17 (MH+).
[00205] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-[l-
(phenylmethyl)-piperidin-4-yl] -4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR
(400MHz, CD3OD): 7.60-7.44 (m, 2H), 7.41-7.25 (m, 10H), 5.16-5.07 (m, IH), 4.25-4.20 (m,
IH), 3.80-3.73 (m, 3H), 3.25-2.92 (m, 4H), 2.52 (d, 3H), 2.44-2.22 (m, 2H), 1.88-1.50 (m, 5H),
1.12-1.00 (m, 2H). MS (EI) for C33H34Cl2F3N3O2, found 632.28 (MH+).
[00206] l-(2,4-dichlorophenyl)-N-[(lS)-2-[3-(dimethylamino)azetidin-l-yl]-2-oxo-l-{[4-
(trifluoromethyljphenyljmethyljethyljcyclopropanecarboxamide: 1H NMR (400 MHz,
CDCl3): δ 7.22-7.53 (m, 7H), 5.88 (m, IH), 4.07 (q, IH), 3.63-4.11 (m, 3H), 2.73-3.29 (m, 3H),
2.01-2.07 (m, 6H), 1.62 (m, 2H), 1.07 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 528.17
(MH+).
[00207] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-
(dimethylamino)ethyl]-N-ethyl-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400
MHz, DMSO-de): δ 7.58 (m, 3H), 7.40 (s, 2H), 7.32 (d, 2H), 6.95-6.77 (m, IH), 4.88 (s, IH),
3.29 (m, 2H), 3.14 (m, 2H), 2.89 (m, 2H), 2.20 (m, 2H), 2.10 (s, 6H), 1.33 (m, 2H), 0.97 (m,
5H). MS (EI) for C26H30Cl2F3 N3O2, found 545 (MH+).
[00208] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-[(3R)-l- methyl-pyrrolidin-3-yl]-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz,
DMSO-de): δ 7.95 (s, IH), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d, 2H), 6.58 (d, IH), 4.48 (m, IH),
3.00 (m, IH), 2.88 (m, 3H), 2.36 (m, 4H), 2.18 (s, 3H), 2.09 (m, 2H), 1.74 (m, IH), 1.28 (m,
3H), 0.94 (m, 2H). MS (EI) for C26H28Cl2F3N3O2, found 543 (MH+).
[00209] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2-pyrrolidin-l- ylethyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 7.89 (t,
IH), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d, 2H), 6.60 (d, IH), 4.50 (m, IH), 3.14 (m, 2H), 2.97 (m,
IH), 2.87 (m, IH), 2.44 (m, 6H), 1.68 (m, 4H), 1.34 (m, 2H), 0.94 (m, 2H). MS (EI) for
C26H28Cl2F3N3O2, found 543 (MH+). Example 4
N-[(lS)-l-({[(4-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l-
(2,4-dichlorophenyl)cyclopropanecarboxamide
Figure imgf000061_0001
EDC HOBt DCM N MM
Figure imgf000061_0002
[00210] Step 1: (S)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 niL, 146.2 mmol), 1-methylpiperazine (1.78 niL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo then partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 3.5 g (83%) of the title compound which was used in the next step without further purification.
[00211] Step 2: (S)-2-amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l- one hydrochloride: To a solution of (S)-tert-butyl 3 -hydroxy- l-(4-methylpiperazin-l-yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at O0C was added sodium hydride (18 mg, 0.77 mmol). The reaction mixture was stirred at O0C for 5 minutes followed by the addition of 4-chlorobenzyl bromide (157 mg, 0.77 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at O0C for 2 h. The reaction was quenched with 5 drops of water and concentrated in vacuo. The concentrated reaction mixture was dissolved in methanol (5 niL), followed by the addition of 4 N HCl in dioxane (3 mL), and the resulting mixture was heated to 65°C for 1 h. Upon cooling the mixture was concentrated in vacuo to give the title compound which was used in the next step without further purification.
[00212] Step 3: N-[(lS)-l-({[(4-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one hydrochloride (0.7 mmol) in dichloromethane (4 mL) was added N-methylmorpholine (0.77 mL, 7 mmol), l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (177 mg, 0.77mmol), l-[3-
(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1- Hydroxybenzotriazole (HOBt) (104 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 43 mg (12%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.63 (dd, IH), 7.44 (dd, 2H), 7.39 (d, IH), 7.38 - 7.36 (m, IH), 7.23 (dd, 2H), 6.83 (d, IH), 4.88 (dt, IH), 4.38 (d, 2H), 3.53 - 3.43 (m, 2H), 3.36 (s, 4H), 2.15 (d, 4H), 2.11 (s, 3H), 1.54 - 1.36 (m, 2H), 1.02 (m, 2H). MS (EI) for C25H28Cl3N3O3, found 525.9 (MH+).
[00213] The following compounds were made in a manner analogous to Example 4: [00214] N-[(lS)-l-({[(3-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2- oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-dβ): δ 7.68 - 7.53 (m, IH), 7.48 - 7.40 (m, 2H), 7.39 - 7.30 (m, 2H), 7.28 (s, IH), 7.20 - 7.06 (m, IH), 6.87 (d, IH), 4.89 (dd, IH), 4.50 - 4.30 (m, 2H), 3.56 - 3.44 (m, 6H), 2.17 (d, 4H), 2.11 (s, 3H), 1.58 - 1.32 (m, 2H), 1.07 -0.95 (m, 2H). MS (EI) for C25H28Cl3N3O3, found 525.9 (MH+). [00215] N-[(lS)-l-({[(2-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2- oxoethyl]-l-(3,5-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 7.61 (d, IH), 7.45 - 7.41 (m, 3H), 7.37 - 7.31 (m, 3H), 6.86 (d, IH), 4.93 - 4.88 (m, IH), 4.48 (s, 2H), 3.60 - 3.52 (m, 2H), 3.83 (m, 4H), 2.71 (m, 4H), 2.10 (s, 3H), 1.51 - 1.40 (m, 2H), 1.09 - 0.96 (m, 2H). MS (EI) for C25H28Cl3N3O3, found 525.9 (MH+). [00216] l-(3,5-dichlorophenyl)-N- [(I S)-l-({ [(4-fluorophenyl)methyl] oxy}methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 7.64 (d, IH), 7.44 (m, 2H), 7.25 (dd, 2H), 7.18 - 7.13 (m, 2H), 6.82 (d, IH), 4.90 - 4.85 (m, IH), 4.36 (d, 2H), 3.51 - 3.42 (m, 4H), 3.35 (m, 2H), 2.71 (m, 4H), 2.10 (s, 3H), 1.51 - 1.40 (m, 2H), 1.09 - 0.96 (m, 2H). MS (EI) for C28H28Cl2FN3O3, found 509.4 (MH+). [00217] l-(3,5-dichlorophenyl)-N- [(I S)- 1- [({ [2-(methyloxy)phenyl] methyl} oxy)methyl] -2- (4-methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 7.63 (s, IH), 7.44 (m, 2H), 7.23 (t, IH), 6.83 - 6.76 (m, 4H), 4.90 - 4.85 (m, IH), 4.36 (d, 2H), 3.72 (s, 3H), 3.51 - 3.42 (m, 6H), 2.16 (m, 4H), 2.11 (s, 3H), 1.52 - 1.40 (m, 2H), 1.08 - 0.95 (m, 2H). MS (EI) for C26H3ICl2N3O4, found 521.5 (MH+). [00218] l-(2,4-dichlorophenyl)-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyljoxyj-methyljethyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- de): δ 7.65 (d, IH), 7.46 (m, 2H), 7.35 (m, 2H), 7.28 (m, IH), 7.22 (d, 2H), 6.83 (d, IH), 4.92 (m, IH), 4.40 (m, 2H), 3.49 (m, 6H), 2.25 (m, 4H), 2.17 (s, 3H), 1.48 (m, 2H), 1.03 (m, 2H). MS (EI) for C25H29Cl2N3O3, found 491 (MH+).
[00219] l-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyljoxyj-methyljethyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 7.66 (d, IH), 7.47 (m, 2H), 7.34 (m, 2H), 7.29 (m, IH), 7.23 (d, 2H), 6.85 (d, IH), 4.92 (m, IH), 4.41 (m, 2H), 3.49 (m, 6H), 2.43 (m, 4H), 2.29 (s, 3H), 1.49 (m, 2H), 1.04 (m, 2H). MS (EI) for C25H29Cl2N3O3, found 491 (MH+).
Example 5
N- [(3 S)- 1-azabicyclo [2.2.2] oct-3-yl] -N '2 '- { [ l-(2,4-dichlorophenyl)-cyclopropyl] -carbonyl}- 3-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-L-alaninamide
J. Med. Chem, 1994, 37, 2090.
Figure imgf000064_0001
[00220] Step 1: Diethyl 2-acetamido-2-((2,3-dihydrobenzo[6][l,4]dioxin-6-yl)methyl)- malonate: To a freshly prepared solution of sodium ethoxide (sodium 0.6 g, 26 mmol, ethanol 50 mL ) were added 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (2 g, 8.73 mmol) and 2-acetamide-diethylmalonate (1.9 g, 8.75 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2h, and concentrated in vacuo to give the title compound that was submitted to the next step without further purification.
[00221] Step 2: 2-Acetamido-3-(2,3-dihydrobenzo[ό] [l,4]dioxin-6-yl)propanoic acid: A solution of diethyl 2-acetamido-2-((2,3-dihydrobenzo[δ][l,4]dioxin-6-yl)methyl)malonate (3.17 g, 8.7 mmol) and potassium hydroxide (1.11 g, 27.7 mmol) in water (35 mL) and ethanol (35 mL) was heated to reflux for 2h. The reaction mixture was concentrated in vacuo and the product was submitted to the next step without further purification.
[00222] Step 3: (S)-2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoic acid: 2-Acetamido-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) was dissolved in a solution of sodium hydroxide (0.42g of NaOH, 50 mL H2O) at 37 0C (39 0C bath temperature), and the pH was adjusted to 7.5 with the addition of 2N HCl. To the resulting solution was added cobaltous chloride hexahydrate (Aldrich, lOmg), and Amano Acylase (Aldrich, 200mg). The reaction mixture was stirred for 16 h at 37 0C (39 0C bath temperature) and the pH 7.5. Concentration under reduced pressure gave the title compound (in the mixture with the (R)-2-acetamido-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid) that was submitted to the next step without further purification.
[00223] Step 4: (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) in ethanol (25mL) was added thionyl chloride (2.0 mL, 27.4 mmol). The reaction mixture was stirred under reflux conditions (9O0C bath temperature) for 2 hours. The resulting solution was concentrated in vacuo and the product was submitted to the next step without further purification.
[00224] Step 5: (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (300 mg, 1.3 mmol) in acetonitrile (15.0 mL) were added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (250 mg, 1.1 mmol), N,N-diisopropylethylamine (1.5 mL, 9.12 mmol), and HATU ( 400 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo, dissolved in dichloromethane (35 mL), and extracted with water (10 mL) 2 times. The layers were separated and the organic layer was concentrated in vacuo. The product was purified by column chromatography (silica-gel, EtOAc, Hexanes), resulting in 350 mg (68.8%) of the title compound.
[00225] Step 6: (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydro- benzo[b] [l,4]dioxin-6-yl)propanoic acid: To a solution of (S)-ethyl 2-amino-3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (350 mg, 0.75 mmol) in 15 mL of MeOH was added 15 mL of 2 N NaOH solution and the reaction mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated down under reduced pressure, acidified with concentrated HCl to pH=3, and extracted with 300 mL of EtOAc. The organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo to give 320 mg (97.5%) of the title compound which was submitted to the next step without further purification. [00226] Step 7: N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N'2'-{[l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl}-3-(2,3-dihydro-l,4-benzodioxin-6-yl)-L-alaninamide: To a solution of (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydrobenzo[b][l,4]dioxin- 6-yl)-propanoic acid (320 mg, 0.73 mmol) in acetonitrile (15.0 mL) were added (S)-quinuclidin- 3-amine (250 mg, 1.9 mmol), N,N-diisopropylethylamine (1.0 mL, 6.0 mmol), and HATU ( 400 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting solution was concentrated in vacuo, and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 133 mg of the title compound. 1H NMR (400 MHz, DMSO-d6):δ 8.19 (s, IH), 7.84 (br s, IH), 7.56 (s, IH), 7.37 (s, 2H), 6.61 (s, IH), 6.43 (m, 2H), 6.25 (d, IH), 4.38 (m, IH), 4.18 (m, 4H), 2.95-3.57 (m, 7H), 2.65 (m, 4H), 1.16-1.38 (m, 5H), 0.93 (m, 2H). MS (EI) for C28H3ICl2N3O4, found 544.35 (MH+). [00227] The following compounds were made in a manner analogous to Example 5 : [00228] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-3-(2,3-dihydro-l,4-benzodioxin-6-yl)-L-alaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, IH), 7.84 (br s, IH), 7.56 (s, IH), 7.37 (s, 2H), 6.61 (s, IH), 6.43 (m, 2H), 6.25 (d, IH), 4.37 (m, IH), 4.12 (m, 4H), 2.95-3.57 (m, 7H), 2.61 (m, 4H), 1.16-1.38 (m, 5H), 0.93 (m, 2H). MS (EI) for C28H3ICl2N3O4, found 544.28 (MH+). [00229] N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-3-(2,3-dihydro-l,4- benzodioxin-6-yl)-N-[2-(dimethylamino)ethyl]-N-methyl-L-alaninamide: 1H NMR (400 MHz, CDCl3): δ 7.25-7.43 (m, 3H), 5.51-6.72 (m, 3H), 5.96 (d, IH), 4.97 (q, IH), 4.23 (s, 4H),
3.66 (m, IH), 3.41 (m, IH), 2.75 (m, 10H), 2.52 (m, 3H), 1.61-1.74 (m, 2H), 1.00-1.08 (m, 2H). MS (EI) for C26H3ICl2N3O4, found 520.23 (MH+).
[00230] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropylj-carbonylJ-S-^rifluoromethylJ-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.25 (m, IH), 8.03 (m, IH), 7.57 (m, 3H), 7.40 (m, 3H), 6.65 (m, IH), 4.56 (m, IH), 3.07 (m, IH), 2.93 (m, 2H), 2.70 (m, 4H), 2.30 (m, IH), 1.68 (m, 2H), 1.53 (m, 3H), 1.33 (m, 3H), 0.96 (m, 2H). MS (EI) for C27H27Cl3F3N3O2, found 589 (MH+). [00231] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-0-methyl-3-(methyloxy)-L-tyrosinamide: 1H NMR (400 MHz, DMSO-de): δ 8.17 (s, IH), 7.92 (m, IH), 7.60 (s, IH), 7.41 (m, 2H), 6.65 (m, IH), 4.47 (m, IH),
3.67 (m, 6H), 3.06 (m, 10H), 2.69 (m, 4H), 2.18 (m, IH), 1.40-1.56 (m, 4H), 0.97 (m, 2H). MS (EI) for C28H33Cl2N3O4, found 546.6 (MH+). [00232] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- yclopropyl]carbonyl}-2-fluoro-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.24 (s, IH), 7.92 (m, IH), 7.64 (s, IH), 7.45 (s, 2H), 7.30 (d, IH), 7.16 (m, 2H), 6.49 (m, IH), 4.54 (m, IH), 2.33-3.59 (m, 12H), 1.32-1.67 (m, 4H), 0.97 (m, 2H). MS (EI) for C26H27Cl3FN3O2, found 538.5 (MH+).
[00233] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- yclopropyl]carbonyl}-2-fluoro-L-phenylalaninamide: 1H NMR (400 MHz, DMSO- d6): δ 8.21 (s, IH), 8.09 (m, IH), 7.76 (d, IH), 7.58 (d, IH), 7.45 (m, 3H), 7.29 (t, IH), 6.69 (m, IH), 4.58 (m, IH), 2.69-3.69 (m, 12H), 1.12-1.76 (m, 4H), 0.97 (m, 2H). MS (EI) for C27H27Cl3F3N3O2, found 588.5 (MH+).
[00234] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-2-oxoethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.24 (m, IH), 7.37 (m, 2H), 7.28 (m, 2H), 6.78 (m, IH), 6.68 (m, IH), 6.50 (m, 2H), 4.60 (m, IH), 4.40-4.05 (m, 6H), 3.11 (m, 2H), 2.64 (m, 2H), 1.86 (m, 3H), 1.49 (m, 4H), 1.27 (m, 2H), 0.97 (m, 2H). MS (EI) for C29H32F3N3O5, found 560 (MH+). [00235] 3-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-[2-(dimethylamino)ethyl]-N-methyl- N~2— [(l-{4- [(trifluoromethyl)oxy] phenyl}cyclopropyl)carbonyl] -L-alaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.15 (s, IH), 7.33 (m, 4H), 7.65 (m, 4H), 4.76 (m, IH), 4.18 (s, 4H), 3.44 (m, IH), 3.13 (m, IH), 2.91 (s, 2H), 2.75 (s, IH), 2.68 (m, 2H), 2.31 (m, 2H), 2.16 (d, 6H), 1.26 (m, 2H), 0.98 (m, 2H). MS (EI) for C27H32F3N3O5, found 536 (MH+). [00236] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-2-oxoethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, IH), 7.62 (d, IH), 7.55 (m, 2H), 7.03 (m, IH), 6.67 (m, IH), 6.52 (m, 2H), 4.60 (m, IH), 4.40-4.05 (m, 6H), 3.02 (m, 2H), 2.67 (m, 2H), 2.02 (m, 2H), 1.68 (m, 3H), 1.39 (m, 4H), 1.03 (m, 2H). MS (EI) for C29H3IF4N3O4, found 562 (MH+). Example 6
N-(azetidin-3-ylmethyl)-4-bromo-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)- carbonyl] -L-phenylalaninamide
Figure imgf000068_0001
Figure imgf000068_0002
2 HCI
[00237] Step 1: l-(4-(trifluoromethoxy)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (15g, 74.6 mmol) in THF (450 mL) was added NaH (100%, 9.0 g, 375 mmol) at 0 0C. The reaction was stirred at room temperature for 30 min and 15 mL of dibromoethane (15 mL, 174 mmol) was added. The reaction was stirred at room temperature for 48 h and quenched by addition of 10OmL of water. The resulting solution was concentrated in vacuo, re-dissolved in EtOAc (500 mL), and washed with 100 mL of water. The organic layer was filtered through a plug of Charcoal and Celite. The resulting solution was concentrated in vacuo to give 14.9 g (88.7%) of the title compound as off white oil which was used in the next step without further purification. MS (EI) for CnH8F3NO, found 228.14 (MH+). [00238] Step 2: l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid: To a solution of NaOH (35 g, 795 mmol) in 400 mL of water was added l-(4-(trifluoromethoxy)- phenyl)cyclopropanecarbonitrile (14.9 g, 65.0 mmol). The reaction mixture was heated to 12O 0C for 48 h. The resulting solution was cooled down to 0 0C and acidified to pH 3 via addition of concentrated HCl. The resulting precipitate was filtered, washed with water, and dried. The dry residue was re-dissolved in Diethyl Ether (50OmL), filtered from salts, and concentrated under reduced pressure. The resulting off white solid was used in the next step without further purification (15.6 g, 97.5%). MS (EI) for CnH9F3O3, found 247.17 (MH+). [00239] Step 3: (S)-ethyl 2-amino-3-(4-bromophenyl)propanoate: To a solution of Boc-L- 4-bromophenylalanine (30.Og, 87.16 mmol, Chem-Impex) in ethanol (450 mL) were added thionyl chloride (8.0 mL, 109.67 mmol). The reaction was refluxed at 9O0C for 18 hours. The resulting solution was concentrated in vacuo to give 27.0 g (90%) of the title compound with HCl salt which was used in the next step without further purification. MS (EI) for CnHi4BrNO2, found 273.14 (MH+).
[00240] Step 4: (S)-ethyl 3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)- cyclopropanecarboxamido)propanoate: To a solution of (S)-ethyl 2-amino-3-(4- bromophenyl)propanoate (11.5 g, 42.26 mmol) in acetonitrile (150.0 mL) were added l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (10.4 g, 42.26 mmol), N5N- diisopropylethylamine (13.9 mL, 84.52 mmol), and HATU ( 19.3 g, 50.71 mmol). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo, dissolved into dichloromethane (350 mL), extracted with water (350 mL) 2 times. The layers were separated and the organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo and chromatographed on silica get eluting with 15% EtOAc in hexane to give 17.4 g (82%) of the title compound. MS (EI) for C22H2iBrF3NO4, found 501.31 (MH+). [00241] Step 5: (S)-3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)cyclopropane- carboxamido)propanoic acid: To a solution of (S)-ethyl 3-(4-bromophenyl)-2-(l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxamido)propanoate (17.4 g, 34.8 mmol) in 300 mL of MeOH was added 100 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours. The resulting solution was concentrated down under reduced pressure, acidified with concentrated HCl to pH=3, and extracted with 300 mL of EtOAc. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 14.5 g (88%) of the title compound which was used in the next step without further purification. MS (EI) for C20Hi7BrF3NO4, found 473.25 (MH+).
[00242] Step 6: N-(azetidin-3-ylmethyl)-4-bromo-Nalpha-[(l-{4-[(trifluoromethyl)oxy]- phenyl}cyclopropyl)carbonyl]-L-phenylalaninamide: To a solution of (S)-3-(4- bromophenyl)-2-( 1 -(4-(trifluoromethoxy)phenyl)cyclopropane-carboxamido)propanoic acid (100 mg, 0.2 mmol) in acetonitrile (5.0 mL) were added tert-butyl 3-(aminomethyl)azetidine-l- carboxylate (Oakwood, 40.0 mg, 0.2 mmol), N,N-diisopropyl-ethylamine (1.1 niL, 6.1 mmol), and HATU ( 76 mg, 0.2 mmol). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo, dissolved into dichloromethane (300 mL), extracted with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in methanol (10 mL) followed by the addition of 4 N HCl in dioxane (5 mL, Aldrich). The reaction was heated to 450C for 2 hours. The resulting solution was concentrated in vacuo. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 20 mg of the title compound. 1H NMR (400MHz, CDCl3): δ 8.54 (s, IH), 8.45 (s, IH), 7.32 (d, 2H), 7.27 (d, 2H), 7.17 (d, 2H), 6.84 (d, 2H), 5.79 (d, IH), 4.62-4.57 (m, IH), 4.05 (s, 2H), 3.93 (s, IH), 3.82 (s, IH), 3.61-3.58 (m, IH), 3.27-3.23 (m, IH), 3.02-2.98 (m, 2H), 2.74-2.68 (m, IH), 1.47-1.31 (m, 2H), 1.08-0.94 (m, 2H); MS (EI) for C24H25BrF3N3O3, found 542.15 (MH+).
[00243] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl]-l-[4-[(trifluoromethyl)oxy]phenyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 6, wherein tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for tert-butyl 3-(aminomethyl)azetidine-l -carboxylate (Oakwood). 1H NMR (400MHz, DMSO-de): δ 7.42 (m, 2H), 7.31 (m, 4H), 7.03(m, 3H), 4.67 (m, IH), 4.27 (m, 2H), 3.10 (m, IH), 2.78 (m, 2H), 1.81 (m, 8H), 1.22 (m, 2H), 0.98 (m, 2H). MS (EI) for C27H29BrF3N3O3, found 581.44 (MH+).
[00244] The following compounds were made in a manner analogous to Example 6. [00245] N- [(I S)-2-(2,6-diazaspiro [3.3] hept-2-yl)-2-oxo-l-{ [4-(trifluoromethyl)phenyl] - methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz,
CDCl3): δ 7.55 (d, 2H), 7.42 (s, IH), 7.26(m, 4H), 5.80 (d, IH), 4.50 (dd, IH), 4.24 (d, IH), 4.05 (d, IH), 3.90 (m, 3H), 3.61 (d, IH), 3.27 (d, IH), 2.98 (dd, 2H), 2.83 (dd, 2H), 1.73 (m, IH), 1.62 (m, IH), 1.12 (m, IH), 1.05 (m, IH). MS (EI) for C25H24Cl2F3N3O2, found 526.09 (MH+). [00246] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2- (methylamino)ethyl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.28 (s, IH), 8.18 (br s, IH), 7.59 (s, IH), 7.41 (m, 3H), 7.01(d, 2H), 6.59 (d, IH), 4.43 (m, IH), 3.6 (br s, IH), 3.17 (m, 2H), 2.89 (m, IH), 2.76 (m, IH), 2.63 (m, 2H), 2.34 (s, 3H), 1.37 (s, 2H), 0.97 (dd, 2H). MS (EI) for C22H24BrCl2N3O2, found 514.06 (MH+).
[00247] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-oxo-2- piperazin-l-ylethyljcyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 8.24 (s, IH), 7.62 (d, IH), 7.53 (d, IH), 7.45-7.40 (m, IH), 7.37-7.35 (dd, IH), 7.23 (d, IH), 6.94 (d, IH), 5.04-4.98 (m, IH), 3.43-3.29 (m, 5H), 2.97-2.84 (m, 2H), 2.67-2.51 (m, 4H), 1.41-1.36 (m, IH), 1.21-1.18 (m, IH), 0.97-0.90 (m, 2H); MS (EI) for C23H23Cl4N3O2, found 516.07 (MH+). [00248] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N- [2-(methylamino)ethyl]-L-phenylalaninamide: 1U NMR (400MHz, CD3OD): 7.50-7.37 (m, 4H), 7.25 (d, IH), 7.18 (d, IH), 5.02-4.97 (m, IH), 3.88-3.80 (m, IH), 3.42-3.37 (m, IH), 3.17- 3.07 (m, 6H), 3.00-2.90 (m, IH), 2.64 (s, 3H), 1.58-1.46 (m, 2H), 1.20-1.00 (m, 2H). MS (EI) for C23H25Cl4N3O2, found 518.03 (MH+).
[00249] 2-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methyl- piperazin-l-yl)-2-oxoethyl]propanamide: 1H NMR (400MHz, CD3OD): 7.46-7.00 (m, 6H), 5.22 (dd, IH), 4.08-4.02 (m, IH), 3.65-3.35 (m, 4H), 3.18-2.97 (m, 2H), 2.47-2.30 (m, 3H), 2.23 (s, 3H), 2.13-2.07 (m, IH), 1.35 (dd, 3H). MS (EI) for C23H25Cl4N3O2, found 518.15 (MH+). [00250] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(pyrrolidin-2- ylmethyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, IH), 8.31 (s, IH), 7.56 (m, 3H), 7.40 (s, 2H), 7.30 (d, 2H), 6.73 (m, IH), 4.51 (m, IH), 3.31 (m, IH), 3.20 (m, 2H), 3.00 (m, 3H), 2.87 (m, IH), 1.74 (m, 3H), 1.37 (m, 3H), 0.94 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 529 (MH+).
[00251] N-[(lS)-2-(3-aminoazetidin-l-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}- ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, CDCl3):δ 7.22- 7.57 (m, 7H), 5.95 (m, IH), 4.58 (q, IH), 3.38-4.30 (m, 4H), 2.77-3.01 (m, 5H), 1.73 (m, 2H), 1.07 (m, 2H). MS (EI) for C23H22Cl2F3N3O2, found 500.17 (MH+). [00252] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(l- methylpiperidin-3-yl)-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.50-7.36 (m, 6H), 7.02-6.98 (m, 2H), 4.53-4.42 (m, IH), 3.84-3.79 (m, IH), 3.05-2.79 (m, 4H), 2.57 (s, 3H), 2.43-2.36 (m, IH), 1.85-1.80 (m, 2H), 1.77-1.45 (m, 4H), 1.39-1.24 (m, IH), 1.18-1.00 (m, 2H). MS (EI) for C25H28Cl2N3O2, found 554.05 (MH+). [00253] N-l-azabicyclo[2.2.2]oct-3-yl-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.44 (s, IH), 7.50-7.37 (m, 5H), 7.04-6.98 (m, 2H), 4.57 (dd, IH), 4.13-3.98 (m, IH), 3.63-3.58 (m, IH), 3.30- 3.02 (m, 5H), 2.98-2.80 (m, 3H), 2.00-1.85 (m, 3H), 1.75-1.50 (m, 3H), 1.20-1.00 (m, 2H). MS (EI) for C26H28BrCl2N3O2, found 567.09 (MH+).
[00254] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.52-7.38 (m, 5H), 7.04-6.99 (m, 2H), 4.57 (dd, IH), 4.07-3.96 (m, IH), 3.58-3.45 (m, IH), 3.20-3.05 (m, 3H), 2.96-2.80 (m, 3H), 1.95-1.80 (m, 3H), 1.65-1.50 (m, 4H), 1.19-1.02 (m, 2H). MS (EI) for C26H28BrCl2N3O2, found 566.09 (MH+).
[00255] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(8aS)- hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 7.57-7.38 (m, 4H), 7.28-7.10 (m, 2H), 5.20 (dd, IH), 4.40 (dd, IH), 4.01 (dd, IH), 3.23-2.93 (m, 6H), 2.64-2.20 (m, 3H), 2.00-1.80 (m, 3H), 1.58-1.40 (m, 3H), 1.15-1.00 (m, 2H). MS (EI) for C26H27Cl4N3O2, found 555.75 (MH+).
[00256] N-[(lS)-2-[(3R)-3-aminopyrrolidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]- methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, IH), 7.56 (m, 3H), 7.40 (s, 2H), 7.30 (m, 2H), 6.80 (m, IH), 4.69 (m, IH), 3.20 (m, 2H), 2.91 (m, 4H), 1.86 (m, IH), 1.60 (m, IH), 1.32 (m, 3H), 0.94 (m, 2H). MS (EI) for C24H24Cl2F3N3O2, found 515 (MH+).
[00257] N-l-azabicyclo[2.2.2]oct-3-yl-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.20 (s, IH), 7.92 (m, IH), 7.54 (m, 3H), 7.37 (s, 2H), 7.23 (m, 2H), 6.49 (m, IH), 4.51 (m, IH), 2.99 (m, IH), 2.86 (m, 2H), 2.59 (m, 4H), 2.25 (m, IH), 1.63-1.13 (m, 8H), 0.93 (m, 2H). MS (EI) for C27H28Cl2F3N3O2, found 555 (MH+).
[00258] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(pyrrolidin-3- ylmethyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.38 (d, IH), 8.13 (s, IH), 7.57 (m, 3H), 7.41 (s, 2H), 7.28 (d, 2H), 6.70 (t, IH), 4.48 (m, IH), 3.12- 2.83 (m, 8H), 2.64 (m, IH), 2.24 (m, IH), 1.81 (m, IH), 1.37 (m, 3H), 0.94 (m, 2H). MS (EI) for C25H26Cl2F3N3O2, found 529 (MH+). [00259] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 7.94 (m, IH), 7.54 (m, 3H), 7.37 (s, 2H), 7.23 (t, 2H), 6.49 (m, IH), 4.51 (m, IH), 3.02 (m, IH), 2.86 (m, 2H), 2.62 (m, 4H), 2.31 (m, IH), 1.63-1.13 (m, 8H), 0.93 (m, 2H). MS (EI) for C27H28Cl2F3N3O2, found 555 (MH+).
[00260] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,4-dichloro-Nalpha-{[l-(2,4- dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.47-7.39 (m, 4H), 7.25-7.15 (m, 2H), 4.60 (dd, IH), 4.18-4.07 (m, IH), 3.68-3.60 (m, IH), 3.33- 3.18 (m, 5H), 3.08-2.97 (m, 3H), 2.01-1.95 (m, 3H), 1.80-1.76 (m, IH), 1.60-1.45 (m, 2H), 1.20- 1.00 (m, 2H). MS (EI) for C26H27Cl4N3O2, found 555.75 (MH+).
[00261] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 7.93 (t, IH), 7.60 (d, IH), 7.44-7.39 (m, 2H), 7.24-7.15 (m, 3H), 7.06-7.04 (m, 2H), 6.51 (d, IH), 4.47-4.42 (m, IH), 3.23- 3.12 (m, 2H), 2.92-2.88 (m, IH), 2.83-2.78 (m, IH), 2.44 (t, 2H), 2.29 (s, 6H), 1.42-1.36 (m, 2H), 1.01-0.93 (m, 2H); MS (EI) for C23H27Cl2N3O2, found 448.11 (MH+). [00262] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-N-methyl-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 7.63-7.61 (m, IH), 7.42-7.41 (m, 2H), 7.26-7.16 (m, 3H), 7.10-7.07 (m, 2H), 6.85-6.68 (dd, IH), 4.88-4.83 (m, IH), 3.50-3.37 (m, IH), 3.23-3.17 (m, IH), 2.90 (s, 2H), 2.87-2.78 (m, 2H), 2.75 (s, IH), 2.42-2.28 (m, 2H), 2.25 (s, 4H), 2.16 (s, 2H), 1.44-1.37 (m, 2H), 0.99-0.98 (m, 2H); MS (EI) for C24H29Cl2N3O2, found 462.22 (MH+).
[00263] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(methylamino)- ethyl]-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.27 (s, IH), 8.19 (t, IH), 7.56 (m, 3H), 7.40 (s, 2H), 7.28 (d, 2H), 6.67 (d, IH), 4.49 (m, IH), 3.18 (m, 2H), 2.98 (m, IH), 2.87 (m, IH), 2.64 (m, 2H), 2.35 (s, 3H), 1.34 (m, 2H), 0.93 (m, 2H). MS (EI) for C23H24Cl2F3N3O2, found 502.4 (MH+).
[00264] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(methylamino)- ethyl]-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, IH), 7.96 (br s, IH), 7.58 (s, IH), 7.50 (s, IH), 7.42 (s, 2H), 7.33 (d, IH), 7.18 (d, IH), 6.79 (d, IH), 4.54 (m, IH), 3.19 (m, 2H), 3.06 (m, IH), 2.87 (m, IH), 2.65 (m, 2H), 2.35 (s, 3H), 1.37 (m, 2H), 0.94 (m, 2H). MS (EI) for C22H23Cl4N3O2, found 503.25 (MH+). [00265] N-(2-aminoethyl)-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 7.69 (m, IH), 7.59 (m, IH), 7.50 (m, IH), 7.43 (m, 2H), 7.32 (m, IH), 7.16 (d, IH), 6.67 (m, IH), 4.51 (m, IH), 2.99 (m, 4H), 2.86 (m, IH), 2.50 (m, 2H), 1.33 (m, 2H), 0.95 (m, 2H); MS (EI) for C2IH2ICl4N3O2, found 489.68 (MH+).
[00266] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(2,4-dichlorophenyl)methyl] - 2-oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 7.50-7.39 (m, 4H), 7.28-7.12 (m, 2H), 4.80-4.60 (m, IH), 4.44-4.27 (m, IH), 3.25-3.08 (m, IH), 3.02-2.95 (m, 2H), 2.63-2.58 (m, IH), 2.23-2.00 (m, IH), 1.83-1.72 (m, 3H), 1.62-1.40 (m, 4H), 1.20-1.00 (m, 2H). MS (EI) for C26H27Cl4N3O2, found 555.94 (MH+).
[00267] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2-methyl-l- azabicyclo [2.2.2] oct-3-yl)-L-phenylalaninamide: 1U NMR (400MHz, CD3OD): 8.57 (s, IH), 7.50-7.38 (m, 5H), 7.06-7.00 (m, 2H), 4.62-4.55 (m, IH), 3.60 (dd, IH), 3.22-2.97 (m, 7H), 2.93- 2.80 (m, 2H), 2.00-1.78 (m, 2H), 1.63-1.46 (m, 3H), 1.30 (dd, 3H), 1.20-1.00 (m, 2H). MS (EI) for C27H30BrCl2N3O2, found 580.07 (MH+).
[00268] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(8- methyl-S-azabicycloβ^.ljoct-S-yO-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.45-7.38 (m, 4H), 7.24 (d, IH), 7.18 (d, IH), 4.63-4.60 (m, IH), 3.85-3.82 (t, IH), 3.68-3.59 (m, IH), 3.19-2.99 (m, 2H), 2.63 (s, 3H), 2.30-2.10 (m, 6H), 2.05-1.88 (m, 3H), 1.61-1.45 (m, 2H), 1.20-1.13 (m, IH), 1.05-1.00 (m, IH). MS (EI) for C27H29Cl4N3O2, found 572.13 (MH+). [00269] N-l-azabicyclo[2.2.2]oct-3-yl-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyljcarbonylJ-N-methyl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.41 (s, IH), 7.52-7.37 (m, 4H), 7.29-7.18 (m, IH), 5.20-4.07 (m, IH), 4.40-4.30 (m, IH), 3.73-3.60 (m, 2H), 3.50-3.40 (m, 2H), 3.28-2.85 (m, 6H), 2.43-2.25 (m, IH), 2.18-1.80 (m, 5H), 1.55-1.40 (m, 2H), 1.10-1.05 (m, 2H). MS (EI) for C27H29Cl4N3O2, found 570.18 (MH+). [00270] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)- ethyl]-beta-methylphenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.10-8.07 (m, IH), 7.60 (m, IH), 7.39-7.29 (m, 2H), 7.22-7.19 (m, 3H), 6.97-6.95 (m, 2H), 6.67 (s, IH), 3.48 (d, IH), 3.20-3.03 (m, 2H), 2.98 (d, IH), 2.35-2.24 (m, 2H), 1.55-1.44 (m, 2H), 1.51 (s, 3H), 1.08 (m, IH), 0.90 (m, IH); MS (EI) for C24H29Cl2N3O2, found 462.22 (MH+). [00271] N-l-azabicyclo[2.2.2]oct-3-yl-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-2,4-bis(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO- d6): δ 8.20 (s, IH), 7.99 (t, IH), 7.88 (s, IH), 7.73 (m, IH), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, IH), 4.58 (m, IH), 3.08 (m, 2H), 2.91 (m, IH), 2.66 (m, 4H), 2.28 (m, IH), 1.55 (m, 4H), 1.31 (m, 2H), 1.14 (m, 2H), 0.91 (m, 2H). MS (EI) for C28H27Cl2F6N3O2, found 623 (MH+). [00272] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.04-7.97 (m, IH), 7.63-7.62 (m, IH), 7.43-7.42 (m, 2H), 7.27-7.16 (m, 3H), 7.10-7.03 (m, 2H), 6.47-6.41 (m, IH), 4.55-4.48 (m, IH), 3.72-3.63 (m, IH), 3.38-3.31 (m, IH), 3.14-3.05 (m, IH), 2.90-2.64 (m, 6H), 2.46-2.29 (m, IH), 1.73-1.51 (m, 3H), 1.41-1.39 (m, 2H), 1.36-1.28 (m, IH), 1.00-0.98 (m, 2H); MS (EI) for C26H29Cl2N3O2, found 486.22 (MH+).
[00273] (betaS)-N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyljcarbonylJ-beta-methyl-L-phenylalaninamide: 1H NMR (400MHz, CDCl3): δ 7.36-7.35 (m, IH), 7.28-7.25 (m, IH), 7.23-7.18 (m, 4H), 6.93-6.91 (m, 2H), 6.50-6.49 (m, IH), 5.48-5.46 (m, IH), 4.38-4.35 (m, IH), 4.00-4.01 (m, IH), 3.44-3.32 (m, 2H), 2.95-2.86 (m, 4H), 2.52-2.48 (m, IH), 1.98-1.97 (m, IH), 1.78-1.68 (m, 3H), 1.63-1.57 (m, 3H), 1.23 (d, 3H), 1.09- 0.99 (m, 2H); MS (EI) for C27H3iCl2N3O2, found 500.14 (MH+). [00274] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.01-7.94 (m, IH), 7.64-7.62 (m, IH), 7.46-7.41 (m, 2H), 7.25-7.16 (m, 3H), 7.08-7.02 (m, 2H), 6.46-6.40 (m, IH), 4.51 (q, IH), 3.71-3.61 (m, IH), 3.11-3.03 (m, IH), 2.84-2.79 (m, 2H), 2.78-2.66 (m, 4H), 2.48-2.27 (m, IH), 1.71-1.49 (m, 4H), 1.41-1.39 (m, 2H), 1.36-1.25 (m, IH), 1.02-0.98 (m, 2H); MS (EI) for C26H29Cl2N3O2, found 486.09 (MH+).
[00275] N-l-azabicyclo[2.2.2]oct-3-yl-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-N-methyl-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 7.63 (s, IH), 7.43 (s, 2H), 7.26-7.18 (m, 3H), 7.11-7.09 (m, 2H), 6.78 (d, IH), 4.91-4.85 (m, IH), 4.35-4.24 (m, IH), 3.39-3.35 (m, 2H), 3.26-3.15 (m, 2H), 3.09 (m, 3H), 2.94-2.84 (m, 5H), 2.07-1.94 (m, IH), 1.83-1.64 (m, 3H), 1.41-1.39 (m, 2H), 1.00 (s, 2H); MS (EI) for C27H3iCl2N3O2, found 500.26 (MH+).
[00276] N-l-azabicyclo[2.2.2]oct-3-yl-Nalpha-({l-[4-(methyloxy)phenyl]cyclopropyl}- carbonyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.29- 8.24 (m, IH), 7.63-7.60 (m, 2H), 7.26-7.18 (m, 4H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, IH), 4.58 (q, IH), 3.75 (s, 4H), 3.15 (t, IH), 2.99-2.88 (m, 2H), 2.85-2.70 (m, 4H), 2.55-2.40 (m, IH), 1.75-1.49 (m, 4H), 1.41-1.28 (m, IH), 1.25-1.23 (m, 2H), 0.95-0.86 (m, 2H); MS (EI) for C28H32F3N3O2, found 516.26 (MH+).
[00277] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.50-7.38 (m, 3H), 7.15-7.00 (m, 3H), 4.84-4.80 (m, IH), 3.63-3.43 (m, 2H), 4.18 (t, IH), 3.23-3.18 (m, IH), 3.19-2.99 (m, 2H), 2.83-2.78 (m, 3H), 2.58-2.50 (m, IH), 2.39-2.30 (m, IH), 2.16-2.03 (m, IH), 1.98-1.80 (m, IH), 1.60-1.40 (m, 5H), 1.20-1.05 (m, 2H). MS (EI) for C26H28BrCl2N3O2, found 565.03 (MH+).
[00278] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-2,4-bis(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-de): δ 8.20 (s, IH), 8.00 (d, IH), 7.87 (s, IH), 7.68 (m, IH), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, IH), 4.58 (m, IH), 3.12 (m, 2H), 2.93 (m, 3H), 2.61 (m, 4H), 2.24 (m, IH), 1.64 (m, IH), 1.50 (m, 3H), 1.27 (m, 2H), 1.12 (m, IH), 0.91 (m, 2H). MS (EI) for C28H27Cl2F6N3O2, found 623 (MH+).
[00279] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, IH), 8.01 (d, IH), 7.62 (s, IH), 7.43 (s, 2H), 7.27 (d, 2H), 7.05 (d, 2H), 6.47 (d, IH), 4.49 (m, IH), 3.08 (m, IH), 2.81 (m, 2H), 2.72 (m, 4H), 2.42 (m, 2H), 1.57 (m, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.26 (m, IH), 0.98 (m, 2H). MS (EI) for C26H28Cl3N3O2, found 521 (MH+). [00280] N-[(lS)-l-{[(3S)-l-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-3-phenylpropyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 7.59 (s, IH), 7.50 (d, IH), 7.40 (d, IH), 7.26-7.10 (m, 5H), 4.40 (dd, IH), 4.02-3.98 (m, IH), 3.55-3.44 (m, IH), 3.20-3.03 (m, 3H), 2.80-2.75 (m, IH), 2.60-2.45 (m, 2H), 2.05-1.93 (m, 7H), 1.78-1.58 (m, 3H), 1.22-1.09 (m, 2H). MS (EI) for C27H3ICl2N3O2, found 589.07 (MH+). [00281] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyljcarbonylJ^-^rifluoromethylJ-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.70-7.58 (m, 2H), 7.43-7.38 (m, 4H), 4.65-4.60 (m, IH), 4.09-3.99 (m, IH), 3.59-3.48 (m, IH), 3.20-3.05 (m, 5H), 3.02-2.95 (m, IH), 2.78-2.73 (m, IH), 2.10-2.04 (m, IH), 1.99-1.83 (m, 3H), 1.80-1.68 (m, IH), 1.57-1.44 (m, 2H), 1.17-1.10 (m, IH), 1.05-0.98 (m, IH). MS (EI) for C27H3ICl2N3O2, found 500.20 (MH+).
[00282] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-l-(phenylmethyl)-L-histidinamide: 1H NMR (400MHz, CD3OD): 8.35 (s, IH), 7.72 (s, IH), 7.43-7.22 (m, 9H), 6.80 (s, IH), 5.18 (s, 2H), 4.44 (t, IH), 4.09-4.03 (m, IH), 3.60 (t, IH), 3.30-3.20 (m, 3H), 3.02-2.80 (m, 3H), 2.15-1.80 (m, 4H), 1.60-1.50 (m, 2H), 1.13-0.97 (m, 3H). MS (EI) for C30H33Cl2N5O2, found 566.21 (MH+). [00283] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N~2-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-3-(2,2-difluoro-l,3-benzodioxol-5-yl)-L-alaninamide: 1H NMR (400MHz, CD3OD): 8.45 (s, IH), 7.45-7.37 (m, 3H), 7.09 (d, IH), 6.96 (s, IH), 6.88 (d, IH), 4.57 (dd, IH), 4.09-4.03 (m, IH), 3.65-3.60 (m, IH), 3.32-3.13 (m, 4H), 3.03-2.80 (m, 3H), 2.17-2.15 (m, IH), 2.02-1.95 (m, 3H), 1.90-1.77 (m, IH), 1.62-1.47 (m, 2H), 1.20-1.02 (m, 2H). MS (EI) for C27H27Cl2F2N3O2, found 567.15 (MH+).
[00284] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[3-(lH- imidazol-l-yl)propyl]-L-phenylalaninamide: 1U NMR (400MHz, CD3OD): 8.84 (s, IH), 7.62 (s, IH), 7.58 (s, IH), 7.44-7.38 (m, 5H), 7.00 (d, 2H), 4.40 (dd, IH), 4.19 (t, 2H), 3.22-3.05 (m, 2H), 3.00-2.95 (m, IH), 2.81-2.77 (dd, IH), 2.05-1.98 (m, 2H), 1.65-1.60 (m, IH), 1.57-1.44 (m, IH), 1.22-1.17 (m, IH), 1.05-0.98 (m, IH). MS (EI) for C25H25BrCl2N4O2, found 566.08 (MH+). [00285] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-2-fluoro-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.22 (s, IH), 8.06 (d, IH), 7.62 (m, IH), 7.58 (d, IH), 7.49 (t, IH), 7.44 (s, 2H), 7.35 (m, IH), 6.53 (m, IH), 4.58 (m, IH), 3.13 (m, IH), 2.93 (m, 2H), 2.75 (m, 4H), 2.37 (m, IH), 1.65 (m, 4H), 1.42 (m, 2H), 1.29 (m, 2H), 0.99 (m, 2H). MS (EI) for C27H27Cl2F4N3O2, found 573 (MH+).
[00286] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(lS,3S,4S)-l- oxido-l-azabicyclo[2.2.2]oct-3-yl]-L-phenylalaninamide: N-[(3S)-l-azabicyclo[2.2.2]oct-3- yl]-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]-carbonyl}-L-phenylalaninamide (50 mg, 0.088 mmol) was dissolved in CH2Cl2 (0.9 rnL). To the solution was added mCPBA (65.4 mg, 0.265 mmol). The reaction mixture was stirred for 30 minutes at room temperature. The solvent was removed in vacuo. The residue was dissolved in MeOH and purified using preparative HPLC (30-45% MeCN in water with 0.1% formic acid). The purified material was lyophilized to produce 23 mg (45%) of the desired product as a white powder. 1H NMR
(400MHz, DMSO-de): δ 8.24 (s, IH), 7.48-7.37 (m, 5H), 7.02 (m, 2H), 6.33 (m, IH), 4.52 (m,
IH), 4.17 (m, IH), 3.72 (m, IH), 4.51 (m, IH), 3.38 (m, 4H), 2.88 (m, 3H), 2.01 (m, 5H), 1.55
(m, 2H), 1.09 (m, 2H); MS (EI) for C26H28BrCl2N3O3, found 489.68 (MH+).
[00287] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-2-fluorophenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.18
(s, IH), 7.60 (m, 2H), 7.37 (m, 5H), 6.97 (m, IH), 4.87 (m, IH), 3.04-3.87 (m, 4H), 2.90 (m,
2H), 2.68 (m, 2H), 2.11 (s, 3H), 1.79 (m, 2H), 1.17-1.48 (m, 4H), 0.93 (m, 2H). MS (EI) for
C27H28Cl2F3N3O2, found 554.35 (MH+).
[00288] l-(2,4-dichlorophenyl)-N-[(lS)-2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2-oxo- l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanecarboxamide: 1H NMR (400
MHz, DMSO-d6):δ 8.19 (s, IH), 7.58 (m, 3H), 7.56 (s, 2H), 7.31 (d, 2H), 6.90 (d, IH), 4.44 (m,
IH), 4.14 (m, IH), 3.85 (m, 3H), 3.27 (m, 4H), 2.85 (m, 2H), 2.27 (s, 3H), 1.35 (m, 2H), 0.93
(m, 2H). MS (EI) for C26H26Cl2F3N3O2, found 540.38 (MH+).
[00289] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -Nalpha-({1- [4-(methyloxy)phenyl] - cyclopropyl}carbonyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400MHz,
DMSO-d6): δ 8.29-8.24 (m, IH), 7.63-7.60 (m, 2H), 7.26-7.24 (m, 2H), 7.21-7.18 (m, 2H), 6.89-
6.86 (m, 2H), 6.28-6.23 (m, IH), 4.61-4.56 (m, IH), 3.75 (s, 3H), 3.72-3.65 (m, IH), 3.18-3.13
(m, IH), 2.99-2.89 (m, 2H), 2.85-2.79 (m, 4H), 2.54-2.42 (m, IH), 1.75-1.45 (m, 4H), 1.40-1.28
(m, IH), 1.25-1.20 (m, 2H), 0.95-0.86 (m, 2H); MS (EI) for C28H32F3N3O3, found 516.26
(MH+).
[00290] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-({l-[4-(methyloxy)phenyl]- cyclopropyl}carbonyl)-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400MHz,
DMSO-d6): δ 8.29-8.27 (m, IH), 7.63-7.60 (m, 2H), 7.27-7.24 (m, 2H), 7.21-7.18 (m, 2H), 6.89-
6.86 (m, 2H), 6.28-6.23 (m, IH), 4.62-4.56 (m, IH), 3.75 (s, 3H), 3.68 (m, IH), 3.19-3.13 (m,
IH), 2.99-2.86 (m, 2H), 2.81-2.69 (m, 4H), 2.55-2.41 (m, IH), 1.75-1.31 (m, 5H), 1.28-1.20 (m,
2H), 0.95-0.86 (m, 2H); MS (EI) for C28H32F3N3O3, found 516.26 (MH+).
[00291] N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-({l-[4-(methyloxy)phenyl]- cyclopropyl}carbonyl)-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.26 (d, IH),
7.45-7.41 (m, 2H), 7.22-7.19 (m, 2H), 6.99-6.95 (m, 2H), 6.91-6.89 (m, 2H), 6.26-6.21 (m, IH),
4.55-4.50 (m, IH), 3.76 (s, 3H), 3.73-3.71 (m, IH), 3.16-3.10 (m, IH), 2.86-2.67 (m, 6H), 2.54- 2.38 (m, IH), 1.74-1.33 (m, 5H), 1.30-1.21 (m, 2H), 0.96-0.87 (m, 2H); MS (EI) for
C27H32BrN3O3, found 528.17 (MH+).
[00292] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl]-4-bromo-Nalpha-({l- [4-(methyloxy)phenyl] - cyclopropyljcarbonyO-L-phenylalaninamide 1H NMR (400MHz, DMSO-d6): δ 8.21 (d, IH),
7.45-7.41 (m, 2H), 7.22-7.20 (m, 2H), 6.99-6.94 (m, 2H), 6.91-6.89 (m, 2H), 6.25-6.20 (m, IH),
4.55-4.50 (m, IH), 3.76 (s, 3H), 3.72-3.62 (m, IH), 3.14-3.08 (m, IH), 2.84-2.67 (m, 6H), 2.52-
2.50 (m, IH), 1.72-1.51 (m, 4H), 1.34-1.28 (m, IH), 1.27-1.21 (m, 2H), 0.96-0.87 (m, 2H); MS
(EI) for C27H32BrN3O3, found 528.17 (MH+).
[00293] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-pyridin-4-yl-
L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.42 (s, IH), 7.70 (s, 2H), 7.50-7.38 (m,
6H), 6.98 (d, 2H), 4.63 (dd, IH), 3.09 (dd, IH), 2.90 (dd, IH), 1.63-1.50 (m, 2H), 1.06-1.00 (m,
IH). MS (EI) for C24H20BrCl2N3O2, found 533.83 (MH+).
[00294] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-phenyl-Nalpha-({l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl)-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.63-7.30 (m,
10H), 7.20-7.15 (m, 2H), 4.60 (t, IH), 3.88-3.82 (m, IH), 3.02-2.78 (m, 7H), 2.47-2.40 (m, IH),
1.97-1.93 (m, IH), 1.82-1.68 (m, 3H), 1.64-1.50 (m, 3H), 1.18-1.03 (m, 2H). MS (EI) for
C32H33Cl2N3O2, found 563.19 (MH+).
[00295] N-l-azabicyclo[2.2.2]oct-4-yl-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.55 (s, IH),
7.50-7.37 (m, 5H), 6.99 (d, 2H), 4.45 (t, IH), 3.40-3.30 (m, 5H), 2.96 (dd, IH), 2.89 (dd, IH),
2.19-2.08 (m, 7H), 1.60-1.48 (m, 2H), 1.17-1.02 (m, 2H). MS (EI) for C26H28BrCl2N3O2, found
566.15 (MH+).
[00296] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-3-cyclohexyl-N~2-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-alaninamide: 1H NMR (400 MHz, DMSO-d6): δ 7.87 (d, IH), 7.62
(m, IH), 7.44 (m, 2H), 6.48 (d, IH), 4.36 (m, IH), 3.63 (m, IH), 3.05 (t, IH), 2.66 (m, 4H), 2.34
(d, IH), 1.72-1.23 (m, 14H), 1.03 (m, 6H), 0.78 (m, 2H). MS (EI) for C26H35Cl2N3O2, found 493
(MH+).
[00297] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -Nalpha-({1- [2-fluoro-4-(trifluoromethyl)- phenyljcyclopropylJcarbonylJ^-^rifluoromethylJ-L-phenylalaninamide: 1H NMR
(400MHz, DMSO-de): δ 8.18 (d, IH), 7.63-7.55 (m, 5H), 7.32-7.28 (m, 2H), 6.86-6.82 (m, IH),
4.59-4.54 (m, IH), 3.74-3.73 (m, IH), 3.23-3.18 (m, IH), 2.98-2.91 (m, 2H), 2.86-2.78 (m, 4H), 2.58-2.45 (m, IH), 1.80-1.60 (m, 4H), 1.44-1.28 (m, 3H), 1.11-0.96 (m, 2H); MS (EI) for C28H28F7N3O2, found 572.26 (MH+).
[00298] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[3-(dimethyl- amino)-8-azabicyclo[3.2.1]oct-8-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR
(400MHz, CD3OD): 7.52-7.38 (m, 4H), 7.24-7.10 (m, 2H), 4.82-4.78 (m, IH), 4.58 (t, IH), 4.37 (t, IH), 3.18-3.00 (m, 3H), 2.90 (s, 6H), 2.62-2.57 (m, 2H), 1.80-1.65 (m, 4H), 1.58-1.47 (m, 4H), 1.28-1.21 (m, IH), 1.03-.097 (m, IH) . MS (EI) for C28H3ICl4N3O2, found 583.50 (MH+). [00299] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.50 (s, IH), 7.50-7.38 (m, 3H), 7.28-7.23 (m, IH), 7.17-7.08 (m, IH), 5.20-5.10 (m, IH), 4.10- 3.80 (m, 2H), 4.60-3.45 (m, IH), 3.18-3.02 (m, 2H), 2.98-2.83 (s, IH), 1.85-1.60 (m, 4H), 1.55- 1.37 (m, 5H), 1.13-1.00 (m, 2H). MS (EI) for C28H3iCl4N3O2, found 543.50 (MH+). [00300] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-N'2'-methyl-5-phenyl-L-norvalinamide: 1H NMR (400MHz, CD3OD): 8.45 (s, IH), 7.45-7.35 (m, 3H), 7.25-7.05 (m, 5H), 4.73-4.69 (m, IH), 4.15-4.08 (m, IH), 3.65-3.58 (m, IH), 3.21-3.13 (m, 2H), 3.00-2.95 (m, IH), 2.68-2.45 (m, 5H), 2.10-1.90 (m, 4H), 1.88-1.65 (m, 4H), 1.65-1.43 (m, 4H), 1.40-1.20 (m, 3H), 0.87-0.80 (m, IH). MS (EI) for C29H35Cl2N3O2, found 528.23 (MH+).
[00301] N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl]- N-methyl-5-phenyl-L-norvalinamide: 1H NMR (400MHz, CD3OD): 8.41 (s, IH), 7.56 (s, IH), 7.43 (d, IH), 7.39 (d, IH), 7.27-7.14 (m, 5H), 4.68 (dd, IH), 3.85-3.80 (m, IH), 3.45-3.38 (m, IH), 3.17-3.11 (m, IH), 3.05 (s, 3H), 2.78 (s, 6H), 2.63-2.55 (m, 3H), 1.75-1.43 (m, 6H), 1.22- 1.05 (m, 2H). MS (EI) for C26H33Cl2N3O2, found 491.76 (MH+). [00302] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(4-methylpiperazin-l-yl)carbonyl]-4- phenylbutyl}cyclo propanecarboxamide: 1U NMR (400MHz, CD3OD): 8.30 (s, IH), 7.59 (s, IH), 7.46 (d, IH), 7.40 (d, IH), 7.28-7.12 (m, 5H), 4.82-4.79 (m, IH), 3.60-3.40 (m, 4H), 2.70-
3.42 (m, 6H), 2.40 (s, 3H), 1.73-1.40 (m, 6H), 1.21-1.18 (m, IH), 1.08-1.03 (m, IH). MS (EI) for C26H3ICl2N3O2, found 489.93 (MH+).
[00303] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(3R)-3- methylpiperazin-l-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD):
8.43 (s, IH), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H), 7.20-7.15 (m, IH), 4.35 (dd, IH), 4.00 (dd, IH), 3.25-2.80 (m, 7H), 1.57-1.43 (m, 2H), 1.20-1.05 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 529.99 (MH+).
[00304] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-[(l-{4-[(trifluoromethyl)- oxyjphenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-dβ): δ 8.18 (d, IH), 7.44 (d, 2H), 7.37 (d, 2H), 7.31 (d, 2H), 7.03 (d, 2H), 6.63 (d, IH), 4.52 (q, IH), 3.70 (s, IH), 3.16 (t, IH), 2.88-2.78 (m, 6H), 2.45-2.43 (m, IH), 1.76-1.56 (m, 4H), 1.40 (s, IH), 1.29-1.22 (m, 2H), 1.04-0.97 (m, 2H); MS (EI) for C27H29BrF3N3O3, found 580.13 (MH+). [00305] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -4-bromo-Nalpha-({l- [2-fluoro-4- (trifluoromethylJphenyljcyclopropylJcarbonylJ-L-phenylalaninamide: 1H NMR (400MHz, DMSO-de): δ 8.18 (d, IH), 7.65 (d, IH), 7.59 (d, 2H), 7.32 (d, 2H), 7.04 (d, 2H), 6.83 (d, IH), 4.49 (q, IH), 3.73 (s, IH), 3.20 (t, IH), 2.84-2.82 (m, 6H), 2.46 (s, IH), 1.80-1.60 (m, 4H), 1.44- 1.30 (m, 3H), 1.11-0.94 (m, 2H); MS (EI) for C27H28BrF4N3O2, found 584.16 (MH+). [00306] (betaS)-N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,4- dichlorophenyl)-cyclopropyl] carbonylj-beta-methylphenylalaninamide: 1H NMR
(400MHz, DMSO-de): δ 8.31-7.94 (m, IH), 7.68-7.65 (m, IH), 7.53-7.31 (m, 4H), 7.13-7.11 (m, IH), 6.97-6.94 (m, IH), 6.46-5.95 (m, IH), 4.54-4.45 (m, IH), 3.71-3.43 (m, IH), 3.23-3.01 (m, IH), 2.96-2.62 (m, 5H), 2.55-2.42 (m, IH), 1.86-1.71 (m, IH), 1.65-1.23 (m, 6H), 1.13-1.09 (m, 3H), 1.06-0.96 (m, 2H), 0.93-0.84 (m, IH); MS (EI) for C27H30BrCl2N3O2, found 580.07 (MH+). [00307] (betaR)-N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,4- dichlorophenyl)cyclopropyl]carbonyl}-beta-methylphenylalaninamide: 1H NMR (400MHz, DMSO-de): δ 8.36-7.98 (m, IH), 7.68-7.64 (m, IH), 7.52-7.36 (m, 4H), 7.13-7.10 (m, IH), 6.97- 6.95 (m, IH), 6.49-5.97 (m, IH), 4.53-4.45 (m, IH), 3.74-3.47 (m, IH), 3.26-3.02 (m, IH), 2.99- 2.67 (m, 5H), 2.57-2.49 (m, IH), 1.90-1.80 (m, IH), 1.67-1.23 (m, 6H), 1.13-1.09 (m, 3H), 1.06- 1.00 (m, 2H), 0.93-0.88 (m, IH); MS (EI) for C27H30BrCl2N3O2, found 580.13 (MH+). [00308] Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[trans-4- phenylpyrrolidin-3-yl]-4-(trifluoromethyl)-L-phenylalaninamide: MS (EI) for
C30H28Cl2F3N3O2, found 590.5 (MH+).
[00309] N-l-azabicyclo[2.2.2]oct-3-yl-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-D-phenylalaninamide: 1H NMR (400 MHz, DMSO-de): δ 8.22 (s, IH), 8.06 (m, IH), 7.61 (s, IH), 7.41 (m, 4H), 7.00 (m, 2H), 6.49 (m, IH), 4.50 (m, IH), 3.14 (m, IH), 2.77 (m, 6H), 2.37 (m, IH), 1.63 (m, 4H), 1.35 (m, 3H), 0.97 (m, 2H). MS (EI) for
C26H28BrCl2N3O2, found 566 (MH+).
[00310] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400
MHz, DMSO-d6):δ 8.29 (s, IH), 7.41 (d, 2H), 7.33 (m, 4H), 6.98 (m, 3H), 4.68 (m, IH), 4.24 (m,
3H), 3.08 (m, IH), 2.82 (m, 2H), 2.30-1.51 (m, 8H), 1.23 (m, 2H), 0.97 (m, 2H). MS (EI) for
C27H29BrF3N3O3, found 581 (MH+).
[00311] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-N~2-{[l-(2,4- dichlorophenyl)-cyclopropyl] carbonyl}-L-norvalinamide: 1H NMR (400MHz, CD3OD): δ 8.40 (s, IH), 7.57 (s, IH), 7.44 (d, IH), 7.38 (d, IH), 7.28-7.23 (m, 2H), 7.17-7.10 (m, 2H),
4.40-4.37 (m, IH), 4.14-4.09 (m, IH), 3.68-3.60 (m, IH), 3.30-3.20 (m, 3H), 2.98-2.85 (m, IH),
2.63-2.49 (m, 2H), 2.16-1.80 (m, 6H), 1.78-1.62 (m, 2H), 1.58-1.48 (m, 4H), 1.21-1.06 (m, 2H).
MS (EI) for C28H32Cl3N3O2, found 550.21 (MH+).
[00312] N-{(lS)-2-[(3R)-3-aminopiperidin-l-yl]-l-[(2,4-dichlorophenyl)methyl]-2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): δ 8.57 (s, IH), 7.50-7.38 (m, 4H), 7.29-7.13 (m, 2H), 5.20-5.10 (m, IH), 4.50 (dd, IH), 3.79-3.60
(m, IH), 3.16-2.94 (m, 6H), 2.90-2.80 (m, IH), 2.18-2.20 (m, IH), 1.82-1.40 (m, 5H), 1.18-1.00
(m, 2H). MS (EI) for C24H25Cl4N3O2, found 530.12 (MH+).
[00313] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD):
8.38 (s, IH), 7.61 (s, 4H), 7.45-7.39 (m, 3H), 7.04 (d, 2H), 6.78 (d, IH), 4.96-4.87 (m, IH), 3.80-
3.42 (m, 2H), 3.40-3.25 (m, 2H), 2.83-2.65 (m, 2H), 1.78-1.30 (m, 4H), 1.19-1.09 (d, 3H), 1.00-
0.95 (m, 2H). MS (EI) for C25H28BrCl2N3O2, found 554.05 (MH+).
[00314] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-l-
(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.38 (s, IH),
7.60-7.50 (m, 2H), 7.43-7.30 (m, 2H), 7.24-7.20 (m, IH), 6.97 (t, IH), 5.03-4.98 (m, IH), 4.21-
4.18 (m, IH), 3.95 (t, 2H), 3.35-2.90 (m, 4H), 2.67-2.57 (m, IH), 1.88-1.78 (m, 2H), 1.40-1.10
(m, 3H), 1.00-0.90 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 529.99 (MH+).
[00315] l-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[(3S)-3- methylpiperazin-l-yl]-2-oxoethyl}cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD):
8.42 (s, IH), 7.53-7.39 (m, 4H), 7.33-7.13 (m, 2H), 5.20-5.15 (m, IH), 4.40 (dd, IH), 4.02 (dd, IH), 3.25-2.84 (m, 6H), 2.80-2.58 (m, IH), 1.55-1.40 (m, 2H), 1.23-1.00 (m, 5H). MS (EI) for
C24H25Cl4N3O2, found 530.12 (MH+).
[00316] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(2S)- pyrrolidin-2-ylmethyl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.40 (br, s, IH),
7.43-7.37 (m, 4H), 7.22 (d, IH), 7.18 (d, IH), 4.58-4.55 (m, IH), 3.68-3.45 (m, 2H), 3.22-3.15
(m, 2H), 3.19-3.13 (m, IH), 3.05-2.97 (m, IH), 2.17-1.96 (m, 4H), 1.80-1.68 (m, IH), 1.80-1.44
(m, 2H), 1.20-1.16 (m, IH), 1.05-0.97 (m, IH). MS (EI) for C24H25Cl4N3O2, found 531.94
(MH+2).
[00317] 2,4-dichloro-Nalpha- { [ l-(2,4-dichlorophenyl)cyclopropyl] carbonyl}-N- [(2R)- pyrrolidin-2-ylmethyl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): 8.28 (s, IH),
7.58 (s, IH), 7.52 (s, IH), 7.40-7.25 (m, 3H), 7.19 (d, IH), 6.91 (d, IH), 4.58-4.55 (m, IH),
3.38-3.10 (m, 2H), 3.05-2.90 (m, 4H), 1.82-1.58 (m, 3H), 1.42-1.18 (m, 3H), 1.00-0.85 (m, 3H).
MS (EI) for C24H25Cl4N3O2, found 530.12 (MH+).
[00318] 2,4-dichloro-Nalpha- { [ l-(2,4-dichlorophenyl)cyclopropyl] carbonyl}-N- [(3R)- pyrrolidin-3-ylmethyl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): 8.35 (s, IH),
8.03 (dt, IH), 7.59 (s, IH), 7.54 (s, IH), 7.42 (s, IH), 7.33 (d, IH), 7.18 (d, IH), 6.80 (dd, IH),
4.55-4.45 (m, IH), 3.18-2.97 (m, 6H), 2.93-2.70 (m, 2H), 2.35-2.25 (m, IH), 1.95-1.88 (m, IH),
1.52-1.25 (m, 3H), 0.99-0.90 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 529.99 (MH+).
[00319] 2,4-dichloro-Nalpha- { [ l-(2,4-dichlorophenyl)cyclopropyl] carbonyl}-N- [(3 S)- pyrrolidin-3-ylmethyl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.48 (s, IH),
7.48-7.38 (m, 4H), 7.24 (d, IH), 7.16 (d, IH), 4.58-4.52 (m, IH), 3.18-2.97 (m, 4H), 3.02-2.88
(m, 2H), 2.55-2.45 (m, IH), 2.15-2.00 (m, IH), 1.75-1.45 (m, 3H), 1.24-1.10 (m, 2H), 1.03-0.97
(m, IH). MS (EI) for C24H25Cl4N3O2, found 529.80 (MH+).
[00320] N-{(1 S)-2- [(3S)-3-aminopyrrolidin-l-yl] -1- [(2,4-dichlorophenyl)methyl] -2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD):
8.23 (s, IH), 7.62-7.52 (m, 2H), 7.44-7.30 (m, 3H), 7.20 (t, IH), 6.84 (dd, IH), 4.82-4.76 (m,
IH), 3.85-3.65 (m, 2H), 3.40-3.25 (m, 2H), 3.20-3.03 (m, IH), 3.00-2.90 (m, IH), 2.85-2.80 (m,
IH), 2.00-1.87 (m, IH), 1.75-1.57 (m, IH), 1.40-1.35 (m, IH), 1.21-1.10 (m, IH), 0.97-0.85 (m,
2H). MS (EI) for C23H23Cl4N3O2, found 516.07 (MH+).
[00321] N-{(lS)-2-[(3R)-3-aminopyrrolidin-l-yl]-l-[(2,4-dichlorophenyl)methyl]-2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): 8.28 (s, IH), 7.62-7.52 (m, 2H), 7.48-7.30 (m, 3H), 7.25-7.20 (m, IH), 6.83 (dd, IH), 4.86-4.77 (m, IH), 3.68-3.57 (m, 3H), 3.45-3.37 (m, IH), 3.34-3.17 (m, 2H), 3.80-2.90 (m, 2H), 2.05-1.90 (m, 2H), 1.85-1.65 (m, 2H), 1.40-1.33 (m, IH), 1.27-1.1.10 (m, IH), 1.03-0.90 (m, 2H). MS (EI) for C23H23Cl4N3O2, found 516.07 (MH+).
[00322] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3R)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): 8.25 (s, IH), 7.88 (d, IH), 7.60 (s, IH), 7.55 (s, IH), 7.43-7.30 (m, 3H), 7.35 (d, IH), 7.18 (d, IH), 6.77 (d, IH), 4.57- 4.45 (m, IH), 3.73-3.65 (m, IH), 3.00-2.80 (m, 4H), 2.65-2.60 (m, IH), 1.70-1.60 (m, 2H), 1.50- 1.20 (m, 4H), 1.00-0.90 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 530.05 (MH+). [00323] N-{(1 S)-2- [(3S)-3-aminopiperidin-l-yl] -1- [(2,4-dichlorophenyl)methyl] -2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.56 (s, IH), 7.50-7.38 (m, 3H), 7.28-7.22 (m, IH), 7.18-7.13 (m, IH), 5.20-5.08 (m, IH), 4.10 (ddd, IH), 3.64-3.58 (m, IH), 3.45-3.38 (m, IH), 3.18-2.80 (m, 4H), 2.10-1.95 (m, IH), 1.89- 1.78 (m, IH), 1.68-1.57 (m, IH), 1.50-1.45 (m, 3H), 1.15-1.00 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 530.05 (MH+).
[00324] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3S)- pyrrolidin-3-yl]-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.94 (d, IH), 7.58 (s, IH), 7.39 (m, 4H), 7.01 (d, 2H), 6.61 (d, IH), 4.38 (m, IH), 4.11 (m, IH), 2.94 (m, 3H), 2.73 (m, 3H), 1.90 (m, IH), 1.60 (m, IH), 1.37 (m, 2H), 0.95 (m, 2H). MS (EI) for C23H24BrCl2N3O2, found 526 (MH+).
[00325] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3R)- pyrrolidin-3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, IH), 7.59 (s, IH), 7.40 (m, 4H), 7.01 (d, 2H), 6.61 (d, IH), 4.40 (m, IH), 4.12 (m, IH), 2.93 (m, 3H), 2.74 (m, 3H), 1.86 (m, IH), 1.48 (m, IH), 1.36 (m, 2H), 0.96 (m, 2H). MS (EI) for C23H24BrCl2N3O2, found 526 (MH+).
[00326] N-(3-aminocyclohexyl)-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.52 (s, IH), 7.50-7.38 (m, 4H), 7.23-7.15 (m, 2H), 4.82-4.75 (m, IH), 3.67-3.58 (m, IH), 2.20-2.13 (m, IH), 2.02-1.83 (m, 3H), 1.77-1.40 (m, 5H), 1.25-1.00 (m, 3H). MS (EI) for C24H27Cl4N3O2, found 544.16 (MH+). [00327] N-[(lS)-l-(biphenyl-4-ylmethyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l-(2,4- dichlorophenyl)cyclopropanecarboxamide: 1U NMR (400MHz, CD3OD): 7.60 (d, IH), 7.55- 7.50 (m, 3H), 7.45-7.39 (m, 3H), 7.38-7.33 (m, 2H), 7.20-7.15 (m, 2H), 5.07 (t, IH), 3.60-3.40 (m, 4H), 2.96 (d, 2H), 2.53-2.40 (m, 2H), 2.38-2.30 (m, IH), 2.24 (s, 3H), 2.05-1.97 (m, IH), 1.65-1.55 (m, 2H), 1.18-1.06 (m, 2H). MS (EI) for C30H3ICl2N3O2, found 537.99 (MH+). [00328] N-[(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-(biphenyl-4-ylmethyl)-2-oxoethyl]- l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.64-7.60 (m, 2H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 4H), 7.38-7.30 (m, 2H), 7.18-7.14 (m, 2H), 5.03 (dd, IH), 3.90-3.65 (m, 2H), 3.55-3.43 (m, IH), 3.30-3.20 (m, IH), 3.00-2.83 (m, 2H), 1.79-1.50 (m, 6H), 1.30 (dd, 3H), 1.20-1.03 (m, 2H). MS (EI) for C3iH33Cl2N3O2, found 550.21 (MH+).
[00329] N-[(lS)-l-(biphenyl-4-ylmethyl)-N-[2-(dimethylamino)ethyl]-2-oxoethyl]-l-(2,4- dichloro phenyl)cyclo propanecarboxamide: 1H NMR (400MHz, CD3OD): 7.60 (d, 2H), 7.56-7.43 (m, 5H), 7.40-7.35 (m, 2H), 7.20-7.16 (m, 2H), 3.80-3.75 (m, IH), 3.47-3.41 (m, 2H), 3.00 (s, 3H), 2.97-2.80 (m, 4H), 2.63 (s, 6H), 1.64-1.55 (m, 2H), 1.18-1.05 (m, 2H). MS (EI) for C30H33Cl2N3O2, found 538.24 (MH+).
[00330] N-(2-aminocyclohexyl)-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.53 (s, IH), 7.45-7.37 (m, 4H), 7.30-7.26 (m, IH), 7.18-7.14 (m, IH), 4.75-4.60 (m, IH), 4.30-4.25 (m, IH), 3.40-3.35 (m, IH), 3.12-3.06 (m, 2H), 1.80-1.40 (m, 10H), 1.28-1.00 (m, 3H). MS (EI) for C25H27Cl4N3O2, found 544.16 (MH+).
[00331] N-[(lR,2R)-2-aminocyclohexyl]-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.44-7.37 (m, 4H), 7.26-7.22 (m, IH), 7.18-7.14 (m, IH), 4.62 (s, IH), 4.28 (t, IH), 3.78 (ddd, IH), 3.07 (d, 2H), 2.93-2.84 (ddd, IH), 2.08-2.00 (m, IH), 1.84-1.62 (m, 4H), 1.52-1.20 (m, 7H), 1.02-0.97 (m, IH). MS (EI) for C25H27Cl4N3O2, found 544.10 (MH+).
[00332] N-[(lS,2S)-2-aminocyclohexyl]-2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.45-7.38 (m, 4H), 7.28 (d, IH), 7.17 (d, IH), 4.63 (s, IH), 4.58 (dd, IH), 3.73 (ddd, IH), 3.25- 3.20 (m, 2H), 3.02-2.95 (m, 2H), 2.05-2.00 (m, IH), 1.90-1.86 (m, 2H), 1.50-1.30 (m, 5H), 1.20- 1.90 (m, IH), 1.03-0.98 (m, IH). MS (EI) for C25H27Cl4N3O2, found 544.04 (MH+). [00333] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3S)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.48-7.38 (m, 4H), 7.23 (d, IH), 7.16 (d, IH), 4.63-4.60 (m, IH), 3.97-3.93 (m, IH), 3.30-3.27 (m, IH), 3.18-3.06 (m, IH), 3.02-2.83 (m, 2H), 2.64-2.57 (m, IH), 2.00-1.95 (m, 2H), 1.82-1.76 (m, IH), 1.60-1.43 (m, 4H), 1.17-1.00 (m, 2H). MS (EI) for C24H25Cl4N3O2, found 530.12 (MH+). [00334] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-l- (2,4-dichlorophenyl)cyclopropanecarboxamide: 1U NMR (400MHz, CD3OD): 8.37 (s, IH), 7.58 (d, IH), 7.40-7.35 (m, 3H), 7.00-6.90 (m, 2H), 4.85-4.80 (m, IH), 4.18-4.05 (m, 2H), 3.86- 3.78 (m, 2H), 3.05-2.85 (m, 2H), 2.80-2.68 (m, 3H), 1.80-1.73 (m, 2H), 1.37-1.00 (m, 3H), 0.95- 0.86 (m, 2H). MS (EI) for C24H26BrCl2N3O2, found 540.07 (MH+). [00335] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3R)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.37 (s, IH), 8.40 (d, IH), 7.60 (s, IH), 7.48-7.37 (m, 3H), 7.03 (d, 2H), 6.60 (d, IH), 4.45-4.39 (m, IH), 3.75-3.65 (m, IH), 3.06-2.88 (m, 2H), 2.83-2.65 (m, 3H), 2.56-2.48 (m, 2H), 1.76-1.60 (m, 2H), 1.56-1.25 (m, 3H), 1.00-0.94 (m, 2H). MS (EI) for C24H26BrCl2N3O2, found 540.01 (MH+). [00336] N-{(1 S)-I- [(4-bromophenyl)methyl] -2- [4-(methylamino)piperidin-l-yl] -2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.50 (s, IH), 7.60-7.40 (m, IH), 7.10-7.00 (m, 2H), 5.10-5.00 (m, IH), 4.40 (t, IH), 4.00 (t, IH), 3.75-3.65 (m, IH), 3.20-2.08 (m, IH), 2.80-2.260 (m, 2H), 2.55-2.45 (m, 5H), 2.00-1.90 (m, 2H), 1.80-1.63 (m, 3H), 1.55-1.40 (m, IH), 1.20-1.09 (m, 2H). MS (EI) for C25H28BrCl2N3O2, found 554.12 (MH+).
[00337] N-(2-amino-2-methylpropyl)-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.47- 8.44 (m, IH), 8.37 (s, 2H), 7.59 (d, 2H), 7.54 (s, IH), 7.41 (s, 2H), 7.32 (d, 2H), 6.82 (d, IH), 4.59-4.53 (m, IH), 3.12 (d, 2H), 3.07-3.02 (m, IH), 2.93-2.87 (m, IH), 1.34-1.31 (m, 2H), 1.05 (s, 6H), 1.01-0.89 (m, 2H); MS (EI) for C24H26Cl2F3N3O2, found 516.20 (MH+). [00338] N-[(lS)-2-[(3R)-3-(methylamino)pyrrolidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)- phenyl] -methyl} ethyl] - 1- {4- [(trifluoromethyl)oxy] phenylj-cyclopropanecarboxamide: 1H NMR (400MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.36-7.28 (m, 2H), 7.24-7.17 (m, 4H), 6.01- 5.84 (m, IH), 4.85-4.74 (m, IH), 3.73-3.65 (m, IH), 3.62-3.25 (m, 3H), 3.17-2.74 (m, 4H), 2.51- 2.46 (m, 3H), 2.17-1.87 (m, 2H), 1.53-1.47 (m, 2H), 1.06-0.99 (m, 2H); MS (EI) for
C26H27F6N3O3, found 544.23 (MH+).
[00339] N-{(lS)-l-[(4-bromophenyl)methyl]-2-[(3R)-3-(methylamino)pyrrolidin-l-yl]-2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, CDCl3): δ 7.38-7.28 (m, 4H), 7.20-7.17 (m, 2H), 7.00-6.90 (m, 2H), 6.00-5.82 (m,
IH), 4.81-4.74 (m, IH), 3.74-3.71 (m, IH), 3.67-3.28 (m, 3H), 3.12-2.71 (m, 3H), 2.52-2.47 (m,
3H), 2.23-2.01 (m, 2H), 1.53-1.46 (m, 2H), 1.05-0.95 (m, 2H); MS (EI) for C25H27BrF3N3O3, found 554.18 (MH+).
[00340] N-(2-amino-2-methylpropyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.35 (s, 3H),
7.57 (s, IH), 7.42 (d, 4H), 7.05 (d, 2H), 6.73 (d, IH), 4.49 (q, IH), 3.12 (d, 2H), 2.95-2.79 (m,
2H), 1.37-1.35 (m, 2H), 1.07 (s, 6H), 1.03-0.91 (m, 2H); MS (EI) for C23H26BrCl2N3O2, found 528.10 (MH+).
[00341] N-[(lS)-2-[(3S)-3-(methylamino)pyrrolidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide:
1H NMR (400MHz, CDCl3): δ 7.50 (d, 2H), 7.35-7.28 (m, 2H), 7.22-7.17 (m, 4H), 6.02-5.85 (m,
IH), 5.41 (s, IH), 4.85-4.79 (m, IH), 3.69-3.68 (m, IH), 3.51-3.37 (m, 3H), 3.08-1.352.83 (m,
3H), 2.43 (d, 3H), 2.14-1.95 (m, 2H), 1.53-1.51 (m, 2H), 1.05-0.96 (m, 2H); MS (EI) for
C26H27F6N3O3, found 544.23 (MH+).
[00342] N-{(lS)-l-[(4-bromophenyl)methyl]-2-[(3S)-3-(methylamino)pyrrolidin-l-yl]-2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 8.25 (s, IH), 7.44-7.41 (m, 2H), 7.38-7.29 (m, 4H), 7.07-7.03 (m, 2H),
6.86-6.78 (m, IH), 4.69-4.60 (m, IH), 3.70-3.58 (m, IH), 3.40-3.23 (m, 4H), 2.89-2.75 (m, 2H),
2.36 (s, 3H), 2.03-1.74 (m, 2H), 1.30-1.23 (m, 2H), 1.04-0.93 (m, 2H); MS (EI) for
C25H27BrF3N3O3, found 556.13 (MH+).
[00343] N- [(I S)-2-(2,7-diazaspiro [4.4] non-2-yl)-2-oxo-l-{ [4-(trifluoromethyl)phenyl] - methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz,
DMSO-d6): δ 8.34 (s, IH), 7.58 (m, 3H), 7.40 (s, 2H), 7.32 (m, 2H), 6.88 (m, IH), 4.67 (m, IH),
3.61-2.78 (m, 10H), 1.66 (m, 4H), 1.29 (m, 2H), 0.94 (m, 2H). MS (EI) for C27H28Cl2F3N3O2, found 555 (MH+). [00344] N- [(I S)-2-(2,8-diazaspiro [4.5] dec-8-yl)-2-oxo- 1- { [4-(trifluor omethyl)phenyl] - methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz,
DMSO-d6): δ 8.34 (s, IH), 7.58 (m, 3H), 7.40 (s, 2H), 7.30 (d, 2H), 6.91 (m, IH), 4.94 (m, IH),
3.34-2.76 (m, 10H), 1.64 (m, 2H), 1.28 (m, 6H), 0.96 (m, 2H). MS (EI) for C28H30Cl2F3N3O2, found 569 (MH+).
[00345] N- [(I S)-2-(l,7-diazaspiro [4.4] non-7-yl)-2-oxo-l-{ [4-(trifluoromethyl)phenyl] - methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: l,7-diazaspiro[4.4]nonane was prepared as described in WO 2004/005293; J. Med Chem, 1990, 33, 2270. 1H NMR (400
MHz, DMSO-d6): δ 8.21 (s, IH), 7.57 (m, 3H), 7.39 (s, 2H), 7.30 (m, 2H), 6.81 (m, IH), 4.67
(m, IH), 3.62-3.08 (m, 5H), 2.90 (m, 4H), 1.73 (m, 5H), 1.30 (m, 2H), 0.94 (m, 2H). MS (EI) for
C27H28Cl2F3N3O2, found 555 (MH+).
[00346] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2-fluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.10 (d, IH),
7.43-7.35 (m, 4H), 7.23-7.18 (m, 2H), 6.99 (d, 2H), 6.40 (d, IH), 4.51 (q, IH), 3.62-3.60 (m,
IH), 3.11-3.06 (m, IH), 2.82-2.67 (m, 6H), 2.35-2.30 (m, IH), 1.72-1.50 (m, 4H), 1.39-1.30 (m,
3H), 1.03-0.95 (m, 2H); MS (EI) for C26H29BrFN3O2, found 516.2 (MH+).
[00347] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(3S)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.50 (s, IH), 7.48-7.37
(m, 5H), 7.00 (d, 2H), 4.52 (t, IH), 3.95-3.88 (m, IH), 3.28-3.20 (m, IH), 2.96-2.77 (m, 4H),
2.58 (t, 2H), 2.00-1.90 (m, 2H), 1.80-1.74 (m, IH), 1.60-1.45 (m, 3H), 1.18-1.04 (m, 2H). MS
(EI) for C24H26BrCl2N3O2, found 539.94 (MH+).
[00348] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-piperidin-3- yl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.54 (s, IH), 7.47-7.38 (m, 5H), 6.98
(d, 2H), 4.53-4.44 (m, IH), 3.90-3.80 (m, IH), 3.25-3.17 (m, 2H), 2.96-2.73 (m, 4H), 2.58 (t,
2H), 2.00-1.65 (m, 4H), 1.60-1.40 (m, 3H), 1.20-1.02 (m, 2H). MS (EI) for C24H26BrCl2N3O2, found 539.94 (MH+).
[00349] l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(lS)-2-[(3S)-3-(methylamino)- pyrrolidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropane- carboxamide: 1H NMR (400MHz, DMSO-d6): δ 8.26 (s, IH), 7.64-7.54 (m, 5H), 7.33 (t, 3H),
7.15-7.05 (m, IH), 4.74-4.66 (m, IH), 3.74-3.63 (m, IH), 3.47-3.25 (m, 4H), 3.00-2.88 (m, 2H), 2.39 (s, 3H), 2.09-1.80 (m, 2H), 1.34-1.31 (m, 2H), 1.08-0.95 (m, 2H); MS (EI) for
C26H26F7N3O2, found 546.24 (MH+).
[00350] N-{(lS)-l-[(4-bromophenyl)methyl]-2-[(3S)-3-(methylamino)pyrrolidin-l-yl]-2- oxoethylj-l-β-fluoro^-^rifluoromethyljphenyllcyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-de): δ 8.24 (s, IH), 7.66 (d, IH), 7.59-7.57 (m, 2H), 7.42 (d, 2H), 7.10-7.01
(m, 3H), 4.65-4.59 (m, IH), 3.70-3.61 (m, IH), 3.41-3.19 (m, 4H), 2.86-2.76 (m, 2H), 2.35 (d,
2H), 2.02-1.73 (m, 2H), 1.39-1.33 (m, 2H), 1.08-0.97 (m, 2H); MS (EI) for C25H26BrF4N3O2, found 558.15 (MH+).
[00351] N-{(lS)-l-[(4-bromophenyl)methyl]-2-[(3R)-3-(methylamino)pyrrolidin-l-yl]-2- oxoethylJ-l-^-fluoro^-^rifluoromethylJphenyljcyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 8.25 (s, IH), 7.68-7.64 (m, IH), 7.59-7.57 (m, 2H), 7.43-7.40 (m, 2H),
7.08-7.03 (m, 3H), 4.65-4.60 (m, IH), 3.57-3.18 (m, 5H), 2.90-2.77 (m, 2H), 2.35 (d, 2H), 2.07-
1.71 (m, 2H), 1.40-1.32 (m, 2H), 1.09-0.97 (m, 2H); MS (EI) for C25H26BrF4N3O2, found 558.15
(MH+).
[00352] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-[(l-{4-[(difluoromethyl)- oxyjphenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ
8.20 (d, IH), 7.43 (d, 2H), 7.08 (d, 2H), 6.97 (d, 2H), 6.71 (d, 2H), 6.21 (d, IH), 4.51 (q, IH),
3.66-3.65 (m, IH), 3.18-3.12 (m, IH), 2.86-2.74 (m, 6H), 2.42-2.37 (m, IH), 1.75-1.54 (m, 4H),
1.41-1.38 (m, IH), 1.24-1.22 (m, 2H), 0.93-0.84 (m, 2H); MS (EI) for C27H30BrF2N3O3, found 514.18 (MH+).
[00353] 1- [2-fluoro-4-(trifluoromethyl)phenyl] -N-[(l S)-2- [(3R)-3-(methylamino)- pyrrolidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropane- carboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.65-7.54 (m, 5H), 7.35-7.31 (m, 2H), 7.13-
7.07 (m, IH), 4.72-4.67 (m, IH), 3.60-3.54 (m, 2H), 3.49-3.19 (m, 4H), 3.03-2.88 (m, 2H), 2.37
(d, 3H), 2.10-1.72 (m, 2H), 1.37-1.28 (m, 2H), 1.10-0.96 (m, 2H); MS (EI) for C26H26F7N3O2, found 546.24 (MH+).
[00354] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-Nalpha-[(l-{4-[(difluoromethyl)oxy]- phenyl}cyclopropyl)carbonyl] -4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR
(400MHz, DMSO-d6): δ 8.24-8.24 (m, 2H), 7.63-7.61 (m, 2H), 7.26-7.21 (m, 2H), 7.08-7.05 (m,
2H), 6.71-6.68 (m, 2H), 6.24-6.22 (m, IH), 4.57 (q, IH), 3.71-3.68 (m, IH), 3.22-3.16 (m, IH), 2.99-2.74 (m, 6H), 2.46-2.42 (m, IH), 1.78-1.54 (m, 4H), 1.45-1.38 (m, IH), 1.24-1.17 (m, 2H), 0.92-0.83 (m, 2H); MS (EI) for C28H30F5N3O3, found 551.28 (MH+).
[00355] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-piperidin-4- yl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.46 (s, IH), 7.48-7.37 (m, 5H), 6.99 (d, 2H), 4.50 (t, IH), 3.84-3.79 (m, IH), 3.40-3.34 (m, 2H), 3.08-3.00 (m, 2H), 2.85 (ddd, 2H), 2.06-1.93 (m, 2H), 1.65-1.48 (m, 4H), 1.08-1.04 (m, 2H). MS (EI) for C24H26BrCl2N3O2, found 540.01 (MH+).
[00356] 4-bromo-N- [(3R)-piperidin-3-yl] -Nalpha- [(l-{4-[(trifluoromethyl)oxy] - phenylJcyclopropyOcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.48 (s, IH), 7.42-7.39 (m, 4H), 7.24 (d, 2H), 6.98 (d, 2H), 4.45 (t, IH), 3.84-3.79 (m, IH), 3.25-3.20 (m, IH), 2.95-2.75 (m, 4H), 2.00-1.68 (m, 3H), 1.52-1.38 (m, 4H), 1.18-1.02 (m, 2H). MS (EI) for C25H27BrF3N3O2, found 556.19 (MH+).
[00357] N-(2-aminoethyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.53 (m, IH), 8.36 (m, IH), 7.58 (s, IH), 7.40 (m, 4H), 7.00 (d, 2H), 6.63 (d, 2H), 4.42 (m, IH), 3.14 (m, 2H), 2.91-2.68 (m, 4H), 1.38 (m, 2H), 0.96 (m, 2H); MS (EI) for C2IH22BrCl2N3O2, found 499.95 (MH+). [00358] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-[2- (methylamino)ethyl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.29 (s, IH), 7.63-7.60 (m, IH), 7.43-7.41 (m, 4H), 7.05 (d, 2H), 6.82 (t, IH), 4.88-4.82 (m, IH), 3.44-3.26 (m, 3H), 2.95 (s, 2H), 2.88-2.73 (m, 3H), 2.66 (t, IH), 2.32 (d, 3H), 1.43-1.31 (m, 2H), 0.98-0.94 (m, 2H); MS (EI) for C23H26BrCl2N3O2, 527.98 (MH+).
[00359] N-(2-aminoethyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-N-methyl-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.39 (t, IH), 8.31 (s, IH), 7.62-7.60 (m, IH), 7.45-7.39 (m, 4H), 7.02 (d, 2H), 6.63 (d, IH), 4.47-4.42 (m, IH), 3.23 (q, 2H), 2.95-2.88 (m, IH), 2.80-2.70 (m, 3H), 2.42 (s, 3H), 1.41-1.38 (m, 2H), 1.02- 0.94 (m, 2H); MS (EI) for C22H24BrCl2N3O2, 513.87 (MH+).
[00360] 4-bromo-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-methyl-N-[2-(methylamino)ethyl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-de): δ 8.25 (s, IH), 7.64 (t, IH), 7.56 (d, 2H), 7.41 (dd, 2H), 7.13 (d, IH), 7.05 (t, 2H), 4.86 - 4.73 (m, IH), 3.39 (ddd, 2H), 2.94 (s, 2H), 2.89 - 2.65 (m, 5H), 2.38 (d, 3H), 1.41 - 1.26 (m, 2H), 1.13 - 0.90 (m, 2H). MS (EI) for C24H26BrF4N3O2, found 545.4 (MH+). [00361] 4-bromo-N-[2-(dimethylamino)ethyl]-Nalpha-{[l-(2-fluorophenyl)cyclopropyl]- carbonyl}-N-methyl-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 7.44-7.34 (m, 4H), 7.22-7.17 (m, 2H), 7.05-7.01 (m, 2H), 6.70 (d, IH), 4.84-4.79 (m, IH), 6.65-3.58 (m, IH), 3.50-3.43 (m, IH), 3.36-3.11 (m, 3H), 2.97 (s, 2H), 2.90-2.84 (m, IH), 2.80-2.77 (m, 7H), 1.34- 1.32 (m, 2H), 1.01-0.96 (m, 2H); MS (EI) for C24H29BrFN3O2, found 492.14 (MH+). [00362] 4-bromo-N-methyl-N-[2-(methylamino)ethyl]-Nalpha-[(l-{4- [(trifluoromethylJoxylphenylJ-cyclopropylJcarbonyll-L-phenylalaninamide: 1H NMR (400MHz, DMSO-de): δ 8.32 (s, IH), 7.44-7.41 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.30 (m, 2H), 7.09-7.03 (m, 2H), 6.93 (d, IH), 4.86-4.81 (m, IH), 3.48-3.45 (m, 2H), 2.98 (s, 2H), 2.93-2.84 (m, 3H), 2.81-2.72 (m, 2H), 2.44 (d, 3H), 1.29-1.24 (m, 2H), 1.02-0.94 (m, 2H); MS (EI) for C24H27BrF3N3O3, found 542.15 (MH+).
[00363] 4-bromo-N- [2-(dimethylamino)ethyl] -N-methyl-Nalpha- [(l-{4- [(trifluoromethylJoxyl-phenylJcyclopropylJcarbonylJ-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.20 (s, IH), 7.45-7.41 (m, 2H), 7.38-7.30 (m, 4H), 7.07-7.03 (m, 2H), 6.81 (d, 2H), 4.88-4.85 (m, IH), 3.51-3.32 (m, 2H), 2.98 (s, 2H), 2.90-2.74 (m, 3H), 2.62 (t, IH), 2.39 (s, 4H), 2.27 (s, 2H), 1.28-1.25 (m, 2H), 1.02-0.97 (m, 2H); MS (EI) for C25H29BrF3N3O3, found 558.15 (MH+).
[00364] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, CD3OD): 8.40 (s, IH), 7.42-7.38 (m, 4H), 7.27-7.22 (m, 2H), 7.01-6.99 (d, 2H), 5.05- 5.01 (t, IH), 4.05-4.00 (m, IH), 3.90-3.70 (m, 2H), 3.55-3.45 (m, IH), 3.30-3.15 (m, IH), 3.00- 2.86 (m, IH), 2.82-2.75 (m, IH), 1.84-1.68 (m, 4H), 1.57-1.38 (m, 6H), 1.18-1.04 (m, 2H). MS (EI) for C27H30BrF3N2O3, found 570.18 (MH+).
[00365] N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-5-phenyl-N-[(3R)-piperidin- 3-yl]-L-norvalinamide: 1H NMR (400MHz, CD3OD): 8.45 (s, IH), 7.55-7.38 (m, 3H), 7.28- 7.20 (m, 2H), 7.17-7.08 (m, 3H), 4.37-4.32 (t, IH), 3.93-3.84 (m, IH), 3.30-3.25 (m, IH), 2.97- 2.93 (m, IH), 2.78-2.73 (m, IH), 2.62-2.47 (m, 2H), 2.02-1.85 (m, 2H), 1.80-1.62 (m, 3H), 1.58- 1.42 (m, 6H), 1.19-1.04 (m, 2H). MS (EI) for C26H31Cl2N3O3, found 490.06 (MH+). [00366] l-(2,4-dichlorophenyl)-N-[(lS)-2-oxo-2-{3-[(phenylmethyl)amino]-8- azabicyclo [3.2.1] oct-8-yl}-l-{ [4-(trifluoromethyl)phenyl] methyl}ethyl] cyclopropane- car boxamide: To a solution of N-^lS^-β-amino-S-azabicycloβ^.lJoct-S-yr^-oxo-l-l^- (trifluoromethyl)phenyl]methyl} ethyl]- 1 -(2,4-dichlorophenyl)cyclopropane-carboxamide (0.18 mmol) in dichloromethane (3 niL) was added benzaldehyde (18 μL, 0.18 mmol, Aldrich) and glacial acetic acid (30 μL). The reaction mixture was stirred at room temperature for 30 minutes followed by the addition of IM sodium cyanoborohydride in THF (0.361 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 90 minutes, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 39 mg (33%) of the title compound. 1H NMR (400 MHz, DMSO-de): δ 7.57 (m, 3H), 7.39 (m, 2H), 7.29 (m, 7H), 7.20 (m, IH), 6.94 (m, IH), 4.77 (m, IH), 4.23 (m, 2H), 3.63 (d, 2H), 3.05-2.63 (m, 3H), 2.10 (m, 2H), 1.84-1.25 (m, 8H), 0.96 (m, 2H). MS (EI) for C34H34Cl2F3N3O2, found 645.0 (MH+).
[00367] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for l-Boc-3-(aminomethyl)azetidine . [00368] l-(2,4-dichlorophenyl)-N-[(lS)-2-{3-[(2-methylpropyl)amino]-8-azabicyclo- [3.2.1]oct-8-yl}-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}-ethyl]-cyclopropane- carboxamide: 1H NMR (400 MHz, DMSO-d6):δ 7.58 (m, 3H), 7.39 (d, 2H), 7.33 (m, 2H), 6.98 (m, IH), 4.77 (m, IH), 4.15 (m, 2H), 3.05-2.53 (m, 3H), 2.25 (m, 2H), 2.04-1.25 (m, HH), 0.98 (m, 2H), 0.85 (m, 6H). MS (EI) for C31H36Cl2F3N3O2, found 611.0 (MH+). [00369] l-(2,4-dichlorophenyl)-N-[(lS)-2-oxo-2-(3-pyrrolidin-l-yl-8-azabicyclo[3.2.1]oct- 8-yl)-l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanecarboxamide: To a solution of N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]- methyl} ethyl]- l-(2,4-dichlorophenyl)cyclopropane-carboxamide (0.18 mmol) in acetonitrile (3 mL) was added potassium carbonate (27 mg, 0.20 mmol) and 1 ,4-dibromobutane (26 μ L, 0.22 mmol, Aldrich). The reaction mixture was heated to 1000C for 4 hours, cooled to room temperature, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 31 mg (28%) of the title compound. 1H NMR (400 MHz, DMSO-d6):δ 8.16 (s, IH), 7.58 (m, 3H), 7.35 (m, 4H), 6.97 (m, IH), 4.77 (m, IH), 4.20 (m, 3H), 2.91 (m, 3H), 2.42 (m, 3H), 2.10 (m, IH),
1.96-1.20 (m, 13 H), 0.95 (m, 2H). MS (EI) for C3IH34Cl2F3N3O2, found 609 (MH+).
[00370] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for
Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl
8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for l-Boc-3-(aminomethyl)azetidine.
[00371] 4-bromo-N-[2-(dimethylamino)ethyl]-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)- phenyljcyclopropylJcarbonylJ-N-methyl-L-phenylalaninamide: 1H NMR (400MHz,
DMSO-d6): δ 7.63 (m, IH), 7.56 (d, 2H), 7.41 (m, 2H), 7.15 - 6.98 (m, 3H), 4.79 (m, IH), 3.58
(m, IH), 3.52 - 3.43 (m, IH), 2.88 (dd, IH), 2.85 - 2.72 (m, 2H), 2.63 (s, 6H), 2.51 (m, IH),
2.48 (dt, 3H), 1.41 - 1.24 (m, 2H), 1.02 (m, 2H). MS (EI) for C25H28BrF4N3O2, found 559.4
(MH+).
[00372] N-8-azabicyclo[3.2.1]oct-3-yl-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.36
(s, IH), 7.79 (s, IH), 7.59 (d, 2H), 7.53 (s, IH), 7.39 (m, 2), 7.30 (d, 2H), 6.74 (d, IH), 4.56 (m,
IH), 3.69 (m, 3H), 2.89 (m, 2H), 2.04 (m, 3H), 1.76 (m, 5H), 1.33 (m, 2H), 0.93 (m, 2H). MS
(EI) for C27H28Cl2F3N3O2, found 555 (MH+).
[00373] 4-bromo-Nalpha-{[l-(3-fluorophenyl)cyclopropyl]carbonyl}-N-piperidin-4-yl-L- phenylalaninamide: 1H NMR (400 MHz, DMSO-d6):δ 8.34 (s, IH), 8.12 (s, IH), 7.40 (d, 2H),
7.34 (m, IH), 7.07 (m, 3H), 6.98 (d, 2H), 6.56 (d, IH), 4.42 (m, IH), 3.05 (m, 2H), 2.75 (m, 2H),
1.70 (m, 2H), 1.37 (m, 2H), 1.23 (m, 2H), 0.97 (m, 2H). MS (EI) for C24H27BrFN3O2, found 489
(MH+).
[00374] 4-bromo-N-piperidin-4-yl-Nalpha-{[l-(2,4,5-trifluorophenyl)cyclopropyl]- carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.28 (s, IH), 8.06 (s, IH),
7.50 (m, 2H), 7.41 (d, 2H), 7.02 (d, 2H), 6.80 (d, IH), 4.38 (m, IH), 3.08 (m, 2H), 2.75 (m, 2H),
1.73 (m, 2H), 1.41 (m, 2H), 1.27 (m, 2H), 0.98 (m, 2H). MS (EI) for C24H25BrF3N3O2, found 525
(MH+).
[00375] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2-chloro-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl}-4-fluoro-L-phenylalaninamide: 1H NMR (400 MHz, DMSO- d6):δ 8.20 (s, IH), 7.81 (m, IH), 7.62 (m, IH), 7.43 (m, 2H), 7.34 (m, IH), 7.16 (m, 2H), 6.57 (m, IH), 4.55 (m, IH), 3.08 (m, IH), 2.91 (m, 3H), 2.69 (m, 4H), 2.33 (m, IH), 1.56 (m, 4H),
1.39 (m, IH), 1.29 (m, 2H), 0.98 (m, 2H). MS (EI) for C26H27Cl3FN3O2, found 539 (MH+). [00376] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl] methyl} ethyl] - 1- {4- [(trifluoromethyl)oxy] phenyljcyclopropane-carboxamide: 1H NMR (400 MHz, DMSO-d6):δ 7.59 (m, 2H), 7.29 (m, 7H), 7.00 (m, IH), 4.73 (m, IH), 4.26 (m, IH), 3.08 (m, 2H), 2.88 (m, 2H), 1.92 (m, 4H), 1.62 (m, 2H), 1.45 (m, 2H), 1.20 (m, 2H), 0.94 (m, 2H). MS (EI) for C28H29F6N3O3, found 570 (MH+).
[00377] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropane-carboxamide:
1H NMR (400 MHz, DMSO-d6): δ 8.23 (m, IH), 7.57 (m, 5H), 7.32 (m, 2H), 7.18 (d, IH), 4.72
(m, IH), 4.27 (m, 2H), 3.02 (m, 2H), 2.87 (m, 2H), 2.18-1.42 (m, 7H), 1.25 (m, 2H), 0.99 (m,
2H). MS (EI) for C28H28F7N3O2, found 572 (MH+).
[00378] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400
MHz, DMSO-d6): δ 8.29 (s, IH), 7.57 (m, 3H), 7.36 (m, 4H), 7.01 (m, IH), 4.76 (m, IH), 4.27
(m, 2H), 2.96 (m, 3H), 2.18-1.26 (m, 8H), 1.12 (m, 2H), 0.91 (m, 2H). MS (EI) for
C27H28Cl2F3N3O2, found 555 (MH+).
[00379] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-
[(3R)-piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 7.57-7.38 (m, 5H),
7.10-7.00 (m, 2H), 4.43-4.37 (m, IH), 3.10-2.80 (m, 9H), 2.05-1.55 (m, 6H), 1.12-1.06 (m, 2H).
MS (EI) for C25H28BrCl2N3O3, found 554.12 (MH+).
[00380] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD):
8.55 (s, IH), 7.52-7.38 (m, 5H), 7.12-7.00 (m, 2H), 4.82-4.77 (m, IH), 4.63-4.45 (m, IH), 4.23-
4.18 (m, IH), 2.85-2.75 (m, 2H), 2.66-2.58 (m, IH), 2.44-2.36 (m, IH), 2.20-2.10 (m, IH), 1.95-
1.40 (m, 9H), 1.20-1.05 (m, 2H). MS (EI) for C26H28BrCl2N3O3, found 566.02 (MH+). [00381] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N- piperidin-4-yl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.40 (s, IH), 7.50-7.37 (m, 5H), 7.02-6.97 (m, 2H), 4.45 (t, IH), 3.40-3.35 (m, IH), 3.10-2.80 (m, 6H), 1.78-1.50 (m, 6H), 1.27-1.04 (m, 5H). MS (EI) for C25H28BrCl2N3O3, found 555.00 (MH+). [00382] N-ICSRJ-piperidin-S-yll-l-φiphenyM-ylmethyO-l-oxoethyll-l-Cl^- dichlorophenyl)-cyclopropanecarboxamide: 1H NMR (400MHz, CD3OD): 8.56 (s, IH), 7.61
(d, 2H), 7.55-7.34 (m, 7H), 7.38-7.30 (m, 2H), 7.14 (d, 2H), 4.57-4.48 (m, IH), 3.90-3.80 (m,
IH), 3.22-3.18 (m, IH), 3.05-2.75 (m, 6H), 2.00-1.80 (m, 2H), 1.78-1.60 (m, 2H), 1.57-1.40 (m,
2H), 1.20-1.00 (m, 2H). MS (EI) for C30H3ICl2N3O3, found 536.23 (MH+).
[00383] N-piperidin-4-yl-l-(biphenyl-4-ylmethyl)-2-oxoethyl]-l-(2,4-dichlorophenyl)- cyclopropane carboxamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.60 (d, 2H), 7.52 (d,
2H), 7.45-7.35 (m, 7H), 7.16 (d, 2H), 4.56 (d, IH), 3.83-3.77 (m, IH), 3.08-2.85 (m, 5H), 2.03-
1.90 (m, 2H), 1.68-1.50 (m, 5H), 1.17-1.03 (m, 2H). MS (EI) for C30H3iCl2N3O3, found 538.23
(MH+).
[00384] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-piperidin-
4-yl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.57 (s, IH), 7.47-7.36 (m, 4H), 7.24
(d, IH), 7.17 (d, IH), 4.59 (t, IH), 3.84-3.79 (m, IH), 3.10-2.95 (m, 5H), 2.02-1.90 (m, 2H),
1.68-1.48 (m, 5H), 1.17-1.03 (m, 2H). MS (EI) for C24H25Cl4N3O3, found 530.12 (MH+).
[00385] 2,4-dichloro-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-piperidin-
4-yl-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.40 (s, IH), 7.40 (dd, 4H), 7.25 (d,
2H), 7.10 (d, 2H), 4.55 (t, IH), 3.40-3.37 (m, IH), 3.10-2.80 (m, 7H), 1.77-1.67 (m, 3H), 1.50-
1.37 (m, 2H), 1.36-1.20 (m, 2H), 1.16-1.10 (m, 2H). MS (EI) for C26H29BrCl4N3O3, found
570.18 (MH+).
[00386] N-(cis-4-aminocyclohexyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.43 (s, IH),
7.50-7.37 (m, 5H), 7.00 (d, 2H), 4.57 (t, IH), 3.40-3.30 (m, IH), 3.20-3.15 (m, IH), 2.98-2.80
(m, 2H), 1.83-1.75 (m, 3H), 1.70-1.50 (m, 8H), 1.16-1.05 (m, 2H). MS (EI) for
C25H28BrCl2N3O2, found 554.12 (MH+).
[00387] N-(trans-4-aminocyclohexyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.45 (s, IH),
7.50-7.37 (m, 5H), 6.98 (d, 2H), 4.45 (t, IH), 3.57-3.47 (m, IH), 3.09-3.00 (m, IH), 2.95-2.77
(m, 2H), 2.07-1.80 (m, 4H), 1.60-1.38 (m, 4H), 1.35-1.05 (m, 4H). MS (EI) for
C25H28BrCl2N3O2, found 554.12 (MH+).
[00388] 4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-(2- methylpiperidin-4-yl)-L-phenylalaninamide: 1H NMR (400MHz, CD3OD): 8.47 (s, IH), 7.47-7.36 (m, 5H), 7.02-6.97 (m, 2H), 4.45 (t, IH), 3.82-3.75 (m, IH), 3.20-3.16 (m, IH), 3.03- 2.79 (m, 3H), 2.07-1.84 (m, 2H), 1.60-1.38 (m, 2H), 1.30-1.23 (m, 3H), 1.17-1.03 (m, 2H). MS (EI) for C25H28BrCl2N3O2, found 554.12 (MH+).
[00389] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-N-alpha-{[l-(2,3-difluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.34 (d, IH), 7.42 (d, 2H), 7.23-7.14 (m, 3H), 7.05 (d, 2H), 7.76 (d, IH), 4.51-4.46 (m, IH), 3.97-3.93 (m, IH), 3.59-3.53 (m, IH), 3.24-3.10 (m, 4H), 2.88-2.80 (m, 2H), 2.75-2.71 (m, IH), 2.01-2.98 (m, IH), 1.95-1.81 (m, 3H) 1.72-1.66 (m, IH) 1.42-1.30 (m, 2H), 1.09-0.98 (m, 2H); MS (EI) for C26H28BrF2N3O2, 532.20 (MH+).
[00390] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-N-alpha-{[l-(2,6-difluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: MS (EI) for C26H28BrF2N3O2, 534.15 (MH+). [00391] 2,4-dichloro-N-[(3R)-piperidin-3-yl]-Nalpha-[(l-{4-[(trifluoromethyl)oxy]- phenyl}cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 7.97 (d, IH), 7.51 (d, IH), 7.42 - 7.35 (m, 2H), 7.35 - 7.28 (m, 3H), 7.16 (d, IH), 6.67 (d, IH), 4.52 (m, IH), 3.60 (m, IH), 3.00 (dd, IH), 2.94 - 2.75 (m, 3H), 2.56 (t, IH), 2.42 (dd, IH), 1.60 (m, 2H), 1.40 (m, IH), 1.34 - 1.21 (m, 2H), 1.17 (m, IH), 0.97 (m, 2H). MS (EI) for C25H26Cl2F3N3O3, found 545.4 (MH+).
[00392] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(2,4-dichlorophenyl)methyl] - 2-oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 7.54 (d, IH), 7.35 (m, 5H), 7.23 (t, IH), 7.04 (dd, IH), 4.79 (dd, IH), 4.28 (m, 2H), 3.12 - 2.94 (m, IH), 2.87 (m, 2H), 2.12 - 1.87 (m, 3H), 1.88 - 1.70 (m, IH), 1.60 (m, 2H), 1.47 (t, 2H), 1.30 - 1.09 (m, 2H), 0.94 (m, 2H). MS (EI) for C27H28Cl2F3N3O3, found 571.4 (MH+).
[00393] 2,4-dichloro-N-[(3S)-pyrrolidin-3-yl]-Nalpha-[(l-{4-[(trifluoromethyl)oxy]- phenylJcyclopropyOcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.29 (s, IH), 7.51 (d, IH), 7.41 - 7.36 (m, 2H), 7.33 (m, 3H), 7.17 (d, IH), 6.66 (d, IH), 4.52 (td, IH), 4.16 (m, IH), 3.13 - 2.92 (m, 4H), 2.85 (dd, IH), 2.69 (m, IH), 1.96 (m, IH), 1.72 - 1.53 (m, IH), 1.33 - 1.20 (m, IH), 1.15 (dd, IH), 1.01 - 0.86 (m, 2H). MS (EI) for C24H24Cl2F3N3O3, found 531.4 (MH+).
[00394] N- [(3R)-piperidin-3-yl] -4-(trifluoromethyl)-Nalpha- [(l-{4- [(trifluoromethyl)- oxylphenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.26 (s, IH), 8.09 (t, IH), 7.58 (d, 2H), 7.39 - 7.30 (m, 2H), 7.26 (d, 4H), 6.65 (d, IH), 4.61 - 4.37 (m, IH), 3.58 (s, IH), 3.04 - 2.71 (m, 4H), 2.55 (t, IH), 2.45 - 2.25 (m, IH), 1.61 (d, 2H), 1.47 - 1.14 (m, 4H), 1.06 - 0.81 (m, 2H). MS (EI) for C26H27F6N3O3, found 544.5 (MH+). [00395] N-[(lS)-2-[(3R)-3-aminopiperidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]- methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, D6-DMSO, 100 0C): δ 7.54 (m, 2H), 7.38-7.20 (m, 6H), 6.56 (bs, IH), 4.99 (bs, IH), 3.74 (bs, IH), ), 3.05-2.82 (m, 3H), 2.56 (bs, IH), 1.8 (bs, IH), 1.62 (bs, IH), 1.28 (m, 4H), 0.96 (m, 2H); MS (EI) for C26H27F6N3O3, found 544.30 (MH+).
[00396] N- [(3 S)-piperidin-3-yl] -4-(trifluoromethyl)-Nalpha- [(1- {4- [(trifluoromethyl)oxy] - phenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, D6-DMSO): δ 8.49 (d, IH), 7.58 (d, 2H), 7.34 (d, 2H), 7.30-7.25 (m, 4H), 6.74 (d, IH), 4.57-4.52 (m, IH), 3.78 (br s, IH), 3.05-2.88 (m, 4H), 2.70-2.75 (m, IH), 2.54-2.59 (m, IH), 1.73-1.78 (m, 2H), 1.52- 1.58 (m, IH), 1.38-1.45 (m, IH), 1.20-1.28 (m, 2H), 0.91-1.04 (m, 2H); MS (EI) for C26H27F6N3O3, found 544.30 (MH+).
[00397] N-[(lS)-2-(4-amino-4-methylpiperidin-l-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyl]methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.64 - 7.49 (m, 2H), 7.39 - 7.30 (m, 2H), 7.28 (m, 4H), 6.82 (d, IH), 4.97 (d, IH), 3.61 - 3.26 (m, 6H), 3.03 - 2.75 (m, 2H), 1.42 (m, 3H), 1.22 (m, 3H), 1.12 (d, 3H), 0.97 (d, 2H). MS (EI) for C27H29F6N3O3, found 558.5 (MH+).
[00398] N-[(3S)-pyrrolidin-3-yl]-4-(trifluoromethyl)-Nalpha-[(l-{4-[(trifluoromethyl)- oxylphenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.61 (d, IH), 7.58 (d, 2H), 7.40 - 7.31 (m, 2H), 7.26 (d, 4H), 6.66 (d, IH), 4.49 (m, IH), 4.13 (m, IH), 3.11 - 2.92 (m, 4H), 2.87 (dd, IH), 2.69 (dd, IH), 1.97 (m, IH), 1.65 (m, IH), 1.29 - 1.13 (m, 2H), 1.05 - 0.81 (m, 2H). MS (EI) for C25H25F6N3O3, found 530.5 (MH+). [00399] 4-bromo-N-[(3S)-pyrrolidin-3-yl]-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.63 (d, IH), 7.41 (d, 2H), 7.38 - 7.32 (m, 2H), 7.29 (d, 2H), 7.00 (d, 2H), 6.63 (d, IH), 4.48 - 4.34 (m, IH), 4.12 (m, IH), 3.13 - 2.90 (m, 3H), 2.86 (dd, IH), 2.82 - 2.62 (m, 2H), 2.02 - 1.87 (m, IH), 1.63 (m, IH), 1.34 - 1.13 (m, 2H), 1.08 - 0.81 (m, 2H). MS (EI) for C24H25BrF3N3O3, found 541.4 (MH+). [00400] N- [(3R)-piperidin-3-yl] -Nalpha- [(l-{4- [(trifluoromethyl)oxy] phenyl}- cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.00 (d, IH), 7.37 - 7.31 (m, 2H), 7.29 (m, 2H), 7.24 - 7.14 (m, 3H), 7.09 - 6.90 (m, 2H), 6.53 (d, IH), 4.50 - 4.39 (m, IH), 3.58 (m, IH), 2.95 - 2.71 (m, 4H), 2.55 (t, IH), 2.40 (dd, IH), 1.60 (m, 2H),
1.39 (m, IH), 1.33 - 1.12 (m, 3H), 1.07 - 0.81 (m, 2H). MS (EI) for C25H28F3N3O3, found 476.5 (MH+).
[00401] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l-(phenylmethyl)ethyl]-l- {4- [(trifluoromethyl)oxy] phenyl} cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.40 - 7.33 (m, 2H), 7.33 - 7.25 (m, 2H), 7.25 - 7.14 (m, 3H), 7.11 - 7.00 (m, 2H), 6.87 (dd, IH), 4.67 (m, IH), 4.46 - 3.99 (m, 2H), 2.93 (dd, IH), 2.84 - 2.63 (m, 2H), 2.13 - 1.83 (m, 3H), 1.64 (m, 2H), 1.46 (d, 3H), 1.34 - 1.18 (m, 2H), 1.11 - 0.85 (m, 2H). MS (EI) for C27H30F3N3O3, found 502.5 (MH+).
[00402] N-[(3S)-pyrrolidin-3-yl]-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.55 (d, IH),
7.40 - 7.25 (m, 4H), 7.25 - 7.10 (m, 3H), 7.08 - 6.89 (m, 2H), 6.55 (d, IH), 4.43 (m, IH), 4.13 (m, IH), 3.14 - 2.93 (m, 3H), 2.94 - 2.82 (m, IH), 2.76 (dd, IH), 2.68 (dd, IH), 1.96 (m, IH), 1.64 (m, IH), 1.24 (m, 2H), 0.96 (m, 2H). MS (EI) for C24H26F3N3O3, found 462.5 (MH+). [00403] 3-cyclohexyl-N-[(3R)-piperidin-3-yl]-N~2—[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-alaninamide: 1H NMR (400MHz, DMSO-d6): δ 7.92 (d, IH), 7.51 - 7.40 (m, 2H), 7.33 (d, 2H), 6.70 (d, IH), 4.25 (q, IH), 3.69 - 3.57 (m, IH), 2.91 (dd, IH), 2.83 (d, IH), 2.56 (m, IH), 2.41 (dd, IH), 1.61 (m, 7H), 1.44 - 1.22 (m, 6H), 1.12 - 0.94 (m, 6H), 0.78 (m, 2H). MS (EI) for C25H34F3N3O3, found 482.6 (MH+).
[00404] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-(cyclohexylmethyl)-2- oxoethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 7.52 - 7.39 (m, 2H), 7.38 - 7.28 (m, 2H), 6.89 (dd, IH), 4.54 (dd, IH), 4.46 - 4.02 (m, 2H), 3.17 (m, 2H), 2.21 - 1.95 (m, 3H), 1.95 - 1.77 (m, 2H), 1.61 (m, 5H), 1.51 - 1.41 (m, 2H), 1.41 - 1.20 (m, 4H), 1.16 - 0.93 (m, 6H), 0.76 (m, 2H). MS (EI) for C27H36F3N3O3, found 508.6 (MH+).
[00405] 3-cyclohexyl-N-[(3S)-pyrrolidin-3-yl]-N~2~ [(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-alaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.46 (dd, IH), 7.51 - 7.39 (m, 2H), 7.33 (d, 2H), 6.70 (dd, IH), 4.24 (dd, IH), 4.16 (d, IH), 3.19 - 2.90 (m, 3H), 2.74 (m, IH), 1.96 (m, IH), 1.70 - 1.45 (m, 6H), 1.42 - 1.23 (m, 4H), 1.15 - 0.92 (m, 6H), 0.78
(m, 2H). MS (EI) for C24H32F3N3O3, found 468.5 (MH+).
[00406] N-piperidin-4-yl-Nalpha- [(1- {4- [(trifluoromethyl)oxy] phenyl} cyclopropyl)- carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.07 (d, IH), 7.41 - 7.25
(m, 4H), 7.25 - 7.12 (m, 3H), 7.02 (d, 2H), 6.49 (d, IH), 4.44 (dd, IH), 3.61 (m, IH), 3.12 - 3.02
(m, 2H), 2.85 (dd, IH), 2.76 (m, 3H), 1.69 (m, 2H), 1.52 - 1.14 (m, 4H), 1.07 - 0.86 (m, 2H).
MS (EI) for C25H28F3N3O3, found 476.5 (MH+).
[00407] N-piperidin-4-yl-4-(trifluoromethyl)-Nalpha-[(l-{4-[(trifluoromethyl)oxy]- phenylJcyclopropyOcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.13
(d, IH), 7.58 (d, 2H), 7.32 (dd, 2H), 7.29 - 7.18 (m, 4H), 6.60 (d, IH), 4.50 (d, IH), 3.61 (m,
IH), 3.06 (m, 2H), 2.98 - 2.81 (m, 2H), 2.70 (t, 2H), 1.71 (m, 2H), 1.48 - 1.13 (m, 4H), 0.97 (d,
2H). MS (EI) for C26H27F6N3O3, found 544.5 (MH+).
[00408] 3-cyclohexyl-N-piperidin-4-yl-N'2'-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-alaninamide: 1U NMR (400MHz, DMSO-d6): δ 7.95 (d, IH), 7.51 -
7.41 (m, 2H), 7.34 (d, 2H), 6.61 (d, IH), 4.26 (d, IH), 3.61 (m, 2H), 3.04 (t, 2H), 2.68 (t, 2H),
1.69 (m, 2H), 1.58 (m, 5H), 1.38 - 1.28 (m, 5H), 1.15 - 0.94 (m, 6H), 0.77 (m, 2H). MS (EI) for
C25H34F3N3O3, found 482.6 (MH+).
[00409] 2,4-dichloro-N-piperidin-4-yl-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.07 (d, IH),
7.51 (d, IH), 7.42 - 7.35 (m, 2H), 7.32 (m, 3H), 7.16 (d, IH), 6.59 (d, IH), 4.58 - 4.46 (m, IH),
3.63 (d, IH), 3.06 (m, 2H), 2.97 (dd, IH), 2.87 (dd, IH), 2.71 (t, 2H), 1.70 (m, 2H), 1.51 - 1.29
(m, 2H), 1.30 - 1.10 (m, 2H), 1.02 - 0.89 (m, 2H). MS (EI) for C25H26Cl2F3N3O3, found 545.4
(MH+).
[00410] N-KlSJ-l-ICl^-dichlorophenyOmethyll-l-^-CmethylaminoJpiperidin-l-yl]-!- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 7.58 - 7.47 (m, IH), 7.39 - 7.30 (m, 5H), 7.20 (dd, IH), 6.89 (dd, IH),
5.01 (m, IH), 4.12 (dd, IH), 3.86 (t, IH), 2.96 (m, 2H), 2.89 - 2.81 (m, IH), 2.68 (m, 2H), 2.34
(d, 3H), 1.83 (m, 2H), 1.30 - 1.03 (m, 4H), 0.93 (d, 2H). MS (EI) for C26H28Cl2F3N3O3, found
559.4 (MH+).
[00411] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-l-
{4- [(trifluoromethyl)oxy] phenyl} cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.57 (dd, 2H), 7.33 (dd, 2H), 7.26 (d, 3H), 6.82 (dd, IH), 4.96 (dd, IH), 4.15 (dd, IH), 3.90 (s, IH), 3.08 - 2.90 (m, 3H), 2.90 - 2.77 (m, IH), 2.66 (dd, IH), 1.81 (t, 2H), 1.37 - 1.04 (m, 4H), 0.96 (q, 2H). MS (EI) for C25H26Cl2F3N3O3, found 545.4 (MH+).
[00412] N-[(lS)-2-[4-(methylamino)piperidin-l-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]- methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.57 (d, 2H), 7.35 - 7.25 (m, 6H), 6.84 (dd, IH), 4.96 (dd, IH), 4.12 (dd, IH), 3.88 (t, IH), 3.00 (dd, 3H), 2.89 - 2.67 (m, 3H), 2.35 (d, 3H), 1.84 (m, 2H), 1.21 (d, 4H), 0.97 (dd, 2H). MS (EI) for C27H29F6N3O3, found 558.5 (MH+).
[00413] N-[(lS)-2-(4-aminopiperidin-l-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}- ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.57 (dd, 2H), 7.34 - 7.24 (m, 6H), 6.82 (dd, IH), 4.96 (dd, IH), 4.15 (dd, IH), 3.90 (t, IH), 3.08 - 2.94 (m, 3H), 2.90 - 2.75 (m, IH), 2.66 (dd, IH), 1.81 (t, 2H), 1.38 - 1.06 (m, 4H), 0.96 (q, 2H). MS (EI) for C26H27F6N3O3, found 544.5 (MH+). [00414] N-{(lS)-l-[(4-bromophenyl)methyl]-2-[4-(methylamino)piperidin-l-yl]-2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 7.40 (dd, 2H), 7.35 - 7.27 (m, 4H), 7.00 (d, 2H), 6.86 (dd, IH), 4.90 (dd, IH), 4.21 - 4.03 (m, IH), 3.87 (t, IH), 3.08 - 2.92 (m, 2H), 2.83 (t, 2H), 2.74 - 2.61 (m, 2H), 2.37 (d, 3H), 1.83 (m, 2H), 1.24 (m, 4H), 0.97 (d, 2H). MS (EI) for C26H29BrF3N3O3, found
569.4 (MH+).
[00415] N- {(1 S)-2-(4-aminopiperidin- 1-yl)- 1- [(4-bromophenyl)methyl] -2-oxoethyl}- 1- {4- [(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.35 (dd, 2H), 7.27 (dd, 4H), 6.95 (dd, 2H), 6.73 (dd, IH), 4.92 - 4.78 (m, IH), 4.09 (dd, IH), 3.83 (t, IH), 3.03 - 2.91 (m, 2H), 2.85 - 2.73 (m, IH), 2.70 - 2.53 (m, 2H), 1.74 (m, 2H), 1.28 - 1.07 (m, 4H), 0.98 - 0.85 (m, 2H). MS (EI) for C25H27BrF3N3O3, found 555.4 (MH+). [00416] N-[(lS)-2-[4-(methylamino)piperidin-l-yl]-2-oxo-l-(phenylmethyl)ethyl]-l-{4- [(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.34 (dd, 2H), 7.28 (d, 3H), 7.22 - 7.19 (m, 2H), 7.03 (d, 2H), 6.84 (dd, IH), 4.91 (dd, IH), 4.09 (dd, IH), 3.83 (t, IH), 3.10 - 2.98 (m, IH), 2.98 - 2.81 (m, 2H), 2.79 - 2.65 (m, 3H), 2.33 (d, 3H), 1.78 (m, 2H), 1.28 - 1.19 (m, 2H), 1.14 - 0.87 (m, 4H). MS (EI) for C26H30F3N3O3, found
490.5 (MH+). [00417] N-[(lS)-2-(4-aminopiperidin-l-yl)-2-oxo-l-(phenylmethyl)ethyl]-l-{4- [(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.31 (dd, 4H), 7.25 - 7.16 (m, 3H), 7.08 - 6.96 (m, 2H), 6.70 (dd, IH), 4.91 (dd, IH), 4.26 - 4.04 (m, IH), 3.88 (t, IH), 3.09 - 2.81 (m, 3H), 2.79 - 2.56 (m, 2H), 1.78 (d, 2H), 1.24 (m, 4H), 1.06
- 0.83 (m, 2H). MS (EI) for C25H28F3N3O3, found 476.5 (MH+).
[00418] N-{(lS)-l-(cyclohexylmethyl)-2-[4-(methylamino)piperidin-l-yl]-2-oxoethyl}-l-
{4- [(trifluoromethyl)oxy] phenyl} cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.40 (d, 2H), 7.34 - 7.21 (m, 2H), 6.86 (dd, IH), 4.74 - 4.64 (m, IH), 4.28 (t, IH), 3.83 (t,
IH), 3.04 (d, 2H), 2.49 (s, 3H), 1.93 (m, 2H), 1.63 (m, IH), 1.53 (m, 3H), 1.41 (m, 2H), 1.27 (d,
5H), 1.16 (m, IH), 1.08 - 0.94 (m, 6H), 0.73 (m, 2H). MS (EI) for C26H36F3N3O3, found 496.6
(MH+).
[00419] N-[(lS)-2-(4-aminopiperidin-l-yl)-l-(cyclohexylmethyl)-2-oxoethyl]-l-{4-
[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ
7.45 (dd, 2H), 7.34 (d, 2H), 6.85 (dd, IH), 4.74 (d, IH), 4.21 (t, IH), 3.78 (t, IH), 3.06 (d, 2H),
2.70 - 2.54 (m, IH), 1.83 (dd, 2H), 1.67 (m, IH), 1.62 - 1.44 (m, 4H), 1.29 (m, 5H), 1.18 - 0.93
(m, 7H), 0.80 (m, 2H). MS (EI) for C25H34F3N3O3, found 482.6 (MH+).
[00420] 4-bromo-N-piperidin-4-yl-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)-carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.11 (d,
IH), 7.41 (d, 2H), 7.37 - 7.32 (m, 2H), 7.29 (d, 2H), 6.99 (d, 2H), 6.58 (d, IH), 4.44 (dd, IH),
3.62 (m, IH), 3.08 (t, 2H), 2.83 - 2.69 (m, 4H), 1.72 (t, 2H), 1.38 (dd, 2H), 1.24 (m, 2H), 1.06 -
0.86 (m, 2H). MS (EI) for C25H27BrF3N3O3, found 555.4 (MH+).
[00421] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2,3,4-trifluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.40 (dd, 2H), 7.29 (dd, IH), 7.18 (m, IH), 7.10 (d, IH), 7.04 (dd, 2H), 4.86 (d, IH), 3.58
- 3.31 (m, 4H), 2.90 - 2.76 (m, IH), 2.76 - 2.67 (m, IH), 1.47 (m, 3H), 1.39 - 1.22 (m, 3H), 1.15 (d, 3H), 0.98 (m, 2H). MS (EI) for C25H27BrF3N3O2, found 539.4 (MH+).
[00422] 4-bromo-N-[(3R)-piperidin-3-yl]-Nalpha-{[l-(2,3,4-trifluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.16 (d, IH), 7.39 (d, 2H), 7.29 (dd, IH), 7.23 - 7.11 (m, IH), 7.03 (d, 2H), 6.91 (d, IH), 4.47 - 4.33 (m, IH), 3.66 (m, IH), 3.06 - 2.91 (m, IH), 2.92 - 2.69 (m, 4H), 2.62 (t, IH), 1.66 (m, 2H), 1.45 (m, IH), 1.37 - 1.21 (m, 3H), 1.11 - 0.84 (m, 2H). MS (EI) for C24H25BrF3N3O2, found 525.4
(MH+).
[00423] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2,3,4-trifluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.43 - 7.35 (m, 2H), 7.29 (m, IH), 7.18 (m, 2H), 7.07 (m, 2H), 4.64 (dd, IH), 4.34 (d, 2H),
4.11 (m, IH), 3.19 - 2.83 (m, 2H), 2.75 (m, 2H), 1.98 (m, 3H), 1.85 - 1.39 (m, 5H), 1.29 (d, 2H),
1.12 - 0.84 (m, 2H). MS (EI) for C26H27BrF3N3O2, found 551.4 (MH+).
[00424] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2,3-difluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.41 (dd, 3H), 7.19 (m, 2H), 7.03 (dd, 2H), 6.92 (dd, IH), 4.90 (m, IH), 3.52 (m, 2H), 2.87 (m,
2H), 2.80 - 2.64 (m, 2H), 1.55 - 1.31 (m, 6H), 1.15 (d, 3H), 1.02 (m, 2H). MS (EI) for
C25H28BrF2N3O2, found 521.4 (MH+).
[00425] 4-bromo-Nalpha-{[l-(2,3-difluorophenyl)cyclopropyl]carbonyl}-N-[(3R)- piperidin-3-yl]-L-phenylalaninamide: 1U NMR (400MHz, DMSO-d6): δ 8.20 (d, IH), 7.32
(d, 3H), 7.22 - 7.04 (m, 2H), 6.95 (d, 2H), 6.66 (d, IH), 4.36 (dd, IH), 3.62 (m, IH), 2.93 (d,
IH), 2.81 (m, 2H), 2.80 - 2.68 (m, 2H), 2.60 (t, IH), 1.62 (d, 2H), 1.42 (d, IH), 1.28 (dd, 3H),
0.94 (m, 2H). MS (EI) for C24H26BrF2N3O2, found 507.4 (MH+).
[00426] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2,3-difluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.35 (m, 3H), 7.09 (m, 2H), 7.05 - 6.83 (m, 3H), 4.62 (d, IH), 4.28 (m, 2H), 4.07 (m, IH), 3.05
(d, IH), 2.70 (d, IH), 2.10 - 1.68 (m, 4H), 1.57 (m, 2H), 1.35 (dd, 4H), 0.97 (d, 2H). MS (EI) for
C26H28BrF2N3O2, found 533.4 (MH+).
[00427] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(4-fluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ
7.46 - 7.39 (m, 2H), 7.26 (d, 2H), 7.13 (d, 2H), 6.99 (d, 2H), 6.67 - 6.48 (m, IH), 4.91 (m, IH),
3.79 (d, 2H), 3.08 (d, 2H), 2.91 - 2.66 (m, 2H), 1.54 (m, 4H), 1.28 (s, 3H), 1.23 (m, 2H), 0.87 (d,
2H). MS (EI) for C25H29BrFN3O2, found 503.4 (MH+).
[00428] 4-bromo-Nalpha-{[l-(4-fluorophenyl)cyclopropyl]carbonyl}-N-[(3R)-piperidin-
3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.16 (d, IH), 7.44 - 7.41 (m,
2H), 7.34 - 7.22 (m, 2H), 7.17 - 7.13 (m, 2H), 6.98 (d, 2H), 6.42 (d, IH), 4.47 - 4.31 (m, IH), 3.73 (d, IH), 3.15 (dd, 3H), 2.80 (m, 3H), 1.86 - 1.64 (m, 2H), 1.57 (d, IH), 1.35 (dd, IH), 1.30 - 1.15 (m, 2H), 1.04 - 0.81 (m, 2H). MS (EI) for C24H27BrFN3O2, found 489.4 (MH+). [00429] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(4-fluorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-dβ): δ 7.39 (dd, 2H), 7.27 - 7.17 (m, 2H), 7.09 (dd, 2H), 6.99 (m, 2H), 6.77 (dd, IH), 4.60 (q, IH), 4.28 (m, 2H), 3.07 (m, IH), 2.78 - 2.62 (m, 2H), 2.21 (m, IH), 1.81 - 1.34 (m, 6H), 1.20 (m, 3H), 1.04 - 0.75 (m, 2H). MS (EI) for C26H29BrFN3O2, found 515.4 (MH+). [00430] 2,4-dichloro-Nalpha-({l- [2-fluoro-4-(trifluoromethyl)phenyl] cyclopropyl}- carbonyl)-N-[(3R)-piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, IH), 7.90 (d, IH), 7.64 (d, IH), 7.58 (d, 2H), 7.51 (d, IH), 7.32 (dd, IH), 7.17 (d, IH), 6.93 (d, IH), 4.51 (td, IH), 3.71 - 3.58 (m, IH), 3.04 - 2.80 (m, 4H), 2.60 (dd, IH), 2.45 - 2.39 (m, IH), 1.62 (t, 2H), 1.49 - 1.19 (m, 4H), 1.07 - 0.94 (m, 2H). MS (EI) For C25H25C12F4N3O2, Found 547.4 (MH+).
[00431 ] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(2,4-dichlorophenyl)methyl] - 2-oxoethyl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.23 (s, IH), 7.61 (t, IH), 7.58 - 7.51 (m, 3H), 7.34 (ddd, IH), 7.24 (dd, 2H), 4.80 (d, IH), 4.28 (t, 2H), 3.15 (s, IH), 3.09 - 2.83 (m, 3H), 2.16 - 1.88 (m, 3H), 1.67 (dd, 3H), 1.49 (d, 2H), 1.38 - 1.10 (m, 2H), 1.01 (d, 2H). MS (EI) For C27H27Cl2F4N3O2, Found 573.4 (MH+).
[00432] 2,4-dichloro-Nalpha-({l- [2-fluoro-4-(trifluoromethyl)phenyl] cyclopropyl}- carbonyl)-N-[(3S)-pyrrolidin-3-yl]-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.44 (d, IH), 8.25 (s, IH), 7.63 (d, IH), 7.59 - 7.54 (m, 2H), 7.50 (d, IH), 7.32 (dd, IH), 7.17 (d, IH), 6.92 (d, IH), 4.51 (td, IH), 4.17 (d, IH), 3.10 (dd, IH), 3.01 (qd, 3H), 2.86 (dd, IH), 2.71 (dd, IH), 1.97 (dq, IH), 1.65 (td, IH), 1.40 - 1.20 (m, 2H), 1.09 - 0.92 (m, 2H). MS (EI) for C24H23Cl2F4N3O2, found 533.4 (MH+).
[00433] N-[(lS)-2-(4-amino-4-methylpiperidin-l-yl)-2-oxo-l-{[4-(trifluoromethyl)- phenyllmethyljethyll-l-β-fluoro^-^rifluoromethyljphenyllcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, IH), 7.63 (d, IH), 7.60 - 7.50 (m, 4H), 7.29 (d, 2H), 7.06 (dd, IH), 4.94 (d, IH), 3.57 - 3.31 (m, 5H), 2.98 - 2.80 (m, 2H), 1.51 - 1.19 (m, 6H), 1.13 (d, 3H), 1.00 (t, 2H). MS (EI) for C27H28F7N3O2, found 560.5 (MH+). [00434] Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)- piperidin-3-yl]-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ
8.25 (s, IH), 8.03 (d, IH), 7.68 - 7.49 (m, 5H), 7.27 (d, 2H), 6.81 (d, IH), 4.49 (td, IH), 3.58 (s, IH), 2.88 (ddd, 4H), 2.40 (dd, IH), 1.60 (d, 2H), 1.46 - 1.20 (m, 4H), 1.12 - 1.01 (m, IH), 1.00
- 0.90 (m, IH). MS (EI) for C26H26F7N3O2, found 546.5 (MH+).
[00435] Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3S)- pyrrolidin-3-yl]-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, IH), 8.29 (s, IH), 7.64 - 7.48 (m, 5H), 7.28 (d, 2H), 6.83 (d, IH), 4.47 (td, IH), 4.14 (d, IH), 3.10 - 2.84 (m, 5H), 2.69 (dd, IH), 1.97 (dq, IH), 1.64 (dt, IH), 1.42 - 1.22 (m, 2H), 1.12 - 1.02 (m, IH), 1.00 - 0.89 (m, IH). MS (EI) for C25H24F7N3O2, Found 532.5 (MH+). [00436] 4-bromo-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-[(3R)-piperidin-3-yl]-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ
8.26 (s, IH), 8.02 (d, IH), 7.64 (d, IH), 7.58 - 7.53 (m, 2H), 7.46 - 7.35 (m, 2H), 7.05 - 6.96 (m, 2H), 6.78 (d, IH), 4.54 - 4.35 (m, IH), 3.58 (d, IH), 2.91 (dd, IH), 2.85 - 2.72 (m, 3H), 2.61 - 2.50 (m, IH), 2.40 (dd, IH), 1.60 (d, 2H), 1.44 - 1.20 (m, 4H), 1.11 - 1.02 (m, IH), 1.01 - 0.91 (m, IH). MS (EI) for C25H26BrF4N3O2, found 557.4 (MH+).
[00437] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethylj-l-β-fluoro^-^rifluoromethyljphenyllcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, IH), 7.63 (d, IH), 7.57 - 7.52 (m, 2H), 7.41 (dd, 2H), 7.11 - 7.01 (m, 3H), 4.67 (dt, IH), 4.25 (t, 2H), 3.20 - 2.86 (m, 2H), 2.79 - 2.65 (m, 2H), 2.04 (dt, 3H), 1.91
- 1.69 (m, 2H), 1.60 (s, 2H), 1.43 (dd, 3H), 1.33 (dt, 2H), 1.12 - 0.90 (m, 2H). MS (EI) for C27H28BrF4N3O2, found 583.4 (MH+).
[00438] 4-bromo-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)- N-[(3S)-pyrrolidin-3-yl]-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.52 (d, IH), 8.29 (s, IH), 7.64 (d, IH), 7.57 (d, 2H), 7.40 (d, 2H), 7.01 (d, 2H), 6.79 (d, IH), 4.41 (td, IH), 4.12 (s, IH), 3.09 - 2.90 (m, 3H), 2.79 (qd, 2H), 2.69 - 2.59 (m, IH), 1.95 (td, IH), 1.61 (d, IH), 1.36 (dd, IH), 1.33 - 1.25 (m, IH), 1.12 - 1.00 (m, IH), 0.99 - 0.90 (m, IH). MS (EI) for C24H24BrF4N3O2, found 543.4 (MH+).
[00439] Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, IH), 7.99 (d, IH), 7.63 (d, IH), 7.59 - 7.47 (m, 2H), 7.32 - 7.12 (m, 3H), 7.03 (dd, IH), 4.54 - 4.32 (m, IH), 3.59 (d, 2H), 2.97 - 2.75 (m, 4H), 2.61 - 2.52 (m, IH), 2.41 (dd, IH), 1.61 (d, 2H), 1.39 (ddd, 2H), 1.34 - 1.21 (m, 2H), 1.10 - 1.02 (m, IH), 1.01 - 0.93 (m, IH). MS (EI) for C25H27F4N302, found 478.5 (MH+).
[00440] N- [(I S)-2-(3-amino-8-azabicyclo [3.2.1] oct-8-yl)-2-oxo-l-(phenylmethyl)ethyl] -1- [2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.27 (s, IH), 7.63 (d, IH), 7.55 (dd, 2H), 7.25 - 7.13 (m, 4H), 7.13 - 7.05 (m, 3H), 4.66 (dq, IH), 4.43 - 4.24 (m, 2H), 4.07 (s, IH), 3.19 - 3.09 (m, IH), 2.94 (dd, IH), 2.76 (t, IH), 2.20 - 2.08 (m, IH), 1.96 (dd, IH), 1.86 - 1.73 (m, 2H), 1.69 - 1.52 (m, IH), 1.51 - 1.29 (m, 5H), 1.14 - 0.89 (m, 2H). MS (EI) for C27H29F4N3O2, found 504.5 (MH+). [00441 ] Nalpha-({ 1- [2-fluoro-4-(trifluoromethyl)phenyl] cyclopropyl} carbonyl)-N- [(3 S)- pyrrolidin-3-yl]-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.61 (d, IH), 8.29 (s, IH), 7.62 (d, IH), 7.58 - 7.50 (m, 2H), 7.24 - 7.12 (m, 3H), 7.04 (dd, 2H), 6.74 (d, IH), 4.48 - 4.35 (m, IH), 4.15 (dt, IH), 3.14 - 2.96 (m, 3H), 2.82 (qd, 2H), 2.73 - 2.65 (m, IH), 2.03 - 1.88 (m, IH), 1.66 (td, IH), 1.45 - 1.25 (m, 2H), 1.11 - 0.89 (m, 2H). MS (EI) for C24H25F4N3O2, found 464.5 (MH+).
[00442] 3-cyclohexyl-N'2'-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-[(3R)-piperidin-3-yl]-L-alaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, IH), 7.92 (d, IH), 7.68 - 7.53 (m, 3H), 6.85 (d, IH), 4.27 (dt, IH), 3.72 - 3.58 (m, IH), 2.95 (dd, IH), 2.86 (d, IH), 2.60 (t, IH), 2.46 - 2.40 (m, IH), 1.59 (dd, 7H), 1.50 - 1.24 (m, 6H), 1.17 - 0.97 (m, 6H), 0.79 (dd, 2H). MS (EI) for C25H33F4N3O2, found 484.5 (MH+). [00443] N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-(cyclohexylmethyl)-2- oxoethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.27 (s, IH), 7.59 (dt, 3H), 7.12 - 7.04 (m, IH), 4.56 (dd, IH), 4.35 (d, IH), 4.12 (s, IH), 3.22 - 3.13 (m, IH), 2.16 - 1.80 (m, 5H), 1.69 - 1.53 (m, 5H), 1.52 - 1.43 (m, 4H), 1.39 (d, 2H), 1.29 - 1.20 (m, IH), 1.17 - 0.98 (m, 7H), 0.79 (dd, 2H). MS (EI) for C27H35F4N3O2, found 510.6 (MH+).
[00444] 3-cyclohexyl-N'2'-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-[(3S)-pyrrolidin-3-yl]-L-alaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, IH), 8.25 (s, IH), 7.63 (dd, 2H), 7.56 (d, IH), 6.84 (d, IH), 4.27 (dt, IH), 4.13 (d, IH), 3.08 (dd, IH), 3.02 - 2.92 (m, 2H), 2.66 (dd, IH), 1.95 (dq, IH), 1.66 - 1.52 (m, 6H), 1.51 - 1.44 (m, IH), 1.42 - 1.30 (m, 3H), 1.18 - 0.97 (m, 6H), 0.78 (dd, 2H). MS (EI) for C24H3IF4N3O2, found 470.5 (MH+).
[00445] 2,4-dichloro-Nalpha-({l- [2-fluoro-4-(trifluoromethyl)phenyl] cyclopropyl}- carbonyl)-N-piperidin-4-yl-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, IH), 7.98 (d, IH), 7.65 (d, IH), 7.58 (s, 2H), 7.51 (d, IH), 7.32 (dd, IH), 7.17 (d, IH), 6.85 (d, IH), 4.58 - 4.42 (m, IH), 3.66 (s, IH), 3.11 (dd, 2H), 2.92 (ddd, 2H), 2.78 (t, 2H), 1.73 (t, 2H), 1.38 (ddd, 4H), 1.02 (s, 2H). MS (EI) for C25H25Cl2F4N3O2, found 547.4 (MH+). [00446] Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N- piperidin-4-yl-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, IH), 8.09 (d, J IH), 7.61 - 7.55 (m, 4H), 7.27 (d, 2H), 6.78 (d, IH), 4.48 (dd, IH), 3.62 (s, 2H), 3.06 (t, 2H), 2.95 - 2.83 (m, 2H), 2.72 (d, 2H), 1.81 - 1.64 (m, 2H), 1.49 - 1.24 (m, 4H), 1.12 - 1.02 (m, IH), 0.97 (dd, IH). MS (EI) for C26H26F7N3O2, found 546.5 (MH+). [00447] 4-bromo-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-piperidin-4-yl-L-phenylalaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.31 (s, IH), 8.05 (d, IH), 7.65 (d, IH), 7.56 (s, 2H), 7.40 (d, 2H), 7.00 (d, 2H), 6.75 (d, IH), 4.42 (dd, IH), 3.61 (s, 2H), 3.06 (t, 2H), 2.84 - 2.62 (m, 4H), 1.69 (d, 2H), 1.45 - 1.22 (m, 4H), 1.10 — 1.03 (m, IH), 0.98 (dd, IH). MS (EI) for C25H26BrF4N3O2, found 557.4 (MH+). [00448] Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N- piperidin-4-yl-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, IH), 8.02 (d, IH), 7.64 (d, IH), 7.55 (d, 2H), 7.23 - 7.12 (m, 3H), 7.05 - 6.98 (m, 2H), 6.66 (d, J = 8.1Hz, IH), 4.46 - 4.38 (m, IH), 3.62 (s, IH), 3.06 (dd, 2H), 2.85 - 2.78 (m, 2H), 2.71 (t, 2H), 1.70 (dd, 2H), 1.47 - 1.26 (m, 4H), 1.09 - 0.92 (m, 2H). MS (EI) for C25H27F4N3O2, found 478.5 (MH+). [00449] 3-cyclohexyl-N'2'-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}- carbonyl)-N-piperidin-4-yl-L-alaninamide: 1U NMR (400 MHz, DMSO-d6): δ 8.31 (s, IH), 7.88 (d, IH), 7.66 (d, IH), 7.59 (dd, 2H), 6.76 (d, IH), 4.27 (dd, IH), 3.63 (s, IH), 3.08 (dd, 2H), 2.74 (t, 2H), 1.72 (t, 2H), 1.59 (d, 5H), 1.48 - 1.28 (m, 6H), 1.16 - 0.98 (m, 6H), 0.84 - 0.71 (m, 2H). MS (EI) for C25H33F4N3O2, found 484.5 (MH+).
[00450] 1- [2-fluoro-4-(trifluoromethyl)phenyl] -N-[(l S)-2- [4-(methylamino)piperidin-l- yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, IH), 7.62 (dd, IH), 7.59 - 7.51 (m, 4H), 7.29 (d, 2H), 7.13 (dd, IH), 4.93 (dd, IH), 4.14 (dd, IH), 3.86 (t, IH), 3.13 - 2.58 (m, 5H), 2.34 (t, 3H), 1.84 (s, 2H), 1.37 - 1.09 (m, 4H), 1.06 - 0.92 (m, 2H). MS (EI) for C27H28F7N3O2, found 560.5 (MH+). [00451] N-[(lS)-2-(4-aminopiperidin-l-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}- ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.35 (s, IH), 7.66 - 7.59 (m, IH), 7.56 (dd, 4H), 7.29 (d, 2H), 7.05 (dd, IH), 4.93 (dd, IH), 4.17 (dd, IH), 3.88 (s, IH), 3.12 - 2.80 (m, 4H), 2.65 (dt, IH), 1.78 (d, 2H), 1.26 (dd, 4H), 1.01 (dt, 2H). MS (EI) for C26H26F7N3O2, found 546.5 (MH+). [00452] N-{(lS)-l-[(2,4-dichlorophenyl)methyl]-2-[4-(methylamino)piperidin-l-yl]-2- oxoethylJ-l-^-fluoro^-^rifluoromethylJphenyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.29 (s, IH), 7.64 (d, IH), 7.59 - 7.54 (m, 2H), 7.54 - 7.50 (m, IH), 7.34 (ddd, IH), 7.25 - 7.12 (m, 2H), 4.99 (dd, IH), 4.18 (dd, IH), 3.87 (d, IH), 3.13 - 2.90 (m, 2H), 2.89 - 2.76 (m, 2H), 2.75 - 2.52 (m, IH), 2.37 (d, 3H), 1.86 (d, 2H), 1.35 - 1.06 (m, 4H), 0.99 (d, 2H). MS (EI) for C26H27Cl2F4N3O2, found 561.4 (MH+).
[00453] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-l- [2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, IH), 7.64 (d, IH), 7.55 (d, 2H), 7.52 (dd, IH), 7.34 (td, IH), 7.26 - 7.13 (m, 2H), 5.00 (d, IH), 4.30 - 4.11 (m, IH), 3.88 (d, IH), 3.12 - 2.81 (m, 5H), 2.75 - 2.56 (m, IH), 1.78 (s, 2H), 1.37 - 1.09 (m, 4H), 0.99 (t, 2H). MS (EI) for C25H25Cl2F4N3O2, found 547.4 (MH+).
[00454] N-{(1 S)-I- [(4-bromophenyl)methyl] -2- [4-(methylamino)piperidin-l-yl] -2- oxoethylJ-l-^-fluoro^-^rifluoromethylJphenyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, IH), 7.60 (dd, IH), 7.50 (s, 2H), 7.35 (dd, 2H), 6.97 (d, 2H), 4.83 (dd, IH), 4.08 (dd, IH), 3.80 (t, IH), 3.01 - 2.85 (m, IH), 2.82 - 2.49 (m, 5H), 2.31 (d, 3H), 1.77 (s, 2H), 1.28 (s, 2H), 1.11 (dd, 2H), 0.98 (t, 2H). MS (EI) for C26H28BrF4N3O2, found 571.4 (MH+).
[00455] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-l-[2- fluoro^-^rifluoromethyljphenyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- de): δ 8.33 (s, IH), 7.65 (dd, IH), 7.56 (s, 2H), 7.39 (dd, 2H), 7.09 - 6.98 (m, 3H), 4.87 (dd, IH), 4.16 (dd, IH), 3.87 (s, IH), 2.99 (dd, 3H), 2.72 (ddt, 3H), 1.78 (d, 2H), 1.39 - 1.28 (m, 2H), 1.17 (s, 2H), 1.09 - 0.94 (m, 2H). MS (EI) for C25H26BrF4N3O2, found 557.4 (MH+). [00456] 1- [2-fluoro-4-(trifluoromethyl)phenyl] -N-[(l S)-2- [4-(methylamino)piperidin-l- yl]-2-oxo-l-(phenylmethyl)ethyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 8.19 (s, IH), 7.64 (dd, IH), 7.55 (d, 2H), 7.25 - 7.15 (m, 3H), 7.09 - 7.03 (m, 2H), 6.90 (d, IH), 4.89 (s, IH), 4.30 - 4.14 (m, IH), 3.90 (s, IH), 3.07 - 2.91 (m, 2H), 2.89 - 2.70 (m, 2H), 2.69 - 2.50 (m, IH), 2.45 (d, 3H), 1.89 (s, 2H), 1.35 (dt, 2H), 1.21 - 0.95 (m, 4H). MS (EI) for C26H29F4N3O2, found 492.5 (MH+).
[00457] N- [(I S)-2-(4-aminopiperidin-l-yl)-2-oxo-l-(phenylmethyl)ethyl] -1- [2-fluoro-4- (trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.33 (d, IH), 7.64 (d, IH), 7.54 (d, 2H), 7.29 - 7.15 (m, 3H), 7.08 - 7.03 (m, 2H), 6.93 (dd, IH), 4.88 (dd, IH), 4.26 - 4.10 (m, IH), 3.88 (s, IH), 3.03 (m, 2H), 2.96 - 2.56 (m, 4H), 1.77 (d, 2H), 1.41 - 1.30 (m, 2H), 1.28 - 1.09 (m, 2H), 1.02 (dd, 2H). MS (EI) for C25H27F4N3O2, found 478.5 (MH+).
[00458] N-{(lS)-l-(cyclohexylmethyl)-2-[4-(methylamino)piperidin-l-yl]-2-oxoethyl}-l- [2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: IH NMR (400 MHz, DMSO-de): δ 8.23 (s, IH), 7.65 (d, IH), 7.58 (dd, 2H), 7.02 (dd, IH), 4.75 (d, IH), 4.21 (d, IH), 3.79 (s, IH), 3.02 (d, IH), 2.84 (s, IH), 2.72 - 2.54 (m, IH), 2.39 (d, 3H), 1.98 - 1.81 (m, 2H), 1.61 (dd, 6H), 1.31 (ddd, 4H), 1.10 (d, 6H), 0.79 (d, 2H). MS (EI) for C26H35F4N3O2, found 498.6 (MH+).
[00459] N-[(lS)-2-(4-aminopiperidin-l-yl)-l-(cyclohexylmethyl)-2-oxoethyl]-l-[2-fluoro- 4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, IH), 7.60 (dt, 3H), 7.00 (dd, IH), 4.76 (s, IH), 4.18 (t, IH), 3.76 (s, IH), 3.02 (d, 2H), 2.69 - 2.54 (m, 2H), 1.89 - 1.65 (m, 3H), 1.65 - 1.43 (m, 5H), 1.43 - 1.24 (m, 3H), 1.07 (dd, 6H), 0.82 (s, 2H). MS (EI) for C25H33F4N3O2, found 484.5 (MH+). [00460] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-[2-fluoro-4-trifluoromethyl)phenyl]cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 7.65 (d, IH), 7.57 (d, 2H), 7.40 (dd, 2H), 7.03 (dd, 3H), 4.88 (d, IH), 3.56 - 3.30 (m, 6H), 2.87 - 2.63 (m, 2H), 1.47 - 1.25 (m, 6H), 1.11 (d, 3H), 1.07 - 0.96 (m, 2H). MS (EI) for C26H28BrF4N3O2, found 571.4 (MH+).
[00461] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2,4-difluorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- de): δ 8.36 (s, IH), 7.40 (dd, 3H), 7.27 - 7.20 (m, IH), 7.05 (td, IH), 7.01 (d, IH), 6.99 (d, IH), 6.79 (dd, IH), 4.88 (d, IH), 3.59 - 3.24 (m, 6H), 2.77 (tdd, 2H), 1.55 - 1.37 (m, 3H), 1.36 - 1.26 (m, 2H), 1.15 (d, 3H), 1.01 - 0.89 (m, 2H). MS (EI) for C25H28BrF2N3O2, found 521.4 (MH+). [00462] 4-bromo-Nalpha-{[l-(2,4-difluorophenyl)cyclopropyl]carbonyl}-N-[(3R)- piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, IH), 8.29 (d, IH), 7.43 - 7.35 (m, 3H), 7.23 (td, IH), 7.06 (td, IH), 6.99 (d, 2H), 6.61 (d, IH), 4.46 - 4.37 (m, IH), 3.67 (s, IH), 2.98 (d, IH), 2.86 (dd, IH), 2.83 - 2.74 (m, 2H), 2.71 - 2.61 (m, IH), 2.52 (d, IH), 1.66 (d, 2H), 1.47 (d, IH), 1.37 - 1.23 (m, 3H), 1.03 - 0.86 (m, 2H). MS (EI) for C24H26BrF2N3O2, found 507.4 (MH+).
[00463] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2,4-difluorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 8.25 (s, IH), 7.36 (dt, 3H), 7.32 - 7.27 (m, IH), 7.17 (tdd, IH), 6.98 (dd, 3H), 6.83 (d, IH), 4.68 - 4.54 (m, IH), 4.35 - 4.17 (m, 2H), 4.07 (s, IH), 3.15 - 2.96 (m, IH), 2.84 (dd, IH), 2.73 - 2.63 (m, 2H), 2.05 - 1.92 (m, IH), 1.92 - 1.68 (m, 3H), 1.57 (s, 2H), 1.42 (t, 2H), 1.24 (dt, 2H), 0.99 - 0.83 (m, 2H). MS (EI) for C26H28BrF2N3O2, found 533.4 (MH+).
[00464] 4-bromo-Nalpha-({l-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)- N-[(3R)-piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, IH), 8.31 (d, IH), 7.58 (dd, 2H), 7.49 - 7.41 (m, IH), 7.39 (d, 2H), 7.02 (d, 2H), 6.93 (d, IH), 4.42 (td, IH), 3.79 - 3.63 (m, IH), 2.98 (dd, IH), 2.93 - 2.81 (m, 2H), 2.76 (dd, IH), 2.71 - 2.61 (m, IH), 2.53 (dd, IH), 1.68 (d, 2H), 1.54 - 1.30 (m, 2H), 1.27 - 1.22 (m, 2H), 1.09 - 0.90 (m, 2H). MS (EI) for C25H26BrF4N3O2, found 557.4 (MH+).
[00465] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethylJ-l-^-fluoro-S-^rifluoromethylJphenyljcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, IH), 7.56 (ddd, 2H), 7.48 - 7.42 (m, IH), 7.42 - 7.38 (m, 2H), 7.22 (dd, IH), 7.05 (t, 2H), 4.71 - 4.58 (m, IH), 4.35 (d, 2H), 4.13 (m, IH), 3.17 - 3.01 (m, IH), 2.74 (dd, 2H), 2.10 (tdlH), 2.02 - 1.78 (m, 3H), 1.68 (dd, 2H), 1.48 (s, 2H), 1.30 - 1.18 (m, 2H), 1.09 - 0.94 (m, 2H). MS (EI) for C27H28BrF4N3O2, found 583.4 (MH+). [00466] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethylJ-l-^-fluoro-S-^rifluoromethylJphenylJcyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-de): δ 8.36 (s, IH), 7.58 (s, 2H), 7.51 - 7.41 (m, IH), 7.41 - 7.36 (m, 2H), 7.07 - 6.99 (m, 3H), 4.87 (d, IH), 3.63 - 3.27 (m, 6H), 2.78 (dd, 2H), 1.43 (m, 3H), 1.25 (d, 2H), 1.14 (s, 3H), 1.08 - 0.93 (m, 2H). MS (EI) for C26H28BrF4N3O2, found 571.4 (MH+). [00467] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2-fluorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 7.44 - 7.30 (m, 5H), 7.18 (t, 2H), 6.97 (d, 2H), 6.60 (dd, IH), 4.99 - 4.77 (m, IH), 3.55 (s, 2H), 3.32 (dd, 2H), 2.79 (ddd, 2H), 1.51 (d, 2H), 1.43 (d, 2H), 1.33 (dd, 3H), 1.17 (d, 3H), 0.97 (m, 2H). MS (EI) for C25H29BrFN3O2, found 503.4 (MH+).
[00468] 4-bromo-Nalpha-{[l-(2-fluorophenyl)cyclopropyl]carbonyl}-N-[(3R)-piperidin- 3-yl]-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, IH), 8.27 (d, IH), 7.46
- 7.29 (m, 4H), 7.24 - 7.12 (m, 2H), 7.00 - 6.88 (m, 2H), 6.43 (d, IH), 4.43 (d, IH), 3.62 (d, IH), 3.07 - 2.87 (m, 2H), 2.86 - 2.71 (m, 2H), 2.71 - 2.51 (m, 2H), 1.65 (s, 2H), 1.46 (m, IH), 1.40 - 1.20 (m, 3H), 1.05 - 0.89 (m, 2H). MS (EI) for C24H27BrFN3O2, found 489.4 (MH+). [00469] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-l-(2-fluorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, IH), 7.41 - 7.24 (m, 4H), 7.12 (m, 2H), 6.96 (dd, 2H), 6.67 (dd, IH), 4.63 (dd, IH), 4.35
- 4.17 (m, 2H), 4.08 (s, IH), 3.05 (d, IH), 2.76 - 2.59 (m, 2H), 2.09 - 1.71 (m, 4H), 1.59 (dd, 2H), 1.44 (t, 2H), 1.32 - 1.19 (m, 2H), 1.00 - 0.84 (m, 2H). MS (EI) for C26H29BrFN3O2, found 515.4 (MH+).
[00470] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,4,5-trifluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.20 (s, IH),
8.10 (d, IH), 7.50 (m, 2H), 7.42 (d, 2H), 7.04 (d, 2H), 6.84 (d, IH), 4.36 (m, IH), 3.69 (m, IH), 3.16 (m, IH), 2.78 (m, 6H), 2.42 (m, IH), 1.60 (m, 4H), 1.40 (m, IH), 1.27 (m, 2H), 0.98 (m, 2H). MS (EI) for C26H27BrF3N3O2, found 551 (MH+).
[00471] N-{(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-(2,4,5-trifluorophenyl)cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO- d6): δ 8.28 (s, IH), 7.45 (m, 4H), 7.20 (m, IH), 7.06 (t, 2H), 4.65 (m, IH), 4.25 (m, 2H), 2.88 (m,
3H), 2.13-1.44 (m, 8H), 1.25 (m, 2H), 0.96 (m, 2H). MS (EI) for C26H27BrF3N3O3, found 551
(MH+).
[00472] 4-bromo-N-[(3R)-piperidin-3-yl]-Nalpha-{[l-(2,4,5-trifluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, IH),
8.11 (d, IH), 7.50 (m, 2H), 7.41 (d, 2H), 7.03 (d, IH), 6.87 (d, 2H), 4.38 (m, IH), 3.64 (m, IH), 2.94 (m, IH), 2.79 (m, 3H), 2.59 (m, IH), 2.43 (m, IH), 1.64 (m, 2H), 1.43 (m, IH), 1.27 (m, 3H), 0.98 (m, 2H). MS (EI) for C47H25BrF3N3O2, found 525 (MH+). [00473] N-{(lR)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, IH), 7.49 (m, 2H), 7.35 (m, 2H), 7.12 (m, IH), 6.98 (m, 3H), 4.62 (m, IH), 4.19 (m, 2H), 2.75 (m, 3H), 2.05-1.37 (m, 8H), 1.28 (m, 2H), 0.97 (m, 2H). MS (EI) for C27H29BrF3N3O3, found 581 (MH+).
[00474] N-(azetidin-3-ylmethyl)-4-bromo-N-methyl-Nalpha-[(l-{4-[(trifluoromethyl)- oxyjphenylJcyclopropylJcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-dβ): δ 7.45-7.41 (m, 2H), 7.38-7.29 (m, 4H), 7.08-7.02 (m, 2H), 6.87-6.81 (m, IH), 4.83-4.78 (m, IH), 3.92-3.79 (m, 2H), 3.75-3.59 (m, 2H), 3.57-3.52 (m, IH), 3.40-3.34 (m, IH), 2.93 (s, 3H), 2.90- 2.72 (m, 4H), 1.29-1.21 (m, 2H), 1.04-0.96 (m, 2H); MS (EI) for C25H27BrF3N3O3, found 554.18 (MH+).
[00475] N- [(I S)-I- [(4-bromophenyl)methyl]-2-(2,5-diazabicyclo [2.2.1] hept-2-yl)-2- oxoethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 8.28 (s, IH), 7.44-7.39 (m, 2H), 7.35-7.27 (m, 4H), 7.10-7.02 (m, 2H), 7.00 (d, IH), 4.71-4.39 (m, 2H), 4.05 (d, IH), 3.65-3.51 (m, IH), 3.30-3.15 (m, IH), 3.05-3.00 (m, 2H), 2.95-2.74 (m, 2H), 1.70-1.69 (m, IH), 1.59 (d, IH), 1.27-1.18 (m, 2H), 1.02-0.90 (m, 2H); MS (EI) for C25H25BrF3N3O3, found 554.18 (MH+).
[00476] N- [(I S)-I- [(4-bromophenyl)methyl]-2-(2,5-diazabicyclo [2.2.1] hept-2-yl)-2- oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 8.34 (s, IH), 7.56-7.54 (m, IH), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.76 (d, IH), 4.76-4.71 (m, IH), 3.72-3.63 (m, 2H), 3.55-3.47 (m, 2H), 3.45-3.30 (m, 2H), 2.84-2.67 (m, 4H), 1.36-1.24 (m, 2H), 0.96-0.87 (m, 2H); MS (EI) for C24H24BrCl2N3O2, found 540.13 (MH+). [00477] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(4-fluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.20 (d, IH), 7.46-7.44 (m, 2H), 7.33-7.28 (m, 2H), 7.19-7.14 (m, 2H), 7.02-6.98 (m, 2H), 6.42 (d, IH), 4.54- 4.49 (m, IH), 3.69-3.68 (m, IH), 2.88-2.72 (m, 6H), 2.45-2.41 (m, IH), 1.76-1.54 (m, 4H), 1.44- 1.40 (m, IH), 1.30-1.22 (m, 2H), 1.00-0.91 (m, 2H); MS (EI) for C26H29BrFN3O2, found 514.18 (MH+).
[00478] N-[(lS)-l-[(4-bromophenyl)methyl]-2-{4-[(l-methylethyl)amino]piperidin-l-yl}- 2-oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- d6): δ 7.60 (d, IH), 7.40 (m, 4H), 7.01 (m, 2H), 6.75 (m, IH), 4.88 (m, IH), 3.86 (m, IH), 3.08- 2.88 (m, 4H), 2.85-2.54 (m, 3H), 1.80 (m, 2H), 1.38 (m, 2H), 1.03 (m, 8H); MS (EI) for C27H32BrCl2N3O3, found 581.89 (MH+).
[00479] N-(azetidin-3-ylmethyl)-4-bromo-Nalpha-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-N-methyl-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 7.56-7.54 (m, IH), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.77-6.71 (m, IH), 4.76-4.71 (m, IH), 3.72-3.65 (m, 2H), 3.55-3.48 (m, 2H), 3.47-3.30 (m, 2H), 2.84 (s, 3H), 2.81-2.66 (m, 3H), 2.64 (s, IH), 1.36- 1.24 (m, 2H), 0.96-0.87 (m, 2H); MS (EI) for C24H26BrCl2N3O2, found 540.13 (MH+). [00480] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,3,4-trifluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.14 (d, IH), 7.42 (d, 2H), 7.35-7.28 (m, IH), 7.22-7.17 (m, IH), 7.07 (d, 2H), 6.90 (d, IH), 4.51-4.45 (m, IH), 3.74-3.73 (m, IH), 3.22-3.17 (m, IH), 2.86-2.78 (m, 6H), 2.45-2.44 (m, IH), 1.80-1.73 (m, 2H), 1.71-1.59 (m, 2H), 1.46-1.42 (m, IH), 1.37-1.27 (m, 2H), 1.09-1.04 (m, IH), 0.98-0.93 (m, IH); MS (EI) for C26H27BrF3N3O2, found 540.13 (MH+).
[00481] N-pSH-azabicyclopj^oct-S-ylM-bromo-Nalpha-tfl-^-fluoro-S- (trifluoromethylJ-phenyllcyclopropylJcarbonylJ-L-phenylalaninamide: 1H NMR (400MHz, DMSO-de): δ 8.20 (d, IH), 7.61-7.59 (m, 2H), 7.50-7.41 (m, 3H), 7.06 (d, 2H), 6.90 (d, IH), 4.53-4.47 (m, IH), 3.78-3.76 (m, IH), 3.26-3.21 (m, IH), 2.90-2.78 (m, 6H), 2.56-2.55 (m, IH), 1.81-1.80 (m, IH), 1.78-1.71 (m, IH), 1.70-1.59 (m, 2H), 1.45 (m, IH), 1.30-1.23 (m, 2H), 1.08- 1.05 (m, IH), 1.01-0.97 (m, IH); MS (EI) for C27H28BrF4N3O2, found 584.16 (MH+). [00482] N-(cis-4-aminocyclohexyl)-4-bromo-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)- phenyljcyclopropylJcarbonyO-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.30 (s, 2H), 8.11 (s, IH), 7.62 (d, IH), 7.56 (s, 2H), 7.41 (d, 2H), 7.07-7.02 (m, 3H), 4.56-4.51 (m, IH), 3.72 (m, IH), 3.02-2.98 (m, IH), 2.88-2.77 (m, 2H), 1.76-1.58 (m, 6H), 1.51-1.47 (m, 2H), 1.40-1.28 (m, 2H), 1.10-1.05 (m, IH), 1.00-0.95 (m, IH); MS (EI) for C26H28BrF4N3O2, found 572.19 (MH+).
[00483] N-(cis-4-aminocyclohexyl)-4-bromo-Nalpha-[(l-{4-[(trifluoromethyl)oxy]- phenylJcyclopropyOcarbonylj-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.39 (s, 2H), 8.16 (d, IH), 7.42 (d, IH), 7.35-7.29 (m, 4H), 7.02 (d, 2H), 6.82 (d, IH), 4.60-4.54 (m, IH), 3.70 (m, IH), 3.00-2.98 (m, IH), 2.91-2.86 (m, IH), 2.81-2.75 (m, IH), 1.74-1.55 (m, 6H), 1.51-1.45 (m, 2H), 1.30-1.19 (m, 2H), 1.05-0.90 (m, 2H); MS (EI) for C26H29BrF3N3O3, found 570.18 (MH+).
I l l [00484] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -4-bromo-Nalpha-({l- [4-fluoro-2- (trifluoromethylJphenyljcyclopropylJcarbonylJ-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.00 (d, IH), 7.65-7.55 (m, 3H), 7.42 (d, 2H), 7.01 (d, 2H), 6.33 (d, IH), 4.46 (q, IH), 3.64-3.63 (m, IH), 3.12-3.07 (m, IH), 2.79-2.68 (m, 6H), 2.34-2.30 (m, IH), 1.72-1.70 (m, IH), 1.67-1.51 (m, 4H), 1.37-1.34 (m, 2H), 1.06 (s, 2H); MS (EI) for C27H28BrF4N3O2, found 584.22 (MH+).
[00485] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-{[l-(2,4-difluorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.10 (d, IH), 7.43-7.36 (m, 3H), 7.27-7.21 (m, IH), 7.09-7.04 (m, IH), 7.00 (d, 2H), 6.55 (d, IH), 4.50-4.45 (q, IH), 3.64 (m, IH), 3.15-3.09 (m, IH), 2.81-2.70 (m, 6H), 2.39-2.35 (m, IH), 1.73-1.53 (m, 4H), 1.38-1.25 (m, 3H), 1.02-0.90 (m, 2H); MS (EI) for C26H28BrF2N3O2, found 532.20 (MH+). [00486] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-fluor ophenyl)methyl] -2- oxoethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR
(400MHz, DMSO-d6): δ 7.39-7.29 (m, 4H), 7.15-7.04 (m, 4H), 6.98-6.88 (m, IH), 4.72-4.65 (m, IH), 4.41-4.36 (m, IH), 4.31-4.30 (m, IH), 4.15 (m, IH), 3.17-3.15 (m, IH), 3.05-2.90 (m, IH), 2.79-2.75 (m, 2H), 2.14-1.91 (m, 3H), 1.89-1.76 (m, IH), 1.68-1.59 (m, 2H), 1.53-1.46 (m, 2H), 1.31-1.21 (m, 2H), 1.01-0.94 (m, 2H); MS (EI) for C27H29F4N3O3, found 520.30 (MH+). [00487] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nalpha-({l-[2-(trifluoromethyl)- phenyljcyclopropylJcarbonyO-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.05 (d, IH), 7.74 (d, IH), 7.69 (t, IH), 7.58 (t, 2H), 7.40 (d, 2H), 6.97 (d, 2H), 6.14 (d, IH), 4.48 (q, IH), 3.63-3.61 (m, IH), 3.12-3.06 (m, IH), 2.78-2.66 (m, 6H), 2.34-2.29 (m, IH), 1.71-1.50 (m, 5H), 1.39-1.35 (m, 2H), 1.07 (s, 2H); MS (EI) for C27H29BrF3N3O2, found 566.21 (MH+). [00488] 4-fluoro-N-[(3R)-piperidin-3-yl]-Nalpha-[(l-{4-[(trifluoromethyl)oxy]phenyl}- cyclopropyl)carbonyl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.39 (d, IH), 8.34 (s, IH), 7.37 (d, 2H), 7.31 (d, 2H), 7.10-7.03 (m, 4H), 6.65 (d, IH), 4.48-4.42 (m, IH), 3.77-3.75 (m, IH), 3.06-3.03 (m, IH), 2.98-2.95 (m, IH), 2.91-2.87 (m, IH), 2.83-2.79 (m, IH), 2.77-2.70 (m, IH), 2.62-2.56 (m, IH), 1.72-1.69 (m, 2H), 1.55-1.50 (m, IH), 1.40-1.34 (m, IH), 1.31-1.21 (m, 2H), 1.04-0.92 (m, 2H); MS (EI) for C25H27F4N3O3, found 494.28 (MH+). [00489] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(4-fluorophenyl)methyl]-2-oxoethyl}-l-{4- [(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-dβ): δ 8.40 (s, 2H), 7.38-7.30 (m, 4H), 7.11-7.02 (m, 4H), 6.84-6.66 (m, IH), 4.94-4.89 (m, IH), 4.24- 4.14 (m, IH), 3.94-3.91 (m, IH), 3.10-2.96 (m, 2H), 2.90-2.82 (m, IH), 2.78-2.70 (m, IH), 2.67- 2.59 (m, IH), 1.90-1.81 (m, 2H), 1.35-1.17 (m, 4H), 1.02-0.94 (m, 2H); MS (EI) for C25H27F4N3O3, found 494.28 (MH+).
[00490] N-[(lS)-l-[(4-bromophenyl)methyl]-2-(4-hydroxypiperidin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 7.61 (m, IH), 7.40 (m, 4H), 7.01 (m, 2H), 6.75 (m, IH), 4.88 (m, IH), 4.74 (m, IH), 3.86 (m, IH), 3.84- 3.56 (m, 4H), 3.19-2.63 (m, 2H), 1.60 (m, 2H), 1.40-1.11 (m, 7H), 0.96 (m, 2H); MS (EI) for C24H25BrCl2N2O3, found 541.01 (MH+).
[00491] 4-fluoro-Nalpha-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)- N-[(3R)-piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.17 (d, IH), 7.64 (d, IH), 7.55 (m, 2H), 7.04 (m, 4H), 6.78 (m, IH), 4.40 (m, IH), 3.67 (m, IH), 3.01- 3.64 (m, 5H), 1.65 (m, 2H), 1.51-1.22 (m, 4H), 1.00 (m, 2H); MS (EI) for C25H26F5N3O2, found 496.17 (MH+).
[00492] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-fluor ophenyl)methyl] -2- oxoethylj-l-β-fluoro^-^rifluoromethyljphenyllcyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.64-7.51 (m, 3H), 7.24-7.00 (m, 5H), 4.67 (m, IH), 4.37 (m, IH), 4.32- 4.10 (m, IH), 3.15-2.70 (m, 2H), 2.21-1.46 (m, 8H), 1.32 (m, 2H), 1.01 (m, 2H); MS (EI) for C27H28F5N3O2, found 522.31 (MH+).
[00493] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(4-fluorophenyl)methyl]-2-oxoethyl}-l-[2- fluoro^-^rifluoromethyljphenyljcyclopropanecarboxamide: 1H NMR (400MHz, DMSO- de): δ 7.64 (m, IH), 7.55 (m, 2H), 7.05 (m, 4H), 6.90 (d, IH), 4.86 (m, IH), 4.14 (m, IH), 3.85 (m, IH), 3.06-2.55 (m, 4H), 1.76 (m, 2H), 1.36-1.08 (m, 4H), 1.00 (m, 2H); MS (EI) for C25H26F5N3O2, found 496.30 (MH+).
[00494] N-{(lS)-2-(4-aminopiperidin-l-yl)-l-[(4-fluorophenyl)methyl]-2-oxoethyl}-l-{4- [(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO-d6): δ 8.40 (s, 2H), 7.38-7.30 (m, 4H), 7.11-7.01 (m, 4H), 6.84-6.66 (dd, IH), 4.94-4.89 (m, IH), 4.24- 4.14 (m, IH), 3.94-3.91 (m, IH), 3.10-2.96 (m, 2H), 2.90-2.82 (m, IH), 2.78-2.70 (m, IH), 2.67- 2.59 (m, IH), 1.90-1.81 (m, 2H), 1.35-1.17 (m, 4H), 1.02-0.94 (m, 2H); MS (EI) for C25H27F4N3O3, found 494.28 (MH+).
[00495] N-{(lS)-2-[(3S)-3-aminopyrrolidin-l-yl]-l-[(4-bromophenyl)methyl]-2-oxoethyl}- l-^-fluoro^-^rifluoromethylJphenyljcyclopropanecarboxamide: 1H NMR (400MHz, DMSO-dg): δ 7.68-7.64 (m, IH), 7.61-7.57 (m, 2H), 7.44-7.40 (m, 2H), 7.09-7.04 (m, 2H), 7.13- 6.96 (dd, IH), 5.67 (br s, 2H), 4.67-4.56 (m, IH), 3.67-3.49 (m, 2H), 3.40-3.33 (m, 2H), 3.32- 3.11 (m, IH), 2.87-2.76 (m, 2H), 2.07-1.90 (m, IH), 1.81-1.63 (m, IH), 1.42-1.30 (m, 2H), 1.10- 0.97 (m, 2H); MS (EI) for C24H24BrF4N3O2, found 542.16 (MH+).
[00496] N-{(lS)-2-[(3S)-3-aminopyrrolidin-l-yl]-l-[(4-fluorophenyl)methyl]-2-oxoethyl}- l-β-fluoro^-^rifluoromethyljphenyljcyclopropanecarboxamide: 1H NMR (400MHz, DMSO-de): δ 7.69-7.64 (m, IH), 7.61-7.56 (m, 2H), 7.15-7.10 (m, 2H), 7.08-7.03 (m, 2H), 7.17- 6.94 (dd, IH), 6.25 (br s, 2H), 4.66-4.54 (m, IH), 3.70-3.50 (m, 2H), 3.41-3.32 (m, 2H), 3.31- 3.15 (m, IH), 2.89-2.77 (m, 2H), 2.04-1.93 (m, IH), 1.84-1.66 (m, IH), 1.42-1.30 (m, 2H), 1.10- 0.97 (m, 2H); MS (EI) for C24H24F5N3O2, found 482.25 (MH+).
[00497] N-{(lS)-2-[(3S)-3-aminopyrrolidin-l-yl]-l-[(4-fluorophenyl)methyl]-2-oxoethyl}- l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- dg): δ 7.89 (br s, IH), 7.41-7.29 (m, 4H), 7.16-7.03 (m, 4H), 6.90-6.69 (dd, IH), 4.69-4.56 (m, IH), 3.75-3.59 (m, 2H), 3.47-3.26 (m, 3H), 2.92-2.76 (m, 2H), 2.10-1.98 (m, IH), 1.94-1.77 (m, IH), 1.34-1.20 (m, 2H), 1.05-0.91 (m, 2H); MS (EI) for C24H25F4N3O3, found 480.29 (MH+). [00498] N-{(lS)-2-[(3S)-3-aminopyrrolidin-l-yl]-l-[(4-bromophenyl)methyl]-2-oxoethyl}- l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanecarboxamide: 1H NMR (400MHz, DMSO- de): δ 7.45-7.42 (m, 2H), 7.40-7.29 (m, 4H), 7.08-7.00 (m, 2H), 6.98 (br s, IH), 6.93-6.73 (dd, IH), 4.69-4.57 (m, IH), 3.71-3.58 (m, 2H), 3.45-3.22 (m, 3H), 2.91-2.75 (m, 2H), 2.09-1.98 (m, IH), 1.89-1.73 (m, IH), 1.33-1.20 (m, 2H), 1.05-0.93 (m, 2H); MS (EI) for C24H25BrF3N3O3, found 542.09 (MH+).
[00499] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -4-(trifluoromethyl)-Nalpha- [(l-{4- [(trifluoromethylJ-oxylphenylJcyclopropylJcarbonylJ-L-phenylalaninamide: 1H NMR (400MHz, DMSO-dg): δ 8.26-8.21 (m, IH), 7.62-7.60 (m, 2H), 7.39-7.34 (m, 2H), 7.29-7.26 (m, 4H), 6.67-6.61 (m, IH), 4.62-4.57 (m, IH), 3.74-3.68 (m, IH), 3.16-3.11 (m, IH), 2.97-2.90 (m, 2H), 2.88-2.68 (m, 4H), 2.50-2.42 (m, IH), 1.75-1.50 (m, 4H), 1.37-1.33 (m, IH), 1.30-1.20 (m, 2H), 1.03-0.94 (m, 2H); MS (EI) for C28H29F6N3O3, found 570.24 (MH+). [00500] N- [(3S)-l-azabicyclo [2.2.2] oct-3-yl] -2,4-dichloro-N-alpha-{ [l-(2,4- dichlorophenyl)-cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, CD3OD): δ 7.52-7.38 (m, 4H), 7.23 (d, IH), 7.17 (d, IH), 4.60 (m, IH), 4.08 (m, IH), 3.62 (m, IH), 3.34-3.13 (m, 3H), 3.08-3.02 (m, IH), 2.83 (ddd, IH), 2.17 (m, IH), 2.02-1.90 (m, 3H), 1.84-1.75 (m, IH), 1.60-1.43 (m, 2H), 1.20-1.13 (m, IH), 1.05-1.00 (m, IH); MS (EI) for
C26H27C14N3O2 found 557.01 (MH+).
[00501] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-N-alpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl}-L-phenylalaninamide: 1H NMR (400 MHz, CD3OD): δ 7.52-7.38 (m,
5H), 7.02 (d, 2H), 4.58 (t, IH), 4.00 (m, IH), 3.58 (t, IH), 3.28-3.03 (m, 4H), 2.95-2.80 (m, 2H),
2.65 (m, IH), 2.08 (m, IH), 2.00-1.65 (m, 4H), 1.62-1.43 (m, 2H), 1.20-1.13 (m, IH), 1.09-1.02
(m, IH); MS (EI) for C26H28BrCl2N3O2 found 566.78 (MH+).
[00502] N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N-alpha-{[l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl}-4-(trifluoromethyl)-L-phenylalaninamide: 1H NMR (400 MHz,
DMSO-d6): δ 8.10 (dd, IH), 7.58 (m, 3H), 7.41 (s, 2H), 7.28 (t, 2H), 6.56 (dd, IH), 4.55 (t, IH),
3.71 (m, IH), 3.15 (m, IH), 2.92 (m, 2H), 2.77 (m, 4H), 2.39 (m, IH), 1.70 (m, IH), 1.55 (m, 3H), 1.36 (m, 3H), 0.96 (m, 2H); MS (EI) for C27H28Cl2F3N3O2 found 555.43 (MH+).
[00503] 4-bromo-Nalpha-[2-(2,4-dichlorophenyl)-2-methylpropanoyl]-N-[(3R)-piperidin- 3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.28 (s, IH), 8.02 (d, IH), 7.44 (d, IH), 7.41 (d, IH), 7.39 (d, IH), 7.37 (d, 2H), 7.23 (d, IH), 7.10 (d, 2H), 4.51 - 4.35 (m, IH),
3.72 (s, IH), 3.01 (dd, IH), 2.92 (d, IH), 2.80 (qd, 2H), 2.66 (dd, IH), 1.68 (d, 2H), 1.49 (d, IH), 1.34 (d, 6H). MS (EI) for C24H28BrCl2N3O2, found 542.3 (MH+).
[00504] 4-bromo-Nalpha-(2-methyl-2-{4-[(trifluoromethyl)oxy]phenyl}propanoyl)-N- [(3R)-piperidin-3-yl]-L-phenylalaninamide: 1H NMR (400MHz, DMSO-d6): δ 8.33 (s, IH), 8.28 (d, IH), 7.54 (d, IH), 7.38 (d, 2H), 7.20 (s, 4H), 7.10 (d, 2H), 4.47 (tt, IH), 3.81 (t, IH), 3.04 (dd, 2H), 2.91 - 2.70 (m, 3H), 2.67 - 2.53 (m, IH), 1.71 (d, 2H), 1.60 - 1.46 (m, IH), 1.34 (s, 6H). MS (EI) for C25H29BrF3N3O3, found 557.4 (MH+)
[00505] N- {(1 S)-2-(3-amino-8-azabicy clo [3.2.1] oct-8-yl)- 1- [(4-bromophenyl)methyl] -2- oxoethyl}-2-methyl-2-{4-[(trifluoromethyl)oxy]phenyl}propanamide: 1H NMR (400MHz, DMSO-de): δ 8.26 (s, IH), 7.72 (dd, IH), 7.39 (m, 2H), 7.24 (dd, 4H), 7.13 (dd, 2H), 4.72 (m, IH), 4.35 (m, 2H), 4.15 (m, IH), 3.17 (m, IH), 3.01 (m, IH), 2.98 - 2.66 (m, 2H), 2.08 - 1.78 (m, 3H), 1.74 - 1.44 (m, 4H), 1.36 (m, 6H). MS (EI) for C27H31BrF3N3O3, found 583.5 (MH+). [00506] N-{(lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl}-2-(2,4-dichlorophenyl)-2-methylpropanamide: 1H NMR (400MHz, DMSO-d6): δ 7.50 - 7.30 (m, 6H), 7.14 (t, 2H), 4.91 (m, IH), 3.77 - 3.51 (m, 2H), 3.36 (m, 2H), 2.89 - 2.68 (m, 2H), 1.54 (m, 3H), 1.39 (m, 7H), 1.21 (d, 3H). MS (EI) for C25H30BrCl2N3O2, found 556.3 (MH+).
Example 7. l-(2,4-dichlorophenyl)-N-[(lS)-l-({[(l-methylcyclopropyl)methyl]oxy}methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide
Figure imgf000117_0001
Figure imgf000117_0002
[00507] Step 1. (S)-l-tert-buty\ 2-methyl aziridine-l,2-dicarboxylate: To a solution of (S)-methyl aziridine-2-carboxylate (prepared according to Tetrahedron Asymmetry, 2002, 13(11), 1129-1134) (1.0 g, 9.89 mmol) in acetonitrile (20 mL) was added boc-anhydride (2.37 g, 10.88 mmol). The reaction mixture was stirred at room temperature for 2 h after which solvent was removed under reduced pressure, resulting in 1.86 g of the title compound that was used in the next step without further purification. 1H NMR (400MHz, DMSO-d6): δ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
[00508] Step 2. (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (S)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous chloroform (16 mL), followed by addition of (l-methylcyclopropyl)methanol (1.2, 14.9 mmol) and 0.04 mL (0.25 mmol) of a 7 M boron trifluoride diethyl etherate (Aldrich). The reaction mixture was stirred at room temperature for 24 hours and quenched with a few drops of methanol. The product was purified by column chromatography (EtOAc, Hexanes, silica-gel) to afford (S)-methyl 2-(tert- butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)propanoate (800 mg) as a clear oil. 1H NMR (400MHz, DMSO-d6): δ 7.13 (d, IH), 4.23 (m, IH), 3.63 (s, 3H), 3.59 (m, 2H), 3.17 (m, 2H), 1.38 (s, 9H), 1.01 (s, 3H), 0.33 (m, 2H), 0.24 (m, 2H).
[00509] Step 3. (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate: (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate (800 mg, 2.8 mmol) was dissolved in anhydrous diethyl ether (6 mL) and 4 M HCl/dioxane (14mL, 55.7 mmol, Aldrich) was added. The reaction mixture was stirred for 4 hours at room temperature and the solvent was removed in vacuo. The resulting 600 mg of (S)-methy 1 2-(tert-butoxycarbonylamino)-3 -(( 1 -methy lcyclopropyl)methoxy)propanoate was used in the nest step without purification. MS (EI) for C9Hi7NO3, found 188.10 (MH+). [00510] Step 4. (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l- methylcyclopropyl)methoxy)propanoate: To a solution of (S)-methyl 2-(tert-butoxycarbonyl- amino)-3-((l-methylcyclopropyl)methoxy)propanoate (600 mg, 5.7 mmol) and N,N-diisopropylethylamine (0.9 mL, 6.5 mmol) in dry acetonitrile (10 mL) was added l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Acros, 500 mg, 2.2 mmol), followed by HATU (Applied Biosystems, 905 mg, 2.4 mmol), and the reaction mixture was stirred for 18 h at room temperature. The resulting solution was concentrated in vacuo, dissolved in dichloromethane (300 mL), extracted with water (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL). The layers were separated and the organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l-methylcyclopropyl)- methoxy)propanoate (850 mg) that was used in the next step without further purification. MS (EI) for Ci9H23Cl2NO4, found 400.09 (MH+).
[00511] Step 5. (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l- methyl-cyclopropyl)methoxy)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropanecarboxamido)-3-((l-methylcyclopropyl)methoxy)propanoate (850 mg, 2.1 mmol) in 10 mL of THF was added 8.5 mL of IN LiOH solution (8.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated down under reduced pressure, acidified with concentrated HCl to pH=3, and extracted with 100 mL of Ethyl Acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 700 mg of the title compound which was used in the next step without further purification. MS (EI) for Ci8H2ICl2NO4, found 386.05 (MH+). [00512] Step 6. l-(2,4-dichlorophenyl)-N-[(lS)-l-({[(l-methylcyclopropyl)methyl]- oxy} methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl] cyclopropanecarboxamide : To a solution of (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l-methyl- cyclopropyl)methoxy)propanoic acid (100 mg, 0.2 mmol) in acetonitrile (1.5 mL) were added N-methylpiperazine (Sigma-Aldrich, 30 mg, 0.3 mmol), N,N-diisopropylethylamine (0.07 mL, 0.5 mmol), and HATU (Applied Biosystems, 115 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 16 hour. The resulting solution was concentrated in vacuo, and the product was then purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM formic acid buffer) to give 12 mg of the title compound. 1H NMR (400MHz, DMSO-d6): δ 7.66 (d, IH), 7.48-7.43 (m, 2H), 6.72 (d, IH), 4.87-4.82 (m, IH), 3.43 (d, 4H), 3.10 (q, 2H), 2.33-2.18 (m, 4H), 2.15 (s, 3H), 1.90 (s, 2H), 1.54-1.41 (m, 2H), 1.11-0.98 (m, 2H), 0.96 (s, 3H), 0.30-0.26 (m, 2H), 0.24-0.20 (m, 2H); MS (EI) for C23H3ICl2N3O2, found 468.27 (MH+).
Example 8
N-l-azabicyclo[2.2.2]oct-3-yl-N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-3-(l- methylcyclopropyl)-L-alaninamide
Figure imgf000119_0001
[00513] Step 1: (S)-methyl 2-(ført-butoxycarbonylamino)-4-methylpent-4-enoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-4-methylpent-4-enoic acid (Alfa Aesar, 1.0 g, 4.4 mmol) in anhydrous acetonitrile (20 mL) was added potassium carbonate (1.8 g, 13.1 mmol) and methyl iodide (0.81 mL, 13.1 mmol). The resulting solution was stirred overnight, concentrated in vacuo, re-dissolved in EtOAc (100 mL), washed with 100 mL of 1 M NaOH, and then dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure resulted in 300 mg of (S)-methyl 2-(tert-butoxycarbonylamino)-4-methylpent-4-enoate, which was used in the next step without further purification. MS (EI) for Ci2H2iNO4, found 244.15 (MH+). [00514] Step 2: (S)-methyl 2-amino-3-(l-methylcyclopropyl)propanoate: To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-methylpent-4-enoate (300 mg, 1.2 mmol) in anhydrous dichloromethane (12 mL) under nitrogen atmosphere was added dimethylzinc (3 mL of a 2 M toluene solution, 6.2 mmol), followed by addition of diiodomethane (0.5 mL, 6.2 mmol). The reaction mixture was stirred overnight at room temperature. The resulting solution was extracted with saturated ammonium chloride (30 mL), and water (10 mL). The layers were separated, and the organic layer was dried over sodium sulfate. Filtration and concentration under reduced pressure resulted in 190 mg of the title compound that was submitted to the next step without further purification. MS (EI) for C8Hi5NO2, found 158.10 (MH+). [00515] Step 3: (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(l- methyl-cyclopropyl)propanoate: To a solution of (S)-methyl 2-amino-3-(l- methylcyclopropyl)propanoate (187 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 5.5 mmol) in dry acetonitrile (5 mL) was added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Acros, 250 mg, 1.1 mmol), followed by HATU (Applied Biosystems, 450 mg, 1.2 mmol). The reaction mixture was stirred for 18 h at room temperature. The resulting solution was concentrated in vacuo, dissolved into dichloromethane (100 mL), extracted with water (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL). The layers were separated and the organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in 350 mg of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropanecarboxamido)-3-(l-methylcyclopropyl)propanoate that was used in the next step without further purification. MS (EI) for Ci8H2iCl2NO3, found 370.07 (MH+). [00516] Step 4: (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxyamido)-3-(l- methylcyclopropyl)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropane-carboxamido)-3-(l-methylcyclopropyl)propanoate (350 mg, 0.9 mmol) in 5 mL of THF was added 1.9 mL of IN LiOH solution (1.9 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated down under reduced pressure, acidified with concentrated HCl to pH=2, and extracted with 50 mL of Ethyl Acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 310 mg of the title compound which was used in the next step without further purification. MS (EI) for Ci7Hi9Cl2NO3, found 356.06 (MH+).
[00517] Step 5: N-l-azabicyclo[2.2.2]oct-3-yl-N'2'-{[l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl}-3-(l-methylcyclopropyl)-L-alaninamide: To a solution of (S)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxyamido)-3-(l-methylcyclopropyl)propanoic acid (300 mg, 0.8 mmol) and N,N-diisopropylethylamine (00.4 mL, 2.6 mmol) in acetonitrile (4 mL) was added quinuclidin-3 -amine (Sigma-Aldrich, 117 mg, 0.9 mmol), followed by HATU (Applied Biosystems, 350 mg, 0.9 mmol). The reaction mixture was stirred for 18 h at room temperature. The resulting solution was concentrated in vacuo, and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM formic acid buffer) to give 7.8 mg of the title compound. 1H NMR (400MHz, CD3OD): δ 8.55-8.47 (m, IH), 7.57 (s, IH), 7.54-7.51 (m, IH), 7.43-7.41 (m, IH), 6.33-6.31 (m, IH), 4.42-4.41 (m, IH), 4.16 (s, IH), 3.75-3.70 (m, IH), 3.14- 3.01 (m, 2H), 2.22-1.79 (m, 9H), 1.72 (m, IH), 1.53 (m, IH), 1.23-1.15 (m, 2H), 1.09-1.08 (m, IH), 1.01 (s, 3H), 0.21-0.15 (m, 2H), 0.07 (m, IH), -0.04 (m, IH); MS (EI) for C24H3ICl2N3O2, found 465.17 (MH+).
Example 9.
GCS Fluorescent Dehydrogenase-Diaphorase-Coupled-Enzyme Assay
[00518] Glucosylceramide synthase (GCS) activity was measured as the amount of UDP-glucose consumed during the synthase-catalyzed reaction by using the enzyme UDP-glucose dehydrogenase to create NADH from UDP-glucose and then quantitatively converting low fluorescence resazurin to high fluorescence resorufm with diaphorase and the NADH that is formed by the dehydrogenase. The synthase-catalyzed reaction transferred glucose from UDP-glucose to C6-ceramide to give UDP and glucosylceramide as products; the assay measured the disappearance of the UDP-glucose substrate. Reactions were conducted in 384-well black, medium binding microtiter plates (Greiner). Synthase reaction mixtures (25 mM HEPES, pH = 7.4, 50 mM KCl and 5 mM MgCl2) were prepared by first adding 0.0005 mL of compound in 100% DMSO to the plate. A volume V = 0.010 mL of 30 mol% C6-ceramide (Avanti Polar Lipids, Inc) and 70 mol % dioleoyl phosphatidylcholine (DOPC, Avanti Polar Lipids) with total concentration = 0.3 mM in 25 mM HEPES, pH = 7.4, was added to the wells. [00519] C6-ceramide and DOPC were prepared as 20 mg/mL stock solutions in 95% ethanol and stored at -20 0C. The appropriate volumes were transferred to a 40 mL glass vial with screw-cap septum and taken to "dryness" with a stream of argon gas. The lipids were resuspended in 1 mL of dH20, frozen and lyophilized overnight. The lipids were hydrated by first adding enough 25 mM HEPES, pH = 7.4, to give 4x the required concentration for addition to the plate, vortexed to suspend the lyophilized lipids and waited for 1 h or more. The solution was then frozen, placed in a bath sonicator and thawed with sonication. This was repeated three additional times to give four freeze-thaw sonication cycles. The resulting solution was diluted four-fold with 25 mM HEPES, pH = 7.4, to give the solution of lipids that was added to the plate.
[00520] Full-activity controls (100% activity) contained DMSO only. No-activity control reactions (0% control) contained 0.010 mL of 100 mol % DOPC (0.3 mM) and DMSO only. The reactions were initiated by the addition of V = 0.020 mL of 0.020 mM UDP-glucose, 1.5 mg/mL CHAPS, 0.17 mg/mL GCS in 25 mM HEPES, pH = 7.4, 75 mM KCl and 7.5 mM MgCl2 to all wells of the plate. The plate was kept at 26 0C for 3 h. The UDP-glucose that remained was measured by the addition of 0.015 mL of 0.30 mM NAD+, 0.30 mM resazurin, 0.11 mg/mL UDP-glucose dehydrogenase and 0.030 mg/mL diaphorase in 25 mM HEPES, pH = 7.4, 50 mM KCl and 5 mM MgCl2. The plate was kept at 26 0C for 30 minutes or longer, and the increase in fluorescence with excitation = 530 nm and emission = 560 nm was measured with an Envision 1 plate reader (Perkin Elmer). Consumption of UDP-glucose was limited to 40-60% of the total UDP-glucose in the assay. IC50 values were calculated by nonlinear regression analysis using the four-parameter equation [Y = max - (max - min) / (1 + (X/ICso)N)] where Y was the observed fluorescence, X was the concentration of inhibitor, max is the fluorescence in the absence of C6-ceramide (0% control), min was the fluorescence in the absence of inhibitor (100% control), IC50 was the concentration of inhibitor that gave 50 increase in fluorescence and N the empirical "Hill" slope. N should approximate unity. Curve fitting was performed using commercial software (idbs ActivityBase XE).
GCS Assay Results
[00521] The IC50 data presented in Table 1 was generated via the testing methodology of Example 9 and is coded as follows: A < 200 nm, B = 200-1000 nm, C > 1000 nm. Compounds of the invention are considered active if their IC50 values were < 4000 nM. In this assay, a compound with a smaller IC50 value, for example an IC50 of 10 nM, is considered more potent than a compound with a larger IC50 value, for example, an IC50 value of 1000 nM.
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
[00522] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

We claim:
1. A compound of the formula,
Figure imgf000168_0001
(I) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein A is isopropyl, t-butyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups, wherein each RA is independently R^, C1-C6 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4)alkyl, or -Ci-C6 alkyl-RA2, wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each R^ is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(0)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3;
L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein p is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen, methyl, or halomethyl; R1 is -N(R10XR1 J) or a moiety of formula (a) ,
Figure imgf000169_0001
wherein
R , 10 is hydrogen or Ci-C4 alkyl; R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and
R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, cyano, nitro, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; w is 0, 1, 2, or 3; ring B in the definition of R1 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms;
R20 is -RB2, hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3,
-S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3,
-C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or
-N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and each R21 is independently halogen or -R20; R2 is methyl optionally substituted with one, two or three halo groups, or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; m is 1, 2, 3, 4 or 5; and each R3 is independently halogen, cyano, nitro, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, -ORC1, -N(RC1)2, -C(O)RC1, -S(O)RC1, -S(O)2R01, -S(O)N(RC1)2, -S(O)2N(RC1)2, -C(O)ORC1, -C(O)N(RC1)2, -N(RC1)C(O)RC1, -N(RC1)C(O)ORC1, -N(RC1)C(O)N(RC1)2, or -N(RC1)S(O)2RC1, wherein each RC1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl, or two R3 taken together with the ring atoms to which they are attached form an aryl, heteroaryl, a monocyclic cycloalkyl, or a heterocyclyl, each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl.
2. The compound of claim 1 , wherein R2 is methyl or both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein both R2 taken together with the carbon atom to which they are attached form a cyclopropyl group; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
4. The compound of any one of claims 1 - 3, wherein A is C3-Cs cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1 - 3, wherein A is phenyl optionally substituted by one, two, or three RA groups; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
6. The compound of any one of claims 1 - 5, wherein when RA is present, each RA is independently halogen, cyano, C1-C4 alkyl, Ci-C4 haloalkyl, phenyl, benzyl, -ORA1, -N(RA1)2, or -C(O)RA1, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl; or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-; each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 1 - 6, wherein R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2; and when R21 is present, each R21 is independently halogen or -R20; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
8. The compound of any one of claims 1 -7, wherein R1 is
(i) -N(R10XR1 ^ wherein
R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 : -Ci-C6 alkyl-N(R12)2, or -C1-C6 alkyl-R13, wherein each R , 12 is independently hydrogen or C1-C4 alkyl; and R13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl is optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, or-N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or R1 is (ii) a moiety of formula (a) ,
Figure imgf000172_0001
wherein w is 0, 1, or 2; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
9. The compound of any one of claims 1 - 8, wherein R1 is
(i) -N(R10XR1 *), wherein R10 is hydrogen or methyl; or R1 is (ii) a moiety of formula (a) ,
Figure imgf000172_0002
wherein ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is:
Figure imgf000173_0001
wherein £ is 1, 2, or 3; and r is 0, 1, 2, or 3; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1 -9, wherein R1 is -N(R10XR11) or a moiety of formula (a) ,
Figure imgf000173_0002
wherein
(a) ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; RB2 is -ORB3 or -N(RB3)2; and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl;
(b) the moiety of formula (a) is
Figure imgf000173_0003
, wherein Hs 1, 2, or 3, R is hydrogen, Ci-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(CrC4)alkyl, or -C1-C4 alkyl-RB2, wherein RB2 is -ORB3 or -N(RB3)2, and R21 is Ci-C4 alkyl or Ci-C4 haloalkyl; or
(c) the moiety of formula (a) is
Figure imgf000173_0004
, wherein r is 0, 1 , 2, or 3, R20 is -N(RB3)2 or -Ci-C4 alkyl-N(RB3)2; and R21 is C1-C4 alkyl or C1-C4 haloalkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
11. The compound of any one of claims 1 - 10, wherein R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000174_0001
wherein ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1 - 10, wherein R1 is -N(R10)(Rπ) or a moiety of formula (a),
wherein said moiety of formula
Figure imgf000174_0002
(a) is , wherein t is 1 , 2, or 3; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
13. The compound of any one of claims 1 - 10, wherein R1 is -N(R10XR11) or a moiety of formula (a),
wherein said moiety of formul
Figure imgf000174_0003
a (a) is , wherein r is 0, 1, 2, or 3; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1 - 13, wherein L is -[C(RL)2]p-L1-[C(RL)2]q-,wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen or methyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
15. The compound of any one of claims 1 -14, wherein R1 is a moiety of formula (a) ,
Figure imgf000175_0001
or a single stereoisomer or mixture of stereoisomers thereof, and additionally as a pharmaceutically acceptable salt thereof.
16. The compound of any one of claims 1 - 14, wherein R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
17. The compound of any one of claims 1 - 14, wherein R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1 - 14, 16, and 17, wherein when R13A is present, each R13A group is independently halogen, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, or -N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1 - 14, wherein R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein R11 is -Ci-C6 alkyl-N(R12)2 or -C3-C6 cycloalkyl-N(R12)2; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
20. The compound of any one of claims 1 - 6, 9, 14, and 16 - 19, wherein R1 is -N(R10)(Rπ); or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1 - 20, wherein R3 is halogen, C1-C4 alkyl,
Ci -C4 haloalkyl, or -OR , wherein each R is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
22. The compound of any one of claims 1-15 and 21, wherein w is zero or 1, and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
23. The compound of any one of claims 1 - 22, wherein L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH2-O-, -CH2CH2-O-, or -CH2-O-CH2-; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
24. The compound of any one of claims 1 - 23, wherein L is Ci-C3 alkylene; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 1 - 24 which is a compound of formula (Ia),
Figure imgf000177_0001
or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
26. The compound of any one of claims 1 - 24 which is a compound of formula (Ib),
Figure imgf000177_0002
or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
27. A compound listed in Table 1, or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition which comprises a compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 27, and a pharmaceutically acceptable excipient, diluent, or carrier.
29. A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any one of claims 1 - 27 or a composition according to claim 28.
30. The method of claim 29, wherein the disease or disorder is cancer.
31. The method of claim 29, wherein the disease or disorder is a metabolic disorder.
32. A method for inducing decreased glucosylceramide synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 - 27.
33. A method of preparing a compound of claim 1, the method comprising: (i) coupling a compound of formula (13),
Figure imgf000178_0001
wherein * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a);
Figure imgf000178_0002
with a compound of formula (14), to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof; or (ii) coupling a compound of formula (15),
Figure imgf000178_0003
wherein * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (16) wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and Rγ is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a);
Figure imgf000178_0004
to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012129084A2 (en) 2011-03-18 2012-09-27 Genzyme Corporation Glucosylceramide synthase inhibitors
WO2014043068A1 (en) * 2012-09-11 2014-03-20 Genzyme Corporation Glucosylceramide synthase inhibitors
CN104311473A (en) * 2014-05-27 2015-01-28 天津市斯芬克司药物研发有限公司 Piperidine compound and preparation method thereof
JP2015505308A (en) * 2011-12-30 2015-02-19 マルク−アンリ、ピティＭａｒｃ−Ｈｅｎｒｙ Ｐｉｔｔｙ Piperazinyl derivatives for the treatment of cancer
US20160311836A1 (en) * 2013-12-17 2016-10-27 Stella Pharma Corporation Production method for 2-fluoro-4-borono-l-phenylalanine, and precursor of 2-fluoro-4-borono-l-phenylalanine
US20170037007A1 (en) * 2014-04-23 2017-02-09 X-Rx, Inc. Substituted n-(2-(amino)-2oxoethyl)benzamide inhibitors of autotaxin and their preparation and use in the treatment of lpa-dependent or lpa-mediated diseases
EP3318277A1 (en) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases
WO2019126776A1 (en) 2017-12-21 2019-06-27 Lysosomal Therapeutics Inc. Crystalline substituted cyclohexyl pyrazolo[1,5-a]pyrimidinyl carboxamide compound and therapeutic uses thereof
WO2021221953A1 (en) 2020-04-28 2021-11-04 The Regents Of The University Of Michigan Pyridine inhibitors of glucosylceramide synthase and therapeutic methods using the same
EP4041733A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 2,3-dihydro-1h-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
EP4041734A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
US11857512B2 (en) 2020-07-24 2024-01-02 Genzyme Corporation Pharmaceutical compositions comprising venglustat

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
WO1999031066A1 (en) * 1997-12-18 1999-06-24 Boehringer Ingelheim Pharmaceuticals, Inc. Pyridones as src family sh2 domain inhibitors
WO2004005293A2 (en) 2002-07-05 2004-01-15 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
WO2005068426A1 (en) 2004-01-14 2005-07-28 Actelion Pharmaceuticals Ltd Piperidine derivatives as gcs inhibitors
WO2006053043A2 (en) 2004-11-10 2006-05-18 Genzyme Corporation Methods of treating diabetes mellitus
WO2008150486A2 (en) * 2007-05-31 2008-12-11 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
WO1999031066A1 (en) * 1997-12-18 1999-06-24 Boehringer Ingelheim Pharmaceuticals, Inc. Pyridones as src family sh2 domain inhibitors
WO2004005293A2 (en) 2002-07-05 2004-01-15 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
WO2005068426A1 (en) 2004-01-14 2005-07-28 Actelion Pharmaceuticals Ltd Piperidine derivatives as gcs inhibitors
WO2006053043A2 (en) 2004-11-10 2006-05-18 Genzyme Corporation Methods of treating diabetes mellitus
WO2008150486A2 (en) * 2007-05-31 2008-12-11 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
EL ALWANI ET AL., PROSTAGLANDINS & OTHER LIPID MEDIATORS, vol. 78, no. 1-4, 2005, pages 249 - 263
J. MED CHEM, vol. 33, 1990, pages 2270
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
TETRAHEDRON ASYMMETRY, vol. 13, no. 11, 2002, pages 1129 - 1134
TREIBER ET AL., XENOBIOTICA, vol. 37, no. 3, 2007, pages 298 - 314
TURZANSKI ET AL., EXPERIMENTAL HEMATOLOGY, vol. 33, no. 1, 2005, pages 62 - 72
YAMASHITA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 96, no. 16, 1999, pages 9142 - 9147

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