TREA

Melanocortin receptor ligands

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Information

  • Patent Grant
  • 7132539
  • Patent Number
    7,132,539
  • Date Filed
    Monday, October 20, 2003
    21 years ago
  • Date Issued
    Tuesday, November 7, 2006
    18 years ago
Information
Abstract
The present invention relates to compounds which comprise a nitrogen-containing ring scaffold substituted by an R1 alkyl units selected from the group consisting of C1–C12 linear or branched alkyl, C3–C8 cyclic alkyl, C2–C12 linear or branched alkenyl, or haloalkyl, for example, the 2-keto-3-alkylpiperazines having the formula:
Description
FIELD OF THE INVENTION

The present invention relates to melanocortin (MC) receptor ligands that have a 4-substituted nitrogen atom-containing ring, which provides for enhanced activity. These ligands preferably exhibit selectivity for the MC-3 and/or MC-4 receptors relative to the other melanocortin receptors (in particular the MC-1 receptor) and are suitable for use in pharmaceutical compositions and in treatment methods.


BACKGROUND OF THE INVENTION

Melanocortin peptides (melanocortins) are natural peptide hormones in animals and man that bind to and stimulate MC receptors. Examples of melanocortins are α-MSH (melanocyte stimulating hormone), β-MSH, γ-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is mainly known for its ability to regulate peripheral pigmentation, whereas ACTH is known to induce steroidoneogenesis. The melanocortin peptides also mediate a number of other physiological effects. They are reported to affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, brain blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual activity, penile erection, blood glucose levels, intrauterine fetal growth, food motivated behavior, as well as other events related to parturition.


Both the MC-4 and MC-3 receptors have been localized to the hypothalamus, a region of the brain believed to be involved in the modulation of feeding behavior. Compounds showing selectivity for the MC-3/MC-4 receptors have been shown to alter food intake following intracerebroventricular and peripheral injection in rodents. Specifically, agonists have been shown to reduce feeding, while antagonists have been shown to increase feeding. The role of the MC-4 and MC-3 receptors have been defined in the control of body weight regulation in mammals. It is believed that the MC-3 receptor influences feed efficiency and the partitioning of fuel stores into fat, whereas the MC-4 receptor regulates food intake and possibly energy expenditure. Thus, these receptor subtypes appear to reduce body weight through distinct and complementary pathways. Therefore compounds that stimulate both the MC-3 and MC-4 receptors may have a greater weight loss effect than those that are selective for either the MC-3 or MC-4 receptor.


Body weight disorders such as obesity, anorexia and cachexia are widely recognized as significant public health issues and there is a need for compounds and pharmaceutical compositions which can treat these disorders.


The Applicants have discovered a class of compounds that surprisingly have high affinity for the MC-4 and/or the MC-3 receptor subtypes, and that are typically selective for these MC receptors relative to the other melanocortin receptor subtypes, particularly the MC-1 subtype.


SUMMARY OF THE INVENTION

The present invention relates to compounds which comprise an alkyl substituted heterocyclic ring. The compounds, including all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof, have the formula:




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wherein L represents a linking unit each of which is independently selected from the group consisting of:

    • a) —(R2)p(CH═CH)q—;
    • b) —(R2)y(X)zC(Y)w(X)z(R2)y—;
    • c) —(R2)y(X)zS(Y)k(X)z(R2)y—;
    • d) —(R2)y(Z)mNR4(Z)m(R2)y—;
    • e) —(R2)y(O)zP(T)k(O)z(R2)y—;


      wherein T is ═O, —OR4, and mixtures thereof; wherein X is —O—, —S—, —NR4—; Y is ═O, ═S, ═NR4, —R4, and mixtures thereof; Z is ═N—, —NR4—, and mixtures thereof; the index k is from 0 to 2; the index m is 0 or 1; the index p is from 0 to 12; the index q is from 0 to 3; the index w is from 0 to 2; the index y is 0 or 1; the index z is 0 or 1;
  • each R2 is independently a substituted or unsubstituted methylene unit represented by the formula:




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wherein R3a and R3b are each independently selected from the group consisting of:

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocycle;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]nCOOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) an R3a and an R3b unit from the same carbon atom can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 8 atoms;
    • xxxiii) an R3a or R3b unit from a first R2 unit can be taken together with an R3a or R3b unit from a second R2 unit to form a carbocyclic or heterocyclic ring comprising from 3 to 8 atoms;
    • xxxiv) and mixtures thereof;
    • wherein R4 units are the same as defined herein below, and any two R4 units can be taken together to form a substituted or unsubstituted carbocyclic ring comprising from 3–8 carbon atoms; R9 is R4, fluorine, chlorine, bromine, iodine, and mixtures thereof; each R11 is hydrogen or R10; the index n has the value from 0 to 10.
  • R4 units are hydrocarbyl units each of which is independently selected from the group consisting of:
    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocycle;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) any two R4 units can be taken together to form a substituted or unsubstituted carbocyclic ring comprising from 3–8 carbon atoms;
  • R is a substituted or unsubstituted hydrocarbyl unit selected from the group consisting of:
    • a) non-aromatic carbocyclic rings;
    • b) aromatic carbocyclic rings;
    • c) non-aromatic heterocyclic rings;
    • d) aromatic heterocyclic rings;
  • W is a pendant unit having the formula:




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wherein the index r is 0 or 1, and the index x is from 0 to 10;

  • Q is:
    • a) hydrogen;
    • b) —N(R4)2;
    • c) —OR4;
    • d) a unit which comprises a substituted or unsubstituted unit selected from the group consisting of:
      • i) non-aromatic carbocyclic rings;
      • ii) aromatic carbocyclic rings;
      • iii) non-aromatic heterocyclic rings;
      • iv) aromatic heterocyclic rings;
      • wherein the number of rings is from 1 to 3;
  • R5a and R5b are each independently selected from the group consisting of
    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclic;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]nCOOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) R5a and R5b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 10 atoms;
    • xxxiv) and mixtures thereof;
  • R4 units are the same as defined herein above, and any two R4 units can be taken together to form a substituted or unsubstituted carbocyclic ring comprising from 3–8 carbon atoms;
  • R1 is substituted or unsubstituted C1–C12 linear or branched alkyl, C3–C8 cyclic alkyl, C2–C12 linear or branched alkenyl, or —[C(R9)2]nC(R9)3; R9 is hydrogen, fluorine, chlorine, bromine, iodine, and mixtures thereof; the index n has the value from 0 to 10 as defined herein above;


A, A1, and A2 are ring components each of which is independently selected from the group consisting of —C(═NR6)—, —C(═O)—, —C(═S)—, —C(R6)2—, —C(R6)2C(R6)2—, —CR6═, —N═, —NR6—, or two A units can be taken together with an adjacent atom or A unit to form a bond having the formula —N═N—, —N—NR6—, —CR6═N—, —C═N—, and mixtures thereof; the index j is 0 or 1;


R6 is hydrogen, R4, or the pendant unit W1 having the formula:




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wherein the index r is equal to 0 or 1;


R7a and R7b are each independently selected from the group consisting of

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclic;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]nCOOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) and mixtures thereof;


R8 is selected from the group consisting of:

    • i) hydrogen;
    • ii) C3–C8 non-aromatic carbocyclic rings;
    • iii) C6–C14 aromatic carbocyclic rings;
    • iv) C1–C7 non-aromatic heterocyclic rings;
    • v) C3–C13 aromatic heterocyclic rings;
    • vi) —C(Y)R4;
    • vii) —C(Y)2R4;
    • viii) —C(Y)N(R4)2;
    • ix) —C(Y)NR4N(R4)2;
    • x) —CN;
    • xi) —CNO;
    • xii) —[C(R9)2]C(R9)2;
    • xiii) —N(R4)2;
    • xiv) —NR4CN;
    • xv) —NR4C(Y)R4;
    • xvi) —NR4C(Y)N(R4)2;
    • xvii) —NHN(R4)2;
    • xviii) —NHOR4;
    • xix) —NCS;
    • xx) —NO2;
    • xxi) —OR4;
    • xxii) —OCN;
    • xxiii) —OCF3, —OCCl3, —OCBr3;
    • xxiv) —F, —Cl, —Br, —I, and mixtures thereof;
    • xxv) —SCN;
    • xxvi) —SO3M;
    • xxvii) —OSO3M;
    • xxviii) —SO2N(R4)2;
    • xxix) —SO2R4;
    • xxx) —P(O)M2;
    • xxxi) —PO2;
    • xxxii) —P(O)(OM)2;
    • xxxiii) and mixtures thereof


      wherein R4 units are the same as defined herein above, and any two R4 units can be taken together to form a substituted or unsubstituted carbocyclic ring comprising from 3–8 carbon atoms.


These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.







DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to melanocortin (MC) receptor ligands. The melanocortin (MC) class of peptides mediates a wide range of physiological effects. Synthetic peptides and peptide mimetics, which modulate the interaction of natural MC ligands have varying degrees of selectivity and binding. The present invention is directed to ligands that are selective for the MC4 receptor, or that are selective for both the MC4 and MC3 receptor while minimizing the interaction at the MC1, MC2, and MC5 receptors.


For the purposes of the present invention the term “hydrocarbyl” is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various unsubstituted non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]-heptan-1-yl, and naphth-2-yl.


Included within the definition of “hydrocarbyl” are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cyclohexenyl, cycloheptanyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.


The term “heterocycle” includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.


An example of a unit defined by the term “alkylenearyl” is a benzyl unit having the formula:




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whereas an example of a unit defined by the term “alkyleneheteroaryl” is a 2-picolyl unit having the formula:




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The terms “arylene” and “heteroarylene” relate to aryl and heteroaryl units which can serve as part of a linking group, for example, units having the formula:




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which represent an arylene and heteroarylene unit respectively.


The term “substituted” is used throughout the specification. The term “substituted” is defined herein as “encompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also substituted can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit.” For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. An epoxide unit is an example of a substituted unit which requires replacement of a hydrogen atom on adjacent carbons. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”, (N,N-dimethyl-5-amino)octanyl is a “substituted C8 alkyl unit, 3-guanidinopropyl is a “substituted C3 alkyl unit,” and 2-carboxypyridinyl is a “substituted heteroaryl unit.”


The following are non-limiting examples of units, herein after also indicated as R10, which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as “substituted.” Non-limiting examples of R10 include:

  • i) —[C(R4)2]p(CH═CH)qR4; wherein p is from 0 to 12; q is from 0 to 12;
  • ii) —[C(R11)2]nC(X)R4;
  • iii) —[C(R11)2]nC(X)2R4;
  • iv) —[C(R11)2]nC(X)CH═CH2;
  • v) —[C(R11)2]nC(X)N(R4)2;
  • vi) —[C(R11)2]nC(X)NR4N(R4)2;
  • vii) —[C(R11)2]nCN;
  • viii) —[C(R11)2]nCNO;
  • ix) —CF3, —CCl3, —CBr3;
  • x) —[C(R11)2]nN(R4)2;
  • xi) —[C(R11)2]nNR4CN;
  • xii) —[C(R11)2]nNR4C(X)R4;
  • xiii) —[C(R11)2]nNR4C(X)N(R4)2;
  • xiv) —[C(R11)2]nNHN(R4)2;
  • xv) —[C(R11)2]nNHOR4;
  • xvi) —[C(R11)2]nNCS;
  • xvii) —[C(R11)2]nNO2;
  • xviii) —[C(R11)2]nOR4;
  • xix) —[C(R11)2]nOCN;
  • xx) —[C(R11)2]nOCF3, —OCCl3, —OCBr3;
  • xxi) —F, —Cl, —Br, —I, and mixtures thereof;
  • xxii) —[C(R11)2]nSCN;
  • xxiii) —[C(R11)2]nSO3M;
  • xxiv) —[C(R11)2]nOSO3M;
  • xxv) —[C(R11)2]nSO2N(R4)2;
  • xxvi) —[C(R11)2]nSO2R4;
  • xxvii) —[C(R11)2]nP(O)(OR4)R4;
  • xxviii) —[C(R11)2]nP(O)(OR4)2;
  • xxix) and mixtures thereof;


    wherein R4 and R11 are defined herein below; M is hydrogen, or a salt forming cation; X is defined herein below. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like. Non-limiting examples of an alkylenearyl unit include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl. For the purposes of the present invention the term “substituted” on a chemical formula bearing an R10 moiety, for example the formula:




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will stand equally well for the substitution of one or more hydrogen atoms.


The compounds of the present invention include all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts of compounds having the core scaffold represented by the formula:




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wherein L represents a linking unit each of which is independently selected from the group consisting of:

    • a) —(R2)p(CH═CH)q—;
    • b) —(R2)y(X)zC(Y)w(X)z(R2)y—;
    • c) —(R2)y(X)zS(Y)k(X)z(R2)y—;
    • d) —(R2)y(Z)mNR4(Z)m(R2)y—;
    • e) —(R2)y(O)zP(T)k(O)z(R2)y—;


      wherein T is ═O, —OR4, and mixtures thereof; wherein X is —O—, —S—, —NR4—; Y is ═O, ═S, ═NR4, —R4, and mixtures thereof; Z is ═N—, —NR4—, and mixtures thereof; the index k is from 0 to 2; the index m is 0 or 1; the index p is from 0 to 12; the index q is from 0 to 3; the index w is from 0 to 2; the index y is 0 or 1; the index z is 0 or 1.


Each R2 is independently a substituted or unsubstituted methylene unit represented by the formula:




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wherein R3a and R3b are each independently selected from the group consisting of:

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclic;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]nCOOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) an R3a and an R3b unit from the same carbon atom can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 8 atoms;
    • xxxiii) an R3a or R3b unit from a first R2 unit can be taken together with an R3a or R3b unit from a second R2 unit to form a carbocyclic or heterocyclic ring comprising from 3 to 8 atoms;
    • xxxiv) and mixtures thereof;
  • R9 is R4, fluorine, chlorine, bromine, iodine, and mixtures thereof; each R11 is hydrogen or R10; the index n has the value from 0 to 10.


R4 units are hydrocarbyl units each of which is independently selected from the group consisting of:

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclic;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof.


Throughout the present specification whenever two or more R4 units comprise a moiety as herein above, any two of said R4 units can be taken together to form a substituted or unsubstituted carbocyclic ring comprising from 3–8 carbon atoms, for example, a unit having the formula:

vi) —[C(R11)2]nC(═NR4)N(R4)2;

can represent a unit having the formula:




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or a unit having the formula:




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One aspect of the linking units relates to peptide and peptide mimetic linking groups each of which are independently selected from units which are represented by the formula:

—(R2)y(X)zC(Y)w(X)z(R2)y—

wherein X is —NR4—; Y is ═O, ═NR4, and mixtures thereof, specific embodiments of which include L units selected from the group consisting of —CH2NR4CH2—; —NR4—; —NR4CH2—; —NR4C(O)NR4—; —NR4C(═NR4)NR4—.


Non-limiting examples of this aspect include a urea unit having the formula:

—NHC(O)NH—

an amide unit having the formula:

—NHC(O)—

or the formula:

—NHC(O)R2—

wherein R2 is C1–C4 alkylene;


an amine unit having the formula:

—NHR2—

wherein R2 is C1–C4 alkylene;


and a guanidine unit having the formula:

—NHC(═NR4)NH—

wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isopentyl, benzyl, and mixtures thereof.


A second aspect of the linking groups of the present invention relates to linking units having the formula:

a) —(R2)p(CH═CH)q—;

wherein the index q is 0 and the index p is 2 or greater thereby providing linking units having the formula:

—[C(R3a)(R3b)]2—

a first iteration of which relates to linking groups formed when the index p is equal to 2, non-limiting examples of which have the formula:




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Another iteration of this aspect of linking units relates to L units which comprise one or more R3a and R3b units which can form a hydrogen bond, non-limiting examples of which include nitrogen atom containing units having the formula:




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Another iteration of this aspect of the linking groups relates to R3a and R3b units which comprise a carbonyl unit, non-limiting examples of which include units having the formula:




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A further aspect of L relates to sulfonamide linking unit having the formula:

—NHSO2—

said unit providing one aspect of W units as defined herein below.


The scaffolds for several of the Categories of melanocortin receptor ligands of the present invention comprise linking units, L, selected from the group consisting of:

    • i) —C(O)—;
    • ii) —CH2—;
    • iii) —NH—;
    • iv) —HNC(O)—;
    • v) —C(O)NH—; and
    • vi) —O—.


      For example, melanocortin receptors ligands, which comprise the first aspect of Category II compounds as described further herein below, have the formula:




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and utilize the linking units —C(O)—; —CH2—; and —HNC(O)—. The formulator may select among any of the herein described linking units to connect or tether the functional units comprising the compounds of the present invention.


W is a pendant unit having the formula:




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wherein the index r is 0 or 1 and the index x is from 0 to 10.


Q is:

    • a) hydrogen;
    • b) —N(R4)2;
    • c) —OR4;
    • d) a unit which comprises a substituted or unsubstituted unit selected from the group consisting of:
      • i) non-aromatic carbocyclic rings;
      • ii) aromatic carbocyclic rings;
      • iii) non-aromatic heterocyclic rings;
      • iv) aromatic heterocyclic rings;
      • wherein the number of rings is from 1 to 3;


R5a and R5b are each independently selected from the group consisting of

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclic;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]COOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) R5a and R5b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 10 atoms;
    • xxxiv) and mixtures thereof;
  • R9 is R4, fluorine, chlorine, bromine, iodine, and mixtures thereof; each R11 is hydrogen or R10; the index n has the value from 0 to 10.


The first aspect of W comprises units having the formula:




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wherein Q is hydrogen. A first iteration of this aspect utilizes the amide and amine linking units for L:

    • i) —NHC(O)—;
    • ii) —NHC(O)CH2—; and
    • iii) —NHCH2—;


      which, when taken together with R5a and R5b units equal to hydrogen or C1–C4 linear or branched hydrocarbyl, provide W units which comprise alkyl and alkenyl amides and amines. Non-limiting examples of these alkyl and alkenyl amides and amines which comprise the first iteration of the first aspect of W units includes:
    • i) —NHC(O)CH3;
    • ii) —NHC(O)CH2CH3;
    • iii) —NHC(O)(CH2)2CH3;
    • iv) —NHC(O)CH(CH3)2;
    • v) —NHC(O)CH(CH3)CH2CH3;
    • vi) —NHC(O)CH2CH(CH3)2;
    • vii) —NHC(O)(CH2)3CH3;
    • viii) —NHC(O)CH2CH═CHCH3; and
    • xix) —NHC(O)CH2CH2CH═CH2.


A second iteration of this aspect relates to R5a and R5b units said units also include from the definitions of R5a and R5b units above, the units:

    • iii) —COR4;
    • xii) —N(R4)2; and
    • xx) —OR4;


      wherein R4 is hydrogen and C1–C4 alkyl. Non-limiting examples of this iteration of the first aspect of W units include:
    • i) —NHC(O)CH(NH2)CH3;
    • ii) —NHC(O)CH(NHCH3)CH3;
    • iii) —NHC(O)CH[N(CH3)2]CH3;
    • iv) —NHC(O)CH2CH(NH2)CH3;
    • v) —NHC(O)CH2CH(NHCH3)CH3;
    • vi) —NHC(O)CH(OH)CH3;
    • vii) —NHC(O)CH(OCH3)CH3;
    • viii) —NHC(O)CH2CH(OH)CH3;
    • xix) —NHC(O)CH2CH(OCH3)CH3; and
    • x) —NHC(O)CH2CH(OH)CH(OH)CH3.


The second aspect of W comprises units having the formula:




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wherein Q is —N(R4)2 and the index x is 1 or 2. A first iteration of this aspect utilizes the amide and amine linking units for L:

    • i) —NHC(O)—;
    • ii) —NHC(O)CH2—; and
    • iii) —NHCH2—;


      which, when taken together with R5a and R5b units equal to hydrogen or C1–C4 linear or branched hydrocarbyl, provide W units which comprise alkyl and alkenyl amides and amines. Non-limiting examples of these alkyl and alkenyl amides and amines which comprise the first iteration of the second aspect of W units includes:
    • i) —NHC(O)CH2NH2;
    • ii) —NHC(O)CH2NHCH3;
    • iii) —NHC(O)CH2N(CH3)2;
    • iv) —NHC(O)CH(CH3)NH2;
    • v) —NHC(O)C(CH3)2NH2;
    • vi) —NHC(O)CH(CH3)NHCH3;
    • vii) —NHC(O)CH(CH3)N(CH3)2; and
    • viii) —NHC(O)C(CH3)2N(CH3)2.


A second iteration of this aspect relates to R5a and R5b units said units also include from the definitions of R5a and R5b units above, the units:

    • iii) —COR4;
    • xii) —N(R4)2; and
    • xx) —OR4;


      wherein R4 is hydrogen and C1–C4 alkyl. Non-limiting examples of this iteration of the second aspect of W units include:
    • i) —NHC(O)CH2CH(NH2)2; (x=2)
    • ii) —NHC(O)CH(CH3)CH(NH2)2; (x=2)
    • iii) —NHC(O)CH(CH2CH2OH)CH2NH2; (x=2)
    • iv) —NHC(O)CH2CH(CH3)NH2; (x=2)
    • v) —NHC(O)C(CH3)(CH2CH3)NH2; (x=1) and
    • vi) —NHC(O)C(CH2CH3)2NH2; (x=1).


The third aspect of W units according to the present invention relates to units having the formula:




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wherein Q is —N(R4)2, R4 is —[C(R9)2]nC(R9)3; the index n is from 0 to 10; and the index x is 1 or 2. A first iteration of this aspect utilizes the amide and amine linking units for L:

    • i) —NHC(O)—;
    • ii) —NHC(O)CH2—; and
    • iii) —NHCH2—;


      non-limiting examples of this iteration of the third aspect of W units include:
    • i) —NHC(O)CFH2;
    • ii) —NHC(O)CF2H;
    • iii) —NHC(O)CF3;
    • iv) —NHC(O)CH2CF2H;
    • v) —NHC(O)CH2CF3; and
    • vi) —NHC(O)CClH2.


A second iteration of this aspect utilizes the amine linking unit for L:

    • i) —NH—;


      non-limiting examples of this iteration of the third aspect of W units include:
    • i) —NHCFH2;
    • ii) —NHCF2H; and
    • iii) —NHCF3.


The fourth aspect of W units according to the present invention relates to units having the formula:




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wherein L can comprise any iteration of the linking unit —(X)zC(Y)w(X)z— wherein each X is —NH—; Y is ═O or ═NH; each index z is independently 0 or 1; the index w is 1 or 2; R5a and R5b are each independently:

    • i) hydrogen;
    • ii) —COR4;
    • iii) —COOR4;
    • iv) —N(R4)2;
    • v) —CON(R4)2; or
    • vi) —NHCOR4;


      and Q units are heterocycles comprising from 4 to 9 carbon atoms.


The first iteration of Q units according to the third aspect of W units relates to substituted and unsubstituted quinolin-2-yl, quinolin-3-yl, and quinolin-4-yl units having the formula:




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The second iteration of Q units according to the third aspect of W units relates to substituted and unsubstituted isoquinolin-1-yl, isoquinolin-3-yl, and 1soquinolin-4-yl units having the formula:




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The third iteration of Q units according to the third aspect of W units relates to substituted and unsubstituted [5,6] fused ring systems, inter alia, 1H-indolin-3-yl having the formula:




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The fourth iteration of Q units according to the third aspect of W units relates to substituted and unsubstituted, saturated and unsaturated 5-member nitrogen containing rings selected from the group consisting of:

    • i) imidazolidines having the formula:




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    • ii) pyrrolines having the formula:







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    • iii) imidazoles having the formula:







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    • iv) imidazolines having the formula:







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    • v) pyrazolines having the formula:







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    • vi) 1H-[1,2,4]triazoles having the formula:







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wherein any of the above Q units can optionally be bonded through or substituted at a nitrogen atom.


The fifth iteration of the fourth aspect of Q units relates to heterocycles which comprise more than one type of heteroatom or which are saturated ring, non-limiting examples of which include, morpholine, piperazine, pyrrolidine, dioxane, imidazoline, pyrazolidine, piperidine, and the like.


The fifth aspect of W units according to the present invention relates to units having the formula:




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wherein L comprises linking units having the formula:

    • a) —[C(R3)2]p(CH═CH)q—; or
    • b) —(X)zC(Y)w(X)z—;


      wherein each X is —NH—; Y is ═O or ═NH; the index p is from 0 to 12; the index q is 0 or 1; each index z is independently 0 or 1; the index w is 1 or 2; R5a and R5b are each independently:
    • i) hydrogen;
    • ii) —COR4;
    • iii) —COOR4;
    • iv) —N(R4)2;
    • v) —CON(R4)2; or
    • vi)
    • NHCOR4;


      and Q units are substituted or unsubstituted carbocyclic or substituted or unsubstituted aryl units comprising from 4 to 12 carbon atoms.


The first iteration of this aspect relates to W units having the formula:




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wherein R10 comprises one or more substitutions for hydrogen, said substitutions selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, methyl, trifluoromethyl, and methoxy. Non-limiting examples of W units which comprise this first iteration of the fifth aspect of W units include, 3-(4-hydroxyphenyl)-acrylamido, 3-(4-fluorophenyl)-acrylamido, 3-(4-chlorophenyl)-acrylamido, and the like. This aspect also includes the unsubstituted example, 3-phenyl-acrylamido.


The second iteration of this aspect relates to W units having the formula:




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wherein R10 comprises one or more substitutions for hyrdrogen, said substitutions selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, methyl, trifluoromethyl, and methoxy. Non-limiting examples of W units which comprise this first iteration of the fifth aspect of W units include, 3-(4-hydroxyphenyl)-propionamido, 3-(4-fluorophenyl)-propionamido, 3-(4-chlorophenyl)-propionamido, and the like. This aspect also includes the unsubstituted example, 3-phenyl-propionamido.


The sixth aspect of W units according to the present invention relates to units having the formula:




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wherein L can comprise any iteration of the linking unit —(X)zC(Y)w(X)z— wherein each X is —NH—; Y is ═O or ═NH; each index z is independently 0 or 1; the index w is 1 or 2; R5a and R5b are each independently:

    • i) hydrogen; or
    • ii) C1–C10 substituted or unsubstitued, linear, branched or cyclic hydrocarbyl;


      and Q units are heterocycles comprising from 4 to 9 carbon atoms as described for the fourth aspect of Q.


The eighth aspect of W units comprises units having the formula:




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wherein R5a and R5b are taken together to form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.


A first iteration of this aspect relates to units wherein Q is —NH2 non-limiting examples of which include W units having the formula:




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which are further exemplified herein below.


The ninth aspect of W units comprises sulfonamide linking units, said W units having the formula:




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R is a substituted or unsubstituted hydrocarbyl unit selected from the group consisting of:

    • a) non-aromatic carbocyclic rings;
    • b) aromatic carbocyclic rings;
    • c) non-aromatic heterocyclic rings;
    • d) aromatic heterocyclic rings;


      wherein said units which substitute for hydrogen on the rings which comprise R units are selected from the group consisting of:
    • i) C1–C20 linear or branched, substituted or unsubstituted hydrocarbyl;
    • ii) halogen;
    • iii) —N(R4)2;
    • iv) —COR4;
    • v) —COOR4;
    • vi) cyano;
    • vii) nitro;
    • viii) hydroxyl;
    • ix) C1–C4 alkoxy;
    • x) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xi) and mixtures thereof;


      wherein R4, R9 and the index n are defined herein above.


A first aspect of R units relates to substituted and non-substituted aryl units, said units comprising phenyl, benzyl, naphthylen-2-yl, and naphthylen-2-ylmethyl.


A first iteration of this aspect encompasses R units which are selected from the group consisting of phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 4-methylphenyl, and 4-acetoxyphenyl.


A second iteration of this aspect encompasses R units which are selected from the group consisting of naphthylen-1-yl, 2-naphthylen-2-yl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, and 1-hydroxynaphthalen-2-ylmethyl.


A second aspect of R units relates to substituted and non-substituted heteroaryl units wherein R units comprise substituted or unsubstituted quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.


A fist iteration of this aspect encompasses R units which are 1,2,3,4-tetrahydroisoquinolinyl and 1,2,3,4-tetrahydroquinolinyl.


A second iteration of this aspect encompasses R units which are 6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl and 6-hydroxy-1,2,3,4-tetrahydroquinolinyl.


Another aspect of R relates to phenyl rings comprising a C1–C4 alkyl unit, non-limiting examples or which include 4-methylphenyl, 2,4-dimethylphenyl, as well as mixed alkyl rings, inter alia, 2-methyl-4-isopropyl.


A yet further aspect of R relates to substituted or unsubstituted heteroaryl rings selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, pyrrolyl, and pyridinyl.


R1 is a substituted or unsubstituted unit selected form the group consisting of:

    • i) C1–C12 linear or branched alkyl;
    • ii) C3–C8 cyclic alkyl;
    • iii) C2–C12 linear or branched alkenyl; and
    • iv) —[C(R9)2]nC(R9)3.


      Wherein R9 is hydrogen, fluorine, chlorine, bromine, iodine, and mixtures thereof; and the units which can substitute for hydrogen are defined herein above; the index n has the value from 0 to 10.


A first aspect of R1 relates to unsubstituted lower alkyl (C1–C4) R1 units, for example, methyl, ethyl, iso-propyl, n-propyl, n-butyl, 2-butyl (1-methylpropyl), allyl, and the like.


A second aspect of R1 relates to the unsubstituted C5–C8 linear alkyl units: n-pentyl, n-hexyl, n-heptyl, and n-octyl.


A third aspect of R1 relates to unsubstituted cyclic alkyl, for example, cyclopropyl, 2-methyl-cyclopropyl, cyclopropylmethyl, cyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, and the like.


A fourth aspect of R1 relates to substituted units which are haloalkyl units, for example, a first iteration relates to R1 units selected from the group consisting of —CF3, —CHF2, —CH2F, —CF2CF3, and —CCl3.


A fifth aspect of R1 relates to substituted lower alkyl units. A first iteration of this aspect relates to R1 units which are substituted with alkoxy units, for example, R1 units selected from the group consisting of methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, and propoxypropyl.


Melanocortin Receptor Ligand Ring Scaffolds


The scaffolds of the present invention, represented by the formula:




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each comprise a nitrogen-containing ring, said ring further comprising A, A1, and A2 ring components each of which is independently selected from the group consisting of —C(═NR6)—, —C(═O)—, —C(═S)—, —C(R6)2—, —C(R6)2C(R6)2—, —CR6═, —N═, —NR6—, or two A units can be taken together with an adjacent atom or another A unit to form a bond having the formula —N═N—, —N—NR6—, —CR6═N—, —C═N—, and mixtures thereof; the index j is equal to 0 or 1.


For example, A comprises —C(═O)—, A1 unit comprises —C(R6)2—, and A2 unit comprises —NR6—, thereforeproviding a keto-piperazine scaffold having the formula:




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wherein R6 is defined herein below.


R6 is hydrogen, R4, or the pendant unit W1 having the formula:




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wherein the index r is equal to 0 or 1;


R7a and R7b are each independently selected from the group consisting of

    • i) hydrogen;
    • ii) C1–C12 hydrocarbyl selected from the group consisting of:
      • a) C1–C12 linear or branched, substituted or unsubstituted alkyl;
      • b) C3–C12 substituted or unsubstituted cycloalkyl;
      • c) C2–C12 linear or branched, substituted or unsubstituted alkenyl;
      • d) C3–C12 substituted or unsubstituted cycloalkenyl;
      • e) C6–C12 substituted or unsubstituted aryl;
      • f) C1–C12 substituted or unsubstituted heterocyclyl;
      • g) C3–C12 substituted or unsubstituted heteroaryl;
      • h) and mixtures thereof;
    • iii) —[C(R11)2]nCOR4;
    • iv) —[C(R11)2]nCOOR4;
    • v) —[C(R11)2]nCOCH═CH2;
    • vi) —[C(R11)2]nC(═NR4)N(R4)2;
    • vii) —[C(R11)2]nCON(R4)2;
    • viii) —[C(R11)2]nCONR4N(R4)2
    • ix) —[C(R11)2]nCN;
    • x) —[C(R11)2]nCNO;
    • xi) —[C(R11)2]nCF3, —[C(R11)2]nCCl3, —[C(R11)2]nCBr3;
    • xii) —[C(R11)2]nN(R4)2;
    • xiii) —[C(R11)2]nNR4COR4;
    • xiv) —[C(R11)2]nNR4CN;
    • xv) —[C(R11)2]nNR4C(═NR4)N(R4)2;
    • xvi) —[C(R11)2]nNHN(R4)2;
    • xvii) —[C(R11)2]nNHOR4;
    • xviii) —[C(R11)2]nNCS;
    • xix) —[C(R11)2]nNO2;
    • xx) —[C(R11)2]nOR4;
    • xxi) —[C(R11)2]nOCN;
    • xxii) —[C(R11)2]nOCF3, —[C(R11)2]nOCCl3, —[C(R11)2]nOCBr3;
    • xxiii) F, Cl, Br, I, and mixtures thereof;
    • xxiv) —[C(R11)2]nSO3M;
    • xxv) —[C(R11)2]nOSO3M;
    • xxvi) —[C(R11)2]nSCN;
    • xxvii) —[C(R11)2]nSO2N(R4)2;
    • xxviii) —[C(R11)2]nSO2R4;
    • xxix) —[C(R11)2]nP(O)(OR4)R4;
    • xxx) —[C(R11)2]nP(O)(OR4)2;
    • xxxi) haloalkyl having the formula —[C(R9)2]nC(R9)3;
    • xxxii) and mixtures thereof;
  • R4 is the same as defined herein above; R9 is R4, fluorine, chlorine, bromine, iodine, and mixtures thereof; each R11 is hydrogen or R10; the index n has the value from 0 to 10.


R8 is selected from the group consisting of:

    • i) hydrogen;
    • ii) C3–C8 non-aromatic carbocyclic rings;
    • iii) C6–C14 aromatic carbocyclic rings;
    • iv) C1–C7 non-aromatic heterocyclic rings;
    • v) C3–C13 aromatic heterocyclic rings;
    • vi) —C(Y)R4;
    • vii) —C(Y)2R4;
    • viii) —C(Y)N(R4)2;
    • ix) —C(Y)NR4N(R4)2;
    • x) —CN;
    • xi) —CNO;
    • xii) —[C(R9)2]C(R9)2;
    • xiii) —N(R4)2;
    • xiv) —NR4CN;
    • xv) —NR4C(Y)R4;
    • xvi) —NR4C(Y)N(R4)2;
    • xvii) —NHN(R4)2;
    • xviii) —NHOR4;
    • xix) —NCS;
    • xx) —NO2;
    • xxi) —OR4;
    • xxii) —OCN;
    • xxiii) —OCF3, —OCCl3, —OCBr3;
    • xxiv) —F, —Cl, —Br, —I, and mixtures thereof;
    • xxv) —SCN;
    • xxvi) —SO3M;
    • xxvii) —OSO3M;
    • xxviii) —SO2N(R4)2;
    • xxix) —SO2R4;
    • xxx) —[C(R11)2]nP(O)(OR4)R4;
    • xxxi) —[C(R11)2]nP(O)(OR4)2;
    • xxxii) and mixtures thereof;
    • wherein R4, M, Y, and the index x are the same as defined herein above.


The first aspect of W1 relates to units having the formula:




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wherein R8 is a unit selected from the group consisting of:

    • a) C6–C14 aromatic carbocyclic rings: (group (iii) above); or
    • b) C3–C13 aromatic heterocyclic rings: (group (v) above);


      and R7a is selected from the group consisting of:
    • a) hydrogen;
    • b) —COR4;
    • c) —COOR4;
    • d) —CON(R4)2; and
    • e) —N(R4)2;


      wherein for this aspect of R8 each R4 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, and mixtures thereof. The index x is equal to 1 or 2.


R8 units which are suitable for use in this aspect of W1 include units selected from the group consisting of (2-fluorophenyl)methyl, (3-fluorophenyl)methyl, (4-fluorophenyl)methyl, (2,3-difluorophenyl)methyl, (2,4-difluorophenyl)methyl, (3,4-difluorophenyl)methyl, (3,5-difluorophenyl)methyl, (2-chlorophenyl)methyl, (3-chlorophenyl)methyl, (4-chlorophenyl)methyl, (2,3-dichlorophenyl)methyl, (2,4-dichlorophenyl)methyl, (3,4-dichlorophenyl)methyl, (3,5-dichlorophenyl)-methyl, and naphthalene-2-ylmethyl.


Iterations of this aspect of the present invention relate to units having the formula:




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and encompass scaffolds wherein R7a is an amide, for example, compounds having the following formulae:




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and to scaffolds wherein R7a and R7b are each hydrogen, for example:




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The second aspect of W1 units comprise R7a units which are short chain alkyl or alkenyl (lower hydrocarbyl) esters having the formula:

—C(O)OR4;

non-limiting examples of which are —C(O)OCH3; —C(O)OCH2CH3; —C(O)OCH2CH2CH3; —C(O)OCH2CH2CH2CH3; —C(O)OCH(CH3)2; —C(O)OCH2CH(CH3)2; —C(O)OCH2CH═CHCH3; —C(O)OCH2CH2CH(CH3)2; —C(O)OCH2C(CH3)3; and the like; and short chain substituted or non-substituted amides having the formula:

—C(O)NHR4 or —NHC(O)R4

non-limiting examples of which are —C(O)NHCH3; —C(O)NHCH2CH3; —C(O)NHCH(CH3)2; —C(O)NHCH2CH2CH3; —C(O)NHCH2CH2CH2CH3; —C(O)NHCH2CH(CH3)2; —C(O)NH2; —C(O)NHCH2CH═CHCH3; —C(O)NHCH2CH2CH(CH3)2; —C(O)NHCH2C(CH3)3; —C(O)NHCH2CH2SCH3; —C(O)NHCH2CH2OH; —NHC(O)CH3; —NHC(O)CH2CH3; —NHC(O)—CH2CH2CH3; and the like.


The third aspect of W1 units comprise units which are guanidine and guanidine mimetics having the formula:




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and R7a is a unit selected from the group consisting of:

    • a) —C(Y)N(R12)2;
    • b) —C(Y)NR12N(R13)2;
    • c) —NR12C(Y)N(R13)2; and
    • d) —NHN(R12)2;


      wherein Y is ═O, ═S, ═NR14, and mixtures thereof, R12, R13 and R14 are each independently hydrogen, methyl, cyano, hydroxy, nitro, and mixtures thereof; the index x is from 0 to 5; and R8 is selected from the group consisting of benzyl, (2-chlorophenyl)methyl, (3-chlorophenyl)methyl, (4-chlorophenyl)methyl, (3,4-dichlorophenyl)methyl, (2-fluorophenyl)-methyl, (3-fluorophenyl)methyl, (4-fluorophenyl)methyl, and naphthalen-2-ylmethyl.


Another iteration of this aspect relates to W1 units wherein R7a is selected from the group consisting of:

    • i) hydrogen;
    • ii) —CO2H;
    • iii) —CO2CH3;
    • iv) —CONH2;
    • v) —CONHCH3;
    • vi) —CON(CH3)2;
    • vii) —CONH(CH2CH2F);
    • viii) —CONCH(CH3)2;
    • ix) —CONH(C3H5);
    • x) —CONHCH2(C3H5);


      and R8 is selected from the group consisting of benzyl, (2-chlorophenyl)methyl, (3-chlorophenyl)methyl, (4-chlorophenyl)methyl, (3,4-dichlorophenyl)methyl, (2-fluorophenyl)-methyl, (3-fluorophenyl)methyl, (4-fluorophenyl)methyl, and naphthalen-2-ylmethyl.


A further aspect of W1 relates to A, A1, or A2 units which comprise a —NR6— unit and R6 has the formula —CH2R8 wherein R8 is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and naphth-2-yl.


Non-limiting examples of W1 wherein R7a units have the formula:

—NR12C(NR14)N(R13)2;

are selected from the group consisting of:




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The fourth aspect of the present invention as it relates to W1 units are the 5-member ring W1 units having the formula:

—(CH2)x—R8

wherein the index x is 0, 1, 2, or 3 and R8 is selected from the group consisting of:

    • i) triazolyl having the formula:




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    • ii) tetrazolyl having the formula:







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    • iii) thiazolyl, 2-methylthiazolyl, 4-mentylthiazolyl, 5-methylthiazolyl having the formula:







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    • iv) 1,3,4-thiadiazolyl, 2-methyl-1,3,4-thiadiazolyl having the formula:







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    • v) 1,2,5-thiadiazolyl, 3-methyl-1,2,5-thiadiazolyl having the formula:







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    • vi) oxazolyl, 2-methyloxazolyl, 4-methyloxazolyl, 5-methyloxazolyl having the formula:







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    • vii) imidazolyl, 2-methylimidazolyl, 5-methylimidazolyl having the formula:







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    • viii) 5-methyl-1,2,4-oxadiazolyl, 2-methyl-1,3,4-oxadiazolyl, 5-amino-1,2,4-oxadiazolyl, having the formula:







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    • ix) 1,2-dihydro[1,2,4]triazol-3-one-1-yl, 2-methyl-1,2-dihydro[1,2,4]triazol-3-one-5-yl, having the formula:







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    • x) oxazolidin-2-one-3-yl; 4,4-dimethyloxazolidin-2-one-3-yl; imidazolidin-2-one-1-yl; 1-methylimidazolidin-2-one-1-yl, having the formula:







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    • xi) 2-methyl-1,3,4-oxadiazolyl, 2-amino-1,3,4-oxadiazolyl, 2-(N,N-dimethylamino)-1,3,4-oxadiazolyl, having the formula:







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A fourth aspect of W1 of this first category of receptor ligands relates to R5 units comprising substituted an unsubstituted, saturated and unsaturated six-member rings having at least one nitrogen, non limiting examples of which include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, morpholinyl, and the like.


A fifth aspect of W1 of this first category of receptor ligands relates to R5 units comprising substituted and unsubstituted fused ring heterocycles for example, quinolin-2-yl, quinolin-3-yl, and quinolin-4-yl units having the formula:




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substituted and unsubstituted isoquinolin-1-yl, isoquinolin-3-yl, and 1soquinolin-4-yl units having the formula:




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and unsubstituted [5,6] fused ring systems, inter alia, 1H-indolin-3-yl having the formula:




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The analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein. The melanocortin receptor ligands of the present invention are differentiated into categories depending upon the ring A unit selections. However, preparation strategies and synthetic routes suitable for one ring scaffold may be suitable or adaptable to other ring systems or ring substituents.


Non-limiting examples of categories of the present invention include Category I analogs comprising a 2-oxo-3-hydrocarbyl-piperazines the first aspect of which has the formula:




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Category II analogs comprise a 2-oxo-3-hydrocarbyl-piperazine having the formula:




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Category III relates to 3-hydrocarbyl-piperazines having the formula:




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Category IV comprises 2-hydrocarbyl-pyrrolidines having the formula:




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Other non-limiting examples of scaffolds according to the present invention include: 2-hydrocarbyl-4-β-aminohydrocarbyl-piperazine having the formula:




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2-hydrocarbyl-4,4-disubstituted-piperidine having the formula:




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2-hydrocarbyl-4,4-disubstituted-piperidine having the formula:




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2-oxo-3-hydrocarbyl-[1,4]diazepane having the formula:




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Category I melanocortin receptor ligands according to the present invention comprise the 2-oxo-3-hydrocarbyl-piperazines having the general scaffold with the formula:




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The first aspect of Category I comprises analogs wherein W is —NH2, said analogs having a scaffold with the formula:




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wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R7a and R8 are provided herein below in Table I.












TABLE I





No.
R1
R7a
R8


















1
methyl
—C(O)NH2
naphthylen-2-ylmethyl


2
ethyl
—C(O)NH2
naphthylen-2-ylmethyl


3
propyl
—C(O)NH2
naphthylen-2-ylmethyl


4
iso-propyl
—C(O)NH2
naphthylen-2-ylmethyl


5
butyl
—C(O)NH2
naphthylen-2-ylmethyl


6
cyclopropyl
—C(O)NH2
naphthylen-2-ylmethyl


7
cyclopropyl-
—C(O)NH2
naphthylen-2-ylmethyl



methyl


8
allyl
—C(O)NH2
naphthylen-2-ylmethyl


9
but-2-enyl
—C(O)NH2
naphthylen-2-ylmethyl


10
propargyl
—C(O)NH2
naphthylen-2-ylmethyl


11
methyl
—C(O)NHCH3
naphthylen-2-ylmethyl


12
ethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


13
propyl
—C(O)NHCH3
naphthylen-2-ylmethyl


14
iso-propyl
—C(O)NHCH3
naphthylen-2-ylmethyl


15
butyl
—C(O)NHCH3
naphthylen-2-ylmethyl


16
cyclopropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


17
cyclopropyl-
—C(O)NHCH3
naphthylen-2-ylmethyl



methyl


18
allyl
—C(O)NHCH3
naphthylen-2-ylmethyl


19
but-2-enyl
—C(O)NHCH3
naphthylen-2-ylmethyl


20
propargyl
—C(O)NHCH3
naphthylen-2-ylmethyl


21
methyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


22
ethyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


23
propyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


24
iso-propyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


25
butyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


26
cyclopropyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


27
cyclopropyl-
—C(O)N(CH3)2
naphthylen-2-ylmethyl



methyl


28
allyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


29
but-2-enyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


30
propargyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


31
methyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


32
ethyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


33
propyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


34
iso-propyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


35
butyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


36
cyclopropyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


37
cyclopropyl-
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl



methyl


38
allyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


39
but-2-enyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


40
propargyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


41
methyl
—C(O)NH2
(4-chlorophen-yl)methyl


42
ethyl
—C(O)NH2
(4-chlorophenyl)methyl


43
propyl
—C(O)NH2
(4-chlorophenyl)methyl


44
iso-propyl
—C(O)NH2
(4-chlorophenyl)methyl


45
butyl
—C(O)NH2
(4-chlorophenyl)methyl


46
cyclopropyl
—C(O)NH2
(4-chlorophenyl)methyl


47
cyclopropyl-
—C(O)NH2
(4-chlorophenyl)methyl



methyl


48
allyl
—C(O)NH2
(4-chlorophenyl)methyl


49
but-2-enyl
—C(O)NH2
(4-chlorophenyl)methyl


50
propargyl
—C(O)NH2
(4-chlorophenyl)methyl


51
methyl
—C(O)NHCH3
(4-chlorophenyl)methyl


52
ethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


53
propyl
—C(O)NHCH3
(4-chlorophenyl)methyl


54
iso-propyl
—C(O)NHCH3
(4-chlorophenyl)methyl


55
butyl
—C(O)NHCH3
(4-chlorophenyl)methyl


56
cyclopropyl
—C(O)NHCH3
(4-chlorophenyl)methyl


57
cyclopropyl-
—C(O)NHCH3
(4-chlorophenyl)methyl



methyl


58
allyl
—C(O)NHCH3
(4-chlorophenyl)methyl


59
but-2-enyl
—C(O)NHCH3
(4-chlorophenyl)methyl


60
propargyl
—C(O)NHCH3
(4-chlorophenyl)methyl


61
methyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


62
ethyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


63
propyl
—C(O)N(CH3)2
(4-chlorophen-yl)methyl


64
iso-propyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


65
butyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


66
cyclopropyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


67
cyclopropyl-
—C(O)N(CH3)2
(4-chlorophenyl)methyl



methyl


68
allyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


69
but-2-enyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


70
propargyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


71
methyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


72
ethyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


73
propyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


74
iso-propyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


75
butyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


76
cyclopropyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


77
cyclopropyl-
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl



methyl


78
allyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


79
but-2-enyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


80
propargyl
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl









The compounds of the first aspect of Category I can be suitably prepared by the procedure outlined herein below in Scheme I.




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EXAMPLE 1
2-{3-Ally-4-[2-amino-3-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (9)

Preparation of (S,S)-2-(2-tert-butoxycarbonylamino-pent-4-enoylamino)-3-naphthalen-2-yl-propionic acid methyl ester (1): To a solution of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid (3.8 g, 18.0 mmol) and 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (4.1 g, 18.0 mmol) in DMF (40 mL) are added 1-hydroxybenzotriazole (3.1 g, 23.4 mmol), N-methylmorpholine (9.1 g, 90.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 g, 23.4 mmol) consecutively and the reaction mixture is stirred for 3 hours. The reaction is quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the residue purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 6.4 g (84% yield) of the desired product.


Preparation of (S,S)-2-(2-amino-pent-4-enoylamino)-3-naphthalen-2-yl-propionic acid methyl ester (2): To a solution of (S,S)-2-(2-tert-butoxycarbonylamino-pent-4-enoylamino)-3-naphthalen-2-yl-propionic acid methyl ester, 1, (6.2 g, 14.64 mmol) in methylene chloride (40 mL) is added trifluoroacetic acid (5 mL). The reaction mixture is stirred for 3 hours and the solvent and excess trifluoroacetic acid are removed under in vacuo. The residue is dried under high vacuum for several hours and 6.35 g of the crude trifluoroacetate salt of the desired product is obtained, which is used without further purification.


Preparation of (S,S)-3-naphthalen-2-yl-2-[2-(2-nitro-benzenesulfonylamino)-pent-4-enoylamino]-propionic acid methyl ester (3): To a solution of (S,S)-2-(2-amino-pent-4-enoylamino)-3-naphthalen-2-yl-propionic acid methyl ester salt, 2, (4.2 g) in CHCl3 (50 mL) are added triethyl amine (3.8 g, 38 mmol) and 2-nitrophenylsulfonyl chloride (2.5 g, 11.5 mmol). The reaction is stirred for 10 hours then quenched with 10% aqueous HCl. The solvent is decanted, and the aqueous phase is extracted with ethyl acetate, the organic layers combined, dried and concentrated in vacuo to afford a crude residue which is purified over silica (hexanes/EtOAc, 3:2) to afford 3.84 g of the desired product.


Preparation of (S,S)-2-[3-Allyl-4-(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester (4): To a solution of (S,S)-3-naphthalen-2-yl-2-[2-(2-nitro-benzenesulfonylamino)-pent-4-enoylamino]-propionic acid methyl ester, 3, (3.6 g, 7.0 mmol) and 1,2-dibromoethane (13.2 g, 70.0 mmol) in DMF (40 mL) is added potassium carbonate (9.6 g, 70.0 mmol). The reaction suspension was stirred at 65° C. for 12 h, quenched with 10% aqueous HCl and extracted with EtOAc. The extract is dried over Na2SO4, concentrated and the residue purified over silica gel (hexanes/EtOAc,1:2) to afford 3.7 g (97% yield) of the desired product.


Preparation of (S,S)-2-(3-allyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester (5): To a solution of (S,S)-2-[3-allyl-4-(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 4, (4.8 g, 8.9 mmol) and 4-mercaptophenol (4.5 g, 35.7 mmol) in DMF (35 mL) is added potassium carbonate (7.4 g, 53.4 mmol). The reaction mixture is stirred 18 hours then quenched with saturated NaHCO3 solution and extracted with EtOAc (200 mL). The extract is dried over Na2SO4 and concentrated in vacuo to afford a bright yellow oil which is purified over silica gel (hexanes/EtOAc, 1:1 to EtOAc/MeOH, 10:1) to afford 2.45 g (79% yield) of the desired product.


Preparation of (S)-2-{3-(S)-allyl-4-[2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (6): To a solution of (S,S)-2-(3-allyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 5, (500 mg, 1.42 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (473 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (960 mg, 1.85 mmol) and triethylamine (169 mg, 1.67 mmol). The reaction mixture is stirred for 20 h, quenched with 10% NaHCO3 aqueous solution and extracted with EtOAc. The extract is dried over Na2SO4, filtered and concentrated. The residue is purified over silica gel (hexanes/ethyl acetate, 4:1 to 3:2) to afford 0.745 g (85% yield) of the desired product.


Preparation of (S)-2-{3-(S)-Allyl-4-[2-tert-butoxycarbonylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (7): To a solution of (S)-2-{3-(S)-allyl-4-[2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 6, (200 mg, 0.324 mmol) in a mixture of THF (1 mL)/CH3OH (0.5 mL)/H2O (0.5 mL) is added LiOH (43 mg, 1.78 mmol). The reaction mixture is stirred for 3 hours, acidified with 1N HCl to pH 3 and extracted with EtOAc. The extract is dried over Na2SO4, filtered, concentrated and dried under high vacuum to afford the desired product in quantitative yield, which is used without further purification.


Preparation of (2-(R)-{2-(S)-allyl-4-[1-(S)-(methylcarbamoyl-2-naphthalen-2-ylethyl)]-3-oxo-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl)-carbamic acid tert-butyl ester (8): To a solution of (S)-2-{3-(S)-allyl-4-[2-tert-butoxycarbonylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 7, (195 mg) in DMF (3 mL) are added methylamine (2M, 0.175 mL, 0.35 mmol), 1-hydroxybenzotriazole (57 mg, 0.42 mmol), N-methylmorpholine (162 mg, 1.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (80 mg, 0.42 mmol) consecutively and the reaction mixture is stirred 18 hours. The reaction is then quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the resulting residue is purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 0.183 g (88% yield) of the desired product.


Preparation of 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (9): To a solution of (2-(R)-{2-(S)-allyl-4-[1-(S)-(methylcarbamoyl-2-naphthalen-2-ylethyl)]-3-oxo-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl)-carbamic acid tert-butyl ester, 8, (32 mg, 0.052 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid. The reaction mixture is stirred for 45 min, concentrated in vacuo and the resulting residue purified by reverse phase HPLC to afford 27 mg of the trifluoroacetate salt of the desired product.


In the above example for the preparation of analogs encompassed by the first aspect of Category I, 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid is used for the preparation of compound 1. Other analogs encompassed within the first aspect of Category I wherein R1 comprises other units as defined herein above, can be prepared by substituting the appropriate starting material in place of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid, for example, 2-(S)-tert-butoxycarbonylamino-propionic acid, 2-(S)-tert-butoxycarbonylamino-butyric acid, 2-(S)-tert-butoxycarbonylamino-pentanoic acid, 2-(S)-tert-butoxycarbonylamino-3-methyl-butyric acid, 2-(S)-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid, and the like. The formulator may also choose to prepare rings which comprise the opposite stereochemistry, for example, those derived from the use of 2-(R)-tert-butoxy-carbonylamino-pent-4-enoic acid or, as a further iteration, the formulator may wish to provide a racemic mixture, for example, an analog derived from 2-(R,S)-tert-butoxycarbonylamino-pent-4-enoic acid.


As described herein above and as exemplified in both Table I and Scheme I, the formulator may choose to substitute for naphthylen-2-ylmethyl (R8 units). Non-limiting examples of suitable groups include benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-benzo[1,3]dioxol-5-ylmethyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 3,5-difluorobenzyl, 3,4-difluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-phenylbenzyl, isoquinolin-6-yl, indol-2-yl, indol-3-yl, and the like.


In addition, the R7a unit may include, for example, —CH2C(O)NH2, —CH2C(O)N(CH3)2, —C(O)N(CH3)2, —C(O)NH2, —C(O)NH(CH2CH2F), —C(O)NHCH2(C3H5), and the like.


In addition, R units can be modified to reflect the choice of the formulator, for example, 2-(R)-tert-butoxycarbonyl-amino-3-(4-fluorophenyl)propionic acid can be replaced by 2-(R)-tert-butoxycarbonyl-amino-3-(4-chlorophenyl)propionic acid to replace the 4-fluorophenyl R unit with the 4-chlorophenyl R unit. Non-limiting examples of other suitable replacements include 2-(R)-tert-butoxycarbonyl-amino-3-(3-fluorophenyl)propionic acid, 2-(R)-tert-butoxycarbonyl-amino-3-(2,4-difluorophenyl)propionic acid, 2-(R)-tert-butoxycarbonyl-amino-3-(4-methylphenyl)propionic acid, 2-(R)-tert-butoxycarbonyl-amino-3-(4-hydroxyphenyl)propionic acid, 2-(R)-tert-butoxycarbonyl-amino-3-(4-trifluoromethylphenyl)propionic acid, and the like.


These changes and iterations can be made by replacement of one or more reagents or starting materials described herein above in Scheme I.


The following are non-limiting examples of compounds which comprise the first aspect of Category I analogs.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 8.02–8.22 (m, 0.4H), 6.95–7.50 (m, 7H), 5.52 (dd, J=11.5, 5.2 Hz, 0.75H), 5.41 (dd, J=10.8, 6.3 Hz, 0.25H), 4.02–4.76 (m, 1.3H), 4.28–4.46 (m, 0.7H), 3.40–3.74 (m, 2H), 2.66 3.30 (m, 9H), 1.12–1.44 (m, 2H), 0.86–1.08 m, 0.6H), 0.75–0.85 (m, 4.4H); MS (ESMS) m/z 537.2, 539.2, 541.2 (M+H)+, Cl2 isotope pattern.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propionamide: MS (ESMS) m/z 563.5 (M+H)+.


2-{4-[2-Amino-3-(4fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) δ 6.90˜7.90 (m, 11H), 5.30˜5.60 (m, 1H), 2.60˜4.00 (m, 13H), 0.80˜1.60 (m, 2H), −0.49˜0.2 (m, 5H); MS (ES-MS) m/z 531 (M+1).


2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) δ 7.00˜8.00 (m, 11H), 4.57 (m, 1H), 4.10˜4.30 (m, 2H), 2.60˜3.75 (m, 12H), 1.85 (bs, 2H), 1.25˜1.50 (m, 2H), 0.40˜0.60 (m, 3H); MS (ES-MS) m/z 592 (M+1).


3-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-methyl-4-naphthalen-2-yl-butyramide. 1H NMR (CDCl3, 300 MHz) 6.80˜7.80 (m, 11H), 2.40˜3.60 (m, 16H), 0.92 (m, 2H), 0.32 (m, 5H); 13C NMR (CDCl3, 75 mHz) 172.01, 168.22, 167.37, 134.53, 133.59, 132.64, 131.56, 131.47, 129.46, 128.50, 127.94, 127.54, 127.16, 126.15, 116.18, 115.89, 56.38, 51.07, 41.18, 39.00, 38.46, 37.87, 37.27, 34.33, 31.22, 26.58, 18.80, 13.55; MS (ES-MS) m/z 533 (M+1).


2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) 7.00˜8.00 (m, 11H), 4.57 (m, 1H), 4.10˜4.30 (m, 2H), 2.60˜3.75 (m, 12H), 1.85 (bs, 2H), 1.25˜1.50 (m, 2H), 0.40˜0.60 (m, 3H); MS (ES-MS) m/z 592 (M+1).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.85–7.54, (m, 4H); 7.54–7.37, (m, 3H); 7.28–7.17, (m, 2H); 7.07–6.96, (m, 2H); 4.67–4.55, (m, 1H); 3.65–2.93, (m, 10H); 2.86–2.69, (m, 4H); 1.89–1.84, (m, 2H), 1.04–0.78, (m, 2H); 0.63–0.26, (m, 4H). 13C NMR (CD3OD, 300 MHz) δ 171.02, 170.91, 168.77, 167.03, 167.00, 164.32, 161.06, 134.27, 133.73, 132,.80, 131.52, 131.41, 131.06, 129.93, 128.12, 127.60, 127.49, 127.32, 127.02, 126.24, 125.71, 115.76, 115.48, 56.28, 56.15, 50.71, 46.25, 46.17, 41.49, 41.32, 36.60, 34.41, 34.23, 26.26, 26.14, 25.26, 18.41, 18.38, 12.58. MS(ESI) m/e 519 [M+1].


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.84–7.68, m, 4H; 7.50–7.31, m, 5H; 7.15–7.08, m, 2H; 4.77–4.57, m, 2H; 4.42–4.34, m, 1H; 4.27–4.17, m, 1H; 4.11–4.05, m, 0.5H; 3.82–2.79, m, 11H; 2.59–2.52, m, 0.5H; 1.77–1.30, m, 2.5H; 1.21–1.13, m, 2H; 0.85–0.83, t, (J=7.13 Hz), 3H; 13C NMR (CD3OD, 300 MHz) δ 170.76, 169.75, 169.54, 134.16, 133.80, 132.78, 132.65, 132.32, 131.76, 131.59, 130.02, 127.99, 127.49, 126.06, 125.65, 115.84, 115.71, 115.55, 82.86, 82.73, 69.53, 69.25, 52.75, 50.88, 50.43, 49.44, 40.36, 39.69, 39.44, 36.63, 34.12, 33.87, 31.89, 31.02, 19.19, 19.02, 12.95, 12.85. MS(ESI) m/e 536 [M+1].


2-{4-[2-Amino-3R-(4-fluorophenyl)-propionyl]-2-oxo-3S-propyl-piperazin-1-yl}-N-methyl-3S-thiazol-4-yl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 8.94 (d, H, J=1.52 Hz) 7.49–7.41 (m, 3H) 7.28–7.08 (m, 2H) 7.01 (t, 1H, J=8.71 Hz) 5.52 (q, 1H, J=6.95 Hz) 4.76 (t, 1H, J=6.69 Hz) 4.68 (t, 1H, J=7.60 Hz) 3.76–3.64 (m, 2H) 3.62–3.46 (m, 2H) 3.17–3.01 (m, 4H) 2.74 (s, 3H) 1.54–29 (m, 2H) 1.08–0.91 (m, 2H) 0.85 (t, 3H, J=7.58 Hz) MS (ESI) m/z 475 (M+H+, 100).


2-{4-[2-Amino-3R-(4-fluorophenyl)-propionyl]-3S-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-isopropyl-3S-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.80–7.68 (m, 3H) 7.59–7.55 (m, 1H) 7.49–7.41 (m, 2H) 7.19–7.07 (m, 2H) 6.96 (t, 3H, J=8.38 Hz) 6.42 (d, 1H, J=7.57 Hz) 5.51–5.42 (m, 1H) 3.69–2.78 (m, 11H) 1.18 (d, 2H, J=6.566 Hz) 1.09–1.00 (m, 6H) 0.3–0.1 (m, 5H) MS (ESI) m/z 559 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(3,4-dichlorophenyl)-N-isopropyl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.50–6.97 (m, 7H) 5.49–5.38 (m, 1H) 4.63–4.60 (m, 1H) 4.21–4.37 (m, 1H) 4.08–3.85 (m, 1H) 3.74–3.61 (m, 2H) 3.44–2.89 (m, 6H) 1.48–1.09 (m, 10H) 0.93–0.77(m, 3H) MS (ESI) m/z 565 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-proponyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(2-chlorophenyl)-N-isopropyl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.42–6.93 (m, 8H) 5.59–5.43 (m, 1H) 4.73–4.61 (m, 1H) 4.06–3.88 (m, 2H) 3.72–3.53 (M, 4H) 3.42–3.21 (m, 2H) 3.14–2.91 (m, 2H) 1.48–0.74 (m, 13H) MS (ESI) m/z 531 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(3-cyano-phenyl)-N-methyl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.67–6.54 (m, 3H) 7.52–7.43 (m, 1H) 7.38–7.18 (m, 2H) 7.16–6.94 (m, 2H) 5.58–5.38 (m, 1H) 4.75–4.60 (m, 1H) 4.38–4.27 (m, 1H) 3.76–3.63 (m, 2H) 3.62–3.43 (m, 2H) 3.20–3.01 (m, 2H) 2.98–2.86 (m, 2H) 2.74 (s, 3H) 1.45–1.14 (m, 4H) 0.93–0.74 (m, 3H) MS (ESI) m/z 494 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-proponyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(3,4-dimethoxy-phenyl)-N-methyl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.32 (q, 2H, J=1.97 Hz) 7.12 (t, 2H, J=8.74) 6.87–6.71 (m, 3H) 5.51 (q, 1H, J=5.50 Hz) 4.70–4.58 (m, 1H) 3.85–3.76 (m, 6H) 3.68–3.45 (m, 1H) 3.28–2.79 (m, 8H) 2.74 (s, 3H) 1.39–1.06 (m, 4H) 0.86–0.72 (m, 3H) MS (ESI) m/z 529 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-isopropyl-3-(S)-p-tolyl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.28–6.82(m, 8H) 6.42(d, 1H, J=7.68 Hz) 5.88(d, 1H, J=6.72) 5.39–5.09 (m, 2H) 4.78–4.51 (m, 2H) 4.09–3.73 (m, 4H) 3.55–2.60 (m, 6H) 2.52–2.15 (m, 6H) 1.43–0.59 (m, 7H) MS (ESI) m/z 511 (M+H+, 100).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(4-chlorophenyl)-N-ethyl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.39–6.97 (m, 8H) 5.53–5.35 (m, 2H) 5.02–4.58(m, 4H) 3.71–2.87(m, 10H) 1.50–0.55 (m, 10H) MS (ESI) m/z 517(M+H+, 100).


N-Allyl-2-{4-[2-amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.92–6.92 (m, 11H) 5.98–5.52 (m, 5H) 5.31–5.05 (m, 3H) 4.68–4.42 (m, 2H) 3.92–2.70 (m, 6H) 1.20–0.21 (m, 7H) MS (ESI) m/z 545(M+H+, 100).


N-Allyl-2-{4-[2-amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CD3OD, 300 MHz) δ 7.98–6.92 (m, 11H) 5.75–5.40 (m, 3H) 5.05–4.00 (m, 2H) 3.82–2.78 (m, 11H) 1.38–0.28 (m, 7H) MS (ESI) m/z 601 (M+H+, 100).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-(2-fluoroethyl)-propionamide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.35–6.85 (m, 8H), 5.52 (m, 1H), 4.69–4.35 (m, 4H), 3.62–2.88 (m, 10H), 1.36–1.17 (m, 2H), 0.84 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 172.1, 171.9, 170.2, 168.4, 168.1, 164.9, 163.3, 136.9, 136.8, 134.1, 132.9, 132.8, 132.3, 132.3, 132.0, 131.9, 131.3, 131.3, 129.8, 129.8, 117.4, 117.3, 117.1, 116.9, 83.8, 83.7, 82.7, 82.5, 59.3, 57.8, 57.5, 57.4, 52.5, 52.3, 42.9, 42.8, 42.7, 41.3, 41.2, 39.3, 38.3, 37.8, 36.8, 35.8, 35.5, 35.1, 20.0, 19.9, 14.4, 14.3; MS m/z (ESI): 535 (M+H, 100), 537 (M+2+H, 37).


2-{4-[2-Amino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(4-cyano-phenyl)-N-methyl-propionamide: 1H NMR (CD3OD OD, 300 MHz) δ 7.71–7.62 (m, 2H) 7.50–7.42 (m, 2H)7.38–7.30 (m, 2H)7.18–7.10 (m, 2H) 5.57–5.41 (m, 1H) 4.71 (t, 1H, J=6.60 Hz) 3.74–3.64 (m, 1H) 3.62–3.46 (m, 4H) 3.18–3.07 (m, 4H) 2.74 (s,3H) 1.42–1.28 (m, 2H) 1.26–1.13 (m, 2H) 0.81 (s, 3H) MS (ESI) m/z 493 (M+H+, 100).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CD3OD) δ 8.42–8.63 (m, 0.6H), 7.62–7.91 (m, 4H), 7.35–7.60 (m, 3H), 7.13–7.35 (m, 2H), 6.93–7.13 (m, 2H), 5.55–5.80 (m, 1H), 4.16–4.71 (m, 4H), 2.68–3.74 (m, 10H), 0.75–1.11 (m, 2H), 0.18–0.74 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 172.58, 172.48, 170.40, 168.60, 168.33, 165.89, 162.64, 135.76, 135.29, 134.38, 133.08, 132.97, 132.59, 132.48, 131.50, 131.47, 131.02, 129.72, 129.16, 129.06, 128.90, 128.67, 128.54, 127.80, 127.29, 117.33, 117.05, 84.62, 84.50, 82.40, 82.28, 59.46, 57.95, 57.74, 52.65, 52.31, 43.21, 42.97, 41.67, 41.39, 39.46, 38.55, 38.15, 36.79, 36.68, 36.18, 35.83, 19.97, 14.11; MS (ESMS) m/z 551.5 (M+H)+.


The following are non-limiting examples of a further iteration of this aspect of Category I wherein R7a is hydrogen:


4-[2-Amino-3-(4-chlorophenyl)-propionyl]-1-(2-naphthalen-2-yl-ethyl)-3-propyl-piperazin-2-one: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.73–7.89 (m, 3H), 7.62 (s, 1H), 7.15–7.55 (m, 7H), 4.68–4.87 (m, 1.3H), 4.32–4.57 (m, 0.7H), 3.92–4.10 (m, 1H), 3.52–3.74 (m, 1H), 3.28–3.51 (m, 1H), 2.74–3.26 (m, 7H), 1.38–1.72 (m, 2H), 0.92–1.37 (m, 2H), 0.74–0.91 (m, 3H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 169.61, 168.62, 168.23, 167.87, 137.74, 137.68, 135.38, 134.32, 134.20, 133.94, 132.80, 132.43, 130.76, 130.54, 129.65, 129.57, 129.15, 128.89, 128.84, 128.76, 127.68, 127.62, 127.05, 59.59, 57.16, 52.04, 51.69, 49.54, 49.31, 47.88, 47.12, 41.66, 39.03, 38.30, 36.21, 35.63, 34.60, 34.39, 20.65, 20.60, 14.63; MS (ESMS) m/z 478.3, 480.3 (M+H)+, Cl isotope pattern.


The second aspect of Category I comprises analogs wherein W is —NH2, said analogs having a scaffold with the formula:




embedded image



wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R4 and R8 are described herein below in Table II.












TABLE II





No.
R1
R4
R8


















81
methyl
—H
naphthylen-2-ylmethyl


82
ethyl
—H
naphthylen-2-ylmethyl


83
propyl
—H
naphthylen-2-ylmethyl


84
iso-propyl
—H
naphthylen-2-ylmethyl


85
butyl
—H
naphthylen-2-ylmethyl


86
cyclopropyl
—H
naphthylen-2-ylmethyl


87
cyclopropylmethyl
—H
naphthylen-2-ylmethyl


88
allyl
—H
naphthylen-2-ylmethyl


89
but-2-enyl
—H
naphthylen-2-ylmethyl


90
propargyl
—H
naphthylen-2-ylmethyl


91
methyl
—H
(4-chlorophenyl)methyl


92
ethyl
—H
(4-chlorophenyl)methyl


93
propyl
—H
(4-chlorophenyl)methyl


94
iso-propyl
—H
(4-chlorophenyl)methyl


95
butyl
—H
(4-chlorophenyl)methyl


96
cyclopropyl
—H
(4-chlorophenyl)methyl


97
cyclopropylmethyl
—H
(4-chlorophenyl)methyl


98
allyl
—H
(4-chlorophenyl)methyl


99
but-2-enyl
—H
(4-chlorophenyl)methyl


100
propargyl
—H
(4-chlorophenyl)methyl


101
methyl
—CH3
naphthylen-2-ylmethyl


102
ethyl
—CH3
naphthylen-2-ylmethyl


103
propyl
—CH3
naphthylen-2-ylmethyl


104
iso-propyl
—CH3
naphthylen-2-ylmethyl


105
butyl
—CH3
naphthylen-2-ylmethyl


106
cyclopropyl
—CH3
naphthylen-2-ylmethyl


107
cyclopropylmethyl
—CH3
naphthylen-2-ylmethyl


108
allyl
—CH3
naphthylen-2-ylmethyl


109
but-2-enyl
—CH3
naphthylen-2-ylmethyl


110
propargyl
—CH3
naphthylen-2-ylmethyl


111
methyl
—CH3
(4-chlorophenyl)methyl


112
ethyl
—CH3
(4-chlorophenyl)methyl


113
propyl
—CH3
(4-chlorophenyl)methyl


114
iso-propyl
—CH3
(4-chlorophenyl)methyl


115
butyl
—CH3
(4-chlorophenyl)methyl


116
cyclopropyl
—CH3
(4-chlorophenyl)methyl


117
cyclopropylmethyl
—CH3
(4-chlorophenyl)methyl


118
allyl
—CH3
(4-chlorophenyl)methyl


119
but-2-enyl
—CH3
(4-chlorophenyl)methyl


120
propargyl
—CH3
(4-chlorophenyl)methyl









The compounds which comprise the second aspect of Category I can be prepared by the procedure outlined herein below in Scheme II which entails de-protection of intermediates such Intermediate 6 to form the ester analogs which comprise this aspect and hydrolysis of the corresponding ester analogs to the free acid analogs.




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EXAMPLE 2
2-{3-Allyl-4-[2-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (10)

Preparation of 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (10): To a solution of (S)-2-{3-(S)-allyl-4-[2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 6, (200 mg, 0.324 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid. The reaction mixture is stirred for 45 min, concentrated in vacuo and the resulting residue purified by reverse phase HPLC to afford the trifluoroacetate salt of the desired product.


EXAMPLE 3
2-{3-Allyl-4-[2-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (11)

Preparation of 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (11): To a solution of 2-{3-allyl-4-[2-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 10, (168 mg, 0.324 mmol) in a mixture of THF (1 mL)/CH3OH (0.5 mL)/H2O (0.5 mL) is added LiOH (43 mg, 1.78 mmol). The reaction mixture is stirred for 3 hours, acidified with 1N HCl to pH 3 and extracted with EtOAc. The extract is dried over Na2SO4, filtered, concentrated and dried under high vacuum to afford the desired product in quantitative yield.


The following are non-limiting examples of other melanocortin receptor ligands encompassed by Category I of the present invention.

  • 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-methyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-ethyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-ethyl-4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-propyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-propyl-4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-iso-propyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-cyclopropylmethyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-iso-butyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-propargyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-benzyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{3-(S)-ally-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N,N-dimethyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-3-(S)-isopropyl-2-oxo-piperazin-1-yl}-N-cyclopropylmethyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-3-(S)-isopropyl-2-oxo-piperazin-1-yl}-N-cyclopropylmethyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-3-(S)-propyl-2-oxo-piperazin-1-yl}-N-methyl-3-(4-trifluoromethylphenyl)-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-3-(S)-allyl-2-oxo-piperazin-1-yl}-N-methyl-3-phenyl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-3-(S)-methyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-3-(S)-propyl-2-oxo-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-3-(S)-propyl-2-oxo-piperazin-1-yl}-N-(2-hydroxyethyl)-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-chlorophenyl)propionyl]-3-(S)-propyl-2-oxo-piperazin-1-yl}-N-(2-dimethylaminoethyl)-3-naphthalen-2-yl-propionamide;
  • 2-(S)-{4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-3-(S)-propyl-2-oxo-piperazin-1-yl}-N-methyl-3-(1H-indol-3-yl)-propionamide;
  • 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide; and
  • 2-(S)-{3-(S)-allyl-4-[2-(R)-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide.


Category II melanocortin receptor ligands according to the present invention comprise the 2-oxo-3-hydrocarbyl-piperazines having the general scaffold with the formula:




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wherein the index x can be 0 or 1.


The first aspect of Category II comprises analogs with a scaffold having the formula:




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wherein R is a substituted or unsubstituted aryl unit as defined herein above and non-limiting examples of R1, R5a, R5b, R7a and R8 are provided herein below in Table III.














TABLE III





No.
R1
R5a
R5b
R7a
R8







121
methyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


122
ethyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


123
propyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


124
iso-propyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


125
butyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


126
tert-butyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


127
cyclopropyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


128
cyclopropylmethyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


129
allyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


130
but-2-enyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


131
methyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


132
ethyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


133
propyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


134
iso-propyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


135
butyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


136
tert-butyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


137
cyclopropyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


138
cyclopropylmethyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


139
allyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


140
but-2-enyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


141
methyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


142
ethyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


143
propyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


144
iso-propyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


145
butyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


146
tert-butyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


147
cyclopropyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


148
cyclopropylmethyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


149
allyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


150
but-2-enyl
—H
—H
—C(O)NH2
(4-chlorophenyl)methyl


151
methyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


152
ethyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


153
propyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


154
iso-propyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


155
butyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


156
tert-butyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


157
cyclopropyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


158
cyclopropylmethyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


159
allyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


160
but-2-enyl
—CH3
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


161
methyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


162
ethyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


163
propyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


164
iso-propyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


165
butyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


166
tert-butyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


167
cyclopropyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


168
cyclopropylmethyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


169
allyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


170
but-2-enyl
—CH3
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


171
methyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


172
ethyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


173
propyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


174
iso-propyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


175
butyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


176
tert-butyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


177
cyclopropyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


178
cyclopropylmethyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


179
allyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


180
but-2-enyl
—CH3
—CH3
—C(O)NH2
(4-chlorophenyl)methyl


181
methyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


182
ethyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


183
propyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


184
iso-propyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


185
butyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


186
tert-butyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


187
cyclopropyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


188
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


189
allyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


190
but-2-enyl
—CH3
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


191
methyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


192
ethyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


193
propyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


194
iso-propyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


195
butyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


196
tert-butyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


197
cyclopropyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


198
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


199
allyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


200
but-2-enyl
—CH3
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


201
methyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


202
ethyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


203
propyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


204
iso-propyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


205
butyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


206
tert-butyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


207
cyclopropyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


208
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


209
allyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


210
but-2-enyl
—CH3
—CH3
—C(O)NHCH3
(4-chlorophenyl)methyl


211
methyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


212
ethyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


213
propyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


214
iso-propyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


215
butyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


216
tert-butyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


217
cyclopropyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


218
cyclopropylmethyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


219
allyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


220
but-2-enyl
—CH3
—CH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


221
methyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


222
ethyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


223
propyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


224
iso-propyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


225
butyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


226
tert-butyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


227
cyclopropyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


228
cyclopropylmethyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


229
allyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


230
but-2-enyl
—CH3
—CH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


231
methyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


232
ethyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


233
propyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


234
iso-propyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


235
butyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


236
tert-butyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


237
cyclopropyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


238
cyclopropylmethyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


239
allyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


240
but-2-enyl
—CH3
—CH3
—C(O)N(CH3)2
(4-chlorophenyl)methyl


241
methyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


242
ethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


243
propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


244
iso-propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


245
butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


246
tert-butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


247
cyclopropyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


248
cyclopropylmethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


249
allyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


250
but-2-enyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


251
methyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


252
ethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


253
propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


254
iso-propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


255
butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


256
tert-butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


257
cyclopropyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


258
cyclopropylmethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


259
allyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


260
but-2-enyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


261
methyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


262
ethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


263
propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


264
iso-propyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


265
butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


266
tert-butyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


267
cyclopropyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


268
cyclopropylmethyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


269
allyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


270
but-2-enyl
—CH3
—CH3
—C(O)NH(CH2CH2F)
(4-chlorophenyl)methyl


271
methyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


272
ethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


273
propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


274
iso-propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


275
butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


276
tert-butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


277
cyclopropyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


278
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


279
allyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


280
but-2-enyl
—CH3
—CH3
—C(O)NHCH(CH3)2
naphthylen-2-ylmethyl


281
methyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


282
ethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


283
propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


284
iso-propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


285
butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


286
tert-butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


287
cyclopropyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


288
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


289
allyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


290
but-2-enyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(3,4-dichlorophenyl)methyl


291
methyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


292
ethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


293
propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


294
iso-propyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


295
butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


296
tert-butyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


297
cyclopropyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


298
cyclopropylmethyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


299
allyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl


300
but-2-enyl
—CH3
—CH3
—C(O)NHCH(CH3)2
(4-chlorophenyl)methyl









Compounds which comprise the first aspect of Category II analogs can be prepared by the procedure outlined herein below in Scheme III.




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EXAMPLE 4
2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (20)

3-Cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionic acid can be prepared as follows: To a solution of 2-amino-3-cyclopropyl propionic acid (1.0 g, 7.74 mmol) and triethyl amine (2.3 g, 10.4 mmol) in THF/H2O (10 ml/20 mL) is added 2-nirtobenzenesulfonyl chloride (2.3 g, 10.4 mmol) in portions at 0° C. The reaction mixture is stirred at room temperature for 15 hours and the THF is removed in vacuo. The residual aqueous layer is then acidified with conc. HCl and extracted with ethyl acetate. The combined ethyl acetate extracts are dried over Na2SO4 and concentrated in vacuo to afford 2.5 g of the N-protected amino acid in purity suitable for direct use. This procedure is suitable for other amino acids which are used as a source of R1 units. 1H NMR (300 MHz, CD3OD) δ 8.10–8.19 (m, 1H), 7.76–7.90 (m, 3H), 4.10–4.18 (m, 1H), 1.71–1.84 (m, 1H), 1.56–1.67 (m, 1H), 0.73–0.88 (m, 1H), 0.28–0.50 (m, 2H), 0.00–0.20 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 173.56, 148.10, 134.10, 133.86, 132.52, 130.42, 124.80, 57.10, 37.83, 7.23, 4.04, 3.48; MS (ESMS) m/z 315.0 (M+H)+.


Preparation of 2-[3-cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester (12): To a solution of cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionic acid (7.74 mmol) in DMF (10 mL) are added 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (3.1 g, 11.7 mmol), N-methylmorpholine (4.67 g, 46.27 mmol), 1-hydroxybenzotriazole (17.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.93 g, 10.07 mmol) consecutively. The resulting mixture is stirred for 4 hours, quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 3.46 g (85% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.04 (dd, J=7.7, 1.4 Hz, 1H), 7.42–7.68 (m, 9H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 4.84–4.96 (m, 1H), 3.98–4.07 (m, 1H), 3.71 (s, 3H), 3.29 (dd, J=14.0, 5.6 Hz, 1H), 3.14 (dd, J=14.0, 7.4 Hz, 1H), 1.62–1.72 (m, 1H), 1.23–1.42 (m, 1H), 0.02–0.40 (m, 3H), −0.14–0.02(, 2H); 13C NMR (75 MHz, CDCl3) δ 171.74, 170.45, 147.91, 134.02, 133.73, 133.61, 133.18, 132.70, 131.07, 128.55, 128.32, 127.89, 127.41, 126.54, 126.12, 125.76, 58.59, 53.56, 52.74, 38.34, 37.55, 6.86, 4.38; MS (ESMS) m/z 526.1 (M+H)+.


Preparation of 2-[3-cyclopropylmethyl-4-(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester (13): To a solution of 2-[3-cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 12, (3.46 g, 6.59 mmol) and 1,2-dibromoethane (12.38 g, 65.9 mmol) in DMF (40 mL) is added potassium carbonate (9.10 g, 65.8 mmol). The reaction mixture is stirred for 15 hours at 65° C., cooled and quenched with aqueous NH4Cl solution. The mixture is then extracted several times with EtOAc and the combined extracts dried over Na2SO4 and concentrated in vacuo. The resulting residue is purified over silica gel (hexanes/EtOAc, 1:2) to afford 3.57 g (98% yield) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.01–8.08 (m, 1H), 7.58–7.84 (m, 7H), 7.43–7.52 (m, 2H), 7.35 (dd, J=8.4 Hz, 1H), 5.38 (dd, J=11.7, 4.8 Hz, 1H), 4.33–4.44 (m, 1H), 3.76–3.88 (m, 1H), 3.69 (s, 3H), 3.21–3.66 (m, 4H), 2.99–3.14 (m, 1H), 1.40–1.53 (m, 1H), 1.02–1.16 (m, 1H), −0.14–−0.02 (m, 3H), −0.34–−0.20 (m, 2H); MS (ESMS) m/z 552.2 (M+H)+.


Preparation of 2-(3-cyclopropylmethyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester (14): To a solution of 2-[3-cyclopropylmethyl-4-(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 13, (3.56 g, 6.46 mmol) and 4-mercaptophenol (4.07 g, 32.3 mmol) in CH3CN (50 mL) is added potassium carbonate (8.91 g, 64.6 mmol). The reaction mixture is stirred for 15 hours, quenched with 10% NaHCO3 solution and extracted several times with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo to yielding a bright yellow oil which is purified over silica gel (hexanes/EtOAc, 1:1 to EtOAc/MeOH, 10:1) to afford 2.10 g (89% yield) of the desired product. 1H NMR (300 MHz, CD3OD) δ 7.76–7.86 (m, 3H), 7.71 (s, 1H), 7.37–7.52 (m, 3H), 5.27 (dd, J=11.7, 4.8 Hz, 1H), 3.79 (s, 3H), 3.25–3.60 (m, 4H), 2.88–3.06 (m, 2H), 2.62–2.75 (m, 1H), 1.56–1.68 (m, 1H), 1.16–1.29 (m, 1H), 0.01–0.25 (m, 3H), −0.19–−0.08 (m, 2H); 13C NMR (75 MHz, MeOD) δ 171.55, 171.01 m 134.88, 133.78, 132.74, 128.15, 127.52, 127.45, 127.11, 126.11, 125.64, 59.42, 58.92, 51.78, 46.77, 41.23, 36.59, 33.97, 6.63, 3.72, 3.46; MS (ESMS) m/z 367.2 (M+H)+.


Preparation of 2-{4-[2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (15): To a solution of 2-(3-cyclopropylmethyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 14, (528 mg, 1.44 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (489 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (951 mg, 1.83 mmol) and triethyl amine (174 mg, 1.72 mmol). The reaction mixture is stirred for 10 hours, quenched with 10% NaHCO3 aqueous solution and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a crude residue which is purified over silica gel (silica gel, hexanes/ethyl acetate, 1:1) to afford 651 mg (71% yield) of the desired product. 1H NMR (300 MHz, CDCl3, Rotamers) δ 7.66–7.85 (m, 3H), 7.55 (s, 1H), 7.39–7.53 (m, 2H), 7.28–7.38 (m, 1H), 7.04–7.18 (m, 2H), 6.86–7.01 (m, 2H), 5.63 (dd, J=11.4, 5.4 Hz, 0.5H), 5.47 (dd, J=11.4, 5.4 Hz, 0.5H), 5.28–5.38 (m, 0.5H), 4.82–4.98 (m, 1H), 4.56–4.80 (m, 1H), 4.30–4.43 (m, 0.5H), 3.75–3.91 (m, 4H), 3.50–3.62 (m, 1H), 2.92–3.36 (m, 4H), 2.64–2.88 (m, 2H), 1.38 (s, 5H), 1.35 (s, 4H), 0.91–1.18 (m, 2H), −0.64–0.17 (m, 5H); 13C NMR (75 MHz, CDCl3, Rotamers) δ 170.69, 170.54, 169.37, 168.55, 167.10, 155.09, 154.84, 134.05, 133.71, 133.53, 133.49, 132.60, 132.41, 131.79, 131.28, 131.17, 130.89, 130.79, 128.74, 128.66, 127.94, 127.86, 127.73, 127.63, 127.50, 127.03, 126.63, 126.57, 126.14, 115.94, 115.66, 115.56, 115.28, 80.34, 79.87, 58.82, 57.26, 56.42, 52.76, 51.66, 51.32, 44.08, 42.79, 41.36, 39.92, 38.75, 37.43, 36.72, 36.58, 34.92, 34.54, 28.44, 7.12, 4.74, 4.69, 4.34, 4.31; MS (ESMS) m/z 632.2 (M+H)+.


Preparation of 2-{4-[2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (16): To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 15, (531 mg, 0.842 mmol) in a mixture of THF (5 mL)/CH3OH (1 mL)/H2O (2 mL) is added LiOH (100 mg, 4.17 mmol). The reaction mixture is stirred for 4 hours, acidified with 1N HCl to pH 3 and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give the free acid in quantitative yield, which is used directly without further purification. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.72–7.87 (m, 3H), 7.68 (s, 1H), 7.37–7.53 (m, 3H), 7.12–7.28 (m, 2H), 6.99–7.06 (m, 2H), 5.54–5.66 (m, 1H), 4.52–4.80 (m, 1.5H), 3.82–4.38 (m, 1.5H), 3.18–3.64 (m, 4H), 2.70–3.02 (m, 3H), 0.80–1.43 (m, 11H), −0.78–0.10 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 171.68, 171.58, 170.23, 169.29, 167.86, 163.70, 156.08, 134.69, 134.57, 133.71, 133.14, 132.70, 131.26, 131.15, 130.73, 130.64, 128.19, 128.12, 127.55, 127.38, 127.29, 127.07, 126.12, 125.64, 79.61, 79.34, 58.68, 57.04, 56.18, 52.13, 51.65, 43.21, 42.29, 41.29, 38.61, 37.32, 37.21, 36.27, 34.23, 33.93, 27.50, 27.41, 6.45, 3.92, 3.66, 3.33; MS (ESMS) m/z 618.2 (M+H)+.


Preparation of [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (17): To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 16, (114 mg, 0.18 mmol)) in DMF (2 mL) are added methylamine (2M, 0.11 mL, 0.22 mmol), 1-hydroxybenzotriazole (53 mg, 0.39 mmol), N-methylmorpholine (63 mg, 0.62 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (41 mg, 0.21 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (hexanes/ethyl acetate, 1:4) to afford 108 mg (93% yield) of the desired product. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.73–7.86 (m, 3H), 7.70 (s, 1H), 7.38–7.52 (m, 3H), 7.14–7.30 (m, 2H), 6.91–7.04 (m, 2H), 5.54–5.72 (m, 1H), 4.50–4.78 (m, 2H), 4.28–4.40 (m, 0.3H), 4.03–4.15 (m, 0.7H), 3.72–3.81 (m, 0.3H), 3.58–3.68 (m, 0.3H), 3.42–3.53 (m, 2H), 3.12–3.32 (m, 2H), 2.70–3.00 (m, 6H), 1.41 (s, 5H), 1.34 (s, 4H), 0.66–1.30 (m, 2H), −0.60–−0.12 (m, 4.3H), −0.80–−0.68 (m, 0.7H); MS (ESMS) m/z 631.3 (M+H)+.


Preparation of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (18): [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 17, (105 mg, 0.16 mmol) is dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 2 mL). The reaction mixture was stirred for 3 minutes, concentrated in vacuo and the residue purified by reverse phase HPLC to afford the TFA salt of the desired compound. MS (ESMS) m/z 531.2 (M+H)+.


Preparation of {1-[2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (19): To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (44 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (44 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford 45 mg (93% yield) of the desired product. MS (ESMS) m/z 716.3 (M+H)+.


Preparation of 2-{4-[2-(2-amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (20). {1-[2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester, 19, (45 mg, 0.063 mmol) is dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 1 mL). The reaction mixture is stirred for 1 hour, concentrated in vacuo and the residue purified by reverse phase HPLC purification to afford the TFA salt of the desired compound. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.65–7.84 (m, 4H), 7.36–7.52 (m, 3H), 7.15–7.31 (m, 2H), 6.90–7.02 (m, 2H), 5.73 (dd, J=11.7, 5.4 Hz, 0.66H), 5.60 (dd, J=11.4, 5.4 Hz, 0.33H), 5.01–5.14 (m, 0.66H), 4.65–4.75 (m, 0.33H), 4.24–4.36 (m, 0.33H), 4.01–4.14 (m, 0.66H), 3.82–3.98 (m, 0.66H), 3.14–3.68 (m, 5H), 2.73–3.10 (m, 6H), 1.25–1.60 (m, 7H), 0.78–0.95 (m, 1H), −0.56–−0.15 (M, 4H), −0.76–−0.62 (m, 1H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 171.66, 171.04, 170.86, 170.34, 169.54, 169.29, 167.78, 163.81, 160.57, 134.36, 133.70, 132.74, 132.21, 131.22, 131.11, 130.89, 130.78, 128.16, 127.69, 127.51, 127.31, 127.10, 126.17, 125.70, 115.47, 115.14, 114.85, 58.73, 56.98, 56.84, 56.42, 56.32, 51.61, 50.96, 48.75, 42.12, 41.62, 37.86, 37.47, 37.25, 36.46, 36.36, 34.57, 34.35, 25.32, 23.05, 22.91, 22.73, 6.56, 3.96, 3.73, 3.40; MS (ESMS) m/z 616.2 (M+H)+.


The above example wherein 3-cyclopropyl-2-(S)-(2-nitro-benzenesulonylamino)-propionic acid is used for the preparation of compound 12, provides one iteration of the analogs encompassed by the first aspect of Category II. Other examples encompassed within the first aspect of Category II, wherein R1 comprises other units, can be suitably prepared by substituting the appropriate starting material in place of 3-cyclopropyl-2-(S)-(2-nitro-benzenesulonylamino)-propionic acid, for example, cyclopropyl-2-(S)-(nitro-benzene-sulonylamino)-acetic acid, 2-(S)-(2-nitro-benzenesulonylamino)-butyric acid, and the like. The formulator may also choose to prepare rings which comprise the opposite stereochemistry, for example, those derived from the use of 3-cyclopropyl-2-(R)-(2-nitro-benzenesulonylamino)-propionic acid or, as a further iteration, the formulator may wish to provide a racemic mixture, for example, an analog derived from, 3-cyclopropyl-2-(R,S)-(2-nitro-benzenesulonylamino)-propionic acid.


Other iterations of this aspect of the present invention, for example, wherein R7a is varied, can be prepared by the procedure outlined herein below in Scheme IV beginning with compounds such as intermediate 16.




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The following are non-limiting examples of compounds which comprise the first aspect of Category II according to the present invention.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propion-amide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 8.40–8.61 (m, 0.6H), 7.53–7.92 (m, 4H), 7.38–7.57 (m, 3H), 7.15–7.36 (m, 2H), 6.90–7.10 (m, 2H), 5.60–5.87 (m, 1H), 5.46–5.58 (m, 0.4H), 5.01–5.15 (m, 0.6H), 4.21–4.78 (m, 3H), 3.88–4.15 (m, 1H), 3.16–3.76 (m, 7H), 2.80–3.13 (m, 2H), 1.35–1.59 (m, 6H), 0.76–1.27 (m, 2H), −0.76–−0.09 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 173.62, 172.82, 172.60, 172.41, 171.92, 171.13, 170.90, 169.45, 165.45, 165.38, 162.81, 162.21, 162.15, 135.84, 135.26, 134.33, 134.22, 134.18, 133.86, 133.84, 132.76, 132.65, 132.39, 132.29, 129.74, 129.26, 129.12, 129.06, 128.86, 128.69, 128.61, 127.73, 127.26, 117.04, 116.68, 116.40, 84.51, 82.29, 60.39, 58.50, 58.05, 57.85, 53.24, 52.55, 43.70, 43.32, 41.66, 41.38, 39.50, 38.92, 38.84, 38.08, 37.90, 36.24, 36.11, 24.45, 24.27, 24.19, 8.20, 8.10, 5.49, 5.29, 4.90; MS (ESMS) m/z 648.9 (M+H)+.


3-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-methyl-4-naphthalen-2-yl-butyramide. 1H NMR (CDCl3, 300 MHz) 6.80˜7.80 (m, 11H), 5.06 (m, 2H), 4.58 (m, 1H), 2.50˜3.50 (m, 13H), 1.54 ( m, 6H), 0.91 (m, 2H). 13C NMR (CDCl3, 75 mHz) 171.90, 171.79, 169.93, 168.70, 134.59, 133.58, 132.62, 131.43, 131.22, 128.45, 127.90, 127.56, 127.26, 126.61, 126.08, 115.80, 115.51, 57.61, 56.03, 50.70, 40.98, 38.69, 38.01, 37.62, 34.05, 26.54, 24.42, 24.18, 23.21, 18.73, 13.50; MS (ES-MS) m/z 618 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 1H NMR (CD3OD, 300 MHz) 7.81–7.70, m, 4H; 7.48–7.39, m, 3H; 7.25, m, 2H; 6.98, m, 2H; 5.67–5.56, m, 1H; 5.06, m, 0.75H, 4.57, m, 0.75H; 4.23–3.96, m, 1H; 3.82–3.63, m, 1.25H; 3.44–3.16, m, 4H; 3.00–2.76, m, 6.5H; 1.54, s, 3H; 1.47, s, 3H; 1.35–0.92, m, 2.25H; 0.41–0.27, m, 5H. 13C NMR (CD3OD, 300 mHz) 171.68, 171.05, 170.13, 169.33, 160.58, 134.28, 133.75, 132.82, 132.43, 131.20, 131.10, 128.12, 127.57, 127.33, 127.05, 126.20, 125.69, 115.16, 114.88, 58.43, 56.93, 56.11, 56.01, 50.90, 41.72, 41.43, 36.57, 34.49, 34.14, 25.28, 23.04, 22.89, 22.70, 18.59, 18.36, 12.63. MS(ESI) m/e 604 [M+1].


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-(2-fluoroethyl)-propionamide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.28 (m, 6H), 7.03 (m, 2H), 5.53 (m, 1H), 5.08 (t, 1H, J=7.8 Hz), 4.66 (t, 1H, J=6.6 Hz), 4.53 (m, 1H), 4.37 (m, 1H), 3.98 (m, 1H), 3.65–3.00 (m, 9H), 1.55 (s, 3H), 1.45 (s, 3H), 1.29 (m, 2H), 0.80 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 173.5, 172.5, 172.0, 171.1, 165.4, 163.0, 162.5, 162.2, 137.1, 134.3, 134.1, 133.9, 132.8, 132.7, 132.2, 130.1, 117.0, 116.7, 116.5, 84.5, 82.3, 60.2, 58.5, 58.1, 57.8, 57.7, 53.1, 52.6, 43.4, 43.1, 41.6, 41.3, 39.7, 38.8, 38.1, 36.9, 36.0, 35.5, 35.4, 24.6, 24.3, 20.5, 20.2, 14.6; MS m/z (ESI): 620 (M+H, 100), 622 (M+2+H, 37).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) 7.63–7.53 (m, 3H) 7.43 (s, 1H) 7.33–7.23 (m, 3H), 7.20–7.13 (m, 2H), 7.00–6.87 (m, 2H) 6.84–6.76 (m, 1H) 6.68 (t, 1H, J=8.29 Hz) 5.78 (d, 1H, J=7.25 Hz) 5.68 (d, 1H, J=7.70 Hz) 5.24–5.04 (m, 2H) 4.92–4.76 (m, 2H) 4.69 (t, 1H, J=5.90 Hz) 4.22–4.10 (m, 1H) 3.95–3.78 (m, 2H) 3.64 (t, 2H, J=6.75 Hz) 3.54–3.46 (m, 2H) 2.70 (d, 2H, J=6.98 Hz) 1.52 (s, 6H) 1.04–0.92 (m, 3H) 0.91 (d, 4H, J=2.654 Hz) MS (ESI) m/z 625 (M+H+, 100).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-(4-isopropoxy-phenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.76 (m, 3H), 1.29 (m, 6H, CH(CH3)2), 1.46, 1.562 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.73, 2.80 (2 singlets, 3H, CH3NHC(O), rotamers), 3.06 (m, 5H), 3.33 (m, 4H), 3.63 (m, 1H), 5.10 (m, 2H), 5.48 (m, 1H), 6.83 (m, 2H), 7.02 (m, 2H), 7.14 (m, 2H), 7.30 (m, 1H); 19F NMR (282 MHz, CD3OD with rotamers) δ 45.26; 13C NMR (75MHz, CD3OD with rotamers) δ 132.8, 132.7, 132.4, 131.4, 119.0, 117.3, 116.7, 116.5, 111.8, 71.3, 61.3, 60.0, 57.9, 57.6, 43.3, 43.0, 38.5, 38.0, 35.8, 35.1, 31.5, 39.9, 26.7, 25.3, 22.8, 20.2, 14.6; MS m/e 612 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-(4-benzyloxy-phenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.78 (m, 3H), 1.24 (m, 2H), 1.462, 1.56 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.73, 2.81 (2 singlets, 3H, CH3NHC(O), rotamers), 3.00 (m, 5H), 3.17 (m, 3H), 3.62 (m, 1H), 3.963 (m, 1H), 4.65 (m, 1H), 5.06 (m, 3H), 5.47 (m, 1H), 6.93 (m, 2H), 7.03 (m, 2H), 7.162 (m, 2H), 7.03 (m, 3H), 7.40 (m, 4H); 19F NMR (282 MHz, CD3OD with rotamers) δ 45.31; 13C NMR (75 MHz, CD3OD with rotamers) δ 132.8, 131.4, 129.9, 129.3, 128.9, 116.7, 116.5, 116.3, 71.4, 61.3, 58.0, 57.6, 52.1, 43.4, 43.0, 38.5, 35.8, 35.2, 31.5, 26.7, 25.3, 20.2, 14.6; MS m/e 660 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-4-(4-chlorophenyl)-N-methyl-butyramide TFA. 1H NMR (CD3OD, with rotamers) δ 7.14 (m, 6H), 6.88 (m, 2H), 5.00 (m, 1H), 4.00 (m, 1H), 3.46 (m, 1H), 3.25 (m, 2H), 2.93 (m, 4H), 2.58, 2.53 (2 singlets, 3H, CH3NHC(O), rotamers), 2.42 (m, 2H), 1.94 (m, 2H), 1.56 (m, 2H), 1.42, 1.39, 1.32, 1.28 (4 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.05 (m, 2H), 0.76 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 173.2, 173.0, 172.0, 171.4, 165.4, 162.2, 141.1, 134.2, 133.5, 132.8, 132.7, 131.5, 130.0, 116.8, 116.5, 113.3, 58.5, 57.5, 57.3, 53.2, 52.5, 43.9, 42.3, 38.2, 36.8, 35.8, 33.0, 31.3, 26.7, 24.6, 24.3, 20.7, 14.5; MS m/z (ESI): 602 (M+H, 100), 604 (M+2+H, 37).


A second aspect of Category II melanocortin receptor ligands according to the present invention comprise the 2-oxo-3-hydrocarbyl-piperazines having the general scaffold with the formula:




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wherein R is a substituted or unsubstituted aryl as defined herein above and non-limiting examples of R1, R7a, R8 and Q are provided herein below in Table IV. THQ-3-yl represents 1,2,3,4-tetrahydroisoquinolin-3-yl.













TABLE IV





No.
R1
Q
R7a
R8







300
methyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


301
ethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


302
propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


303
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


304
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


305
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


306
allyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


307
methyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


308
ethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


309
propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


310
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


311
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


312
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


313
allyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


314
methyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


315
ethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


316
propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


317
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


318
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


319
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


320
allyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


321
methyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


322
ethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


323
propyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


324
iso-propyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


325
cyclopropyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


326
cyclopropylmethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


327
allyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


328
methyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


329
ethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


330
propyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


331
iso-propyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


332
cyclopropyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


333
cyclopropylmethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


334
allyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


335
methyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


336
ethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


337
propyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


338
iso-propyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


339
cyclopropyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


340
cyclopropylmethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


341
allyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


342
methyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


343
ethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


344
propyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


345
iso-propyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


346
cyclopropyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


347
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


348
allyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


349
methyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


350
ethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


351
propyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


352
iso-propyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


353
cyclopropyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


354
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


355
allyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


356
methyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


357
ethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


358
propyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


359
iso-propyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


360
cyclopropyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


361
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


362
allyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


363
methyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


364
ethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


365
propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


366
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


367
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


368
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


369
allyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


370
methyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


371
ethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


372
propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


373
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


374
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


375
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


376
allyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


377
methyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


378
ethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


379
propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


380
iso-propyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


381
cyclopropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


382
cyclopropylmethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


383
allyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


384
methyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


385
ethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


386
propyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


387
iso-propyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


388
cyclopropyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


389
cyclopropylmethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


390
allyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


391
methyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


392
ethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


393
propyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


394
iso-propyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


395
cyclopropyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


396
cyclopropylmethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


397
allyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


398
methyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


399
ethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


400
propyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


401
iso-propyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


402
cyclopropyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


403
cyclopropylmethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


404
allyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


405
methyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


406
ethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


407
propyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


410
iso-propyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


411
cyclopropyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


412
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


413
allyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


414
methyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


415
ethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


416
propyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


417
iso-propyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


418
cyclopropyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


419
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


420
allyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


421
methyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


422
ethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


423
propyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


424
iso-propyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


425
cyclopropyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


426
cyclopropylmethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


427
allyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl









The compounds which comprise the second aspect of Category II can be suitably prepared according to Scheme V below from final analogs which comprise Category I, for example, utilizing as starting materials compounds such as 18.




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EXAMPLE 5
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide (23)

Preparation of 3-[2-[2-cyclopropylmehtyl-4-(1-methylcarbamoyl-2-naphthylen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenxyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (22): To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (44 mg, 0.068 mmol) in DMF (1 mL) are added 3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (21 mg, 0.079 mmol), 1-hydroxybenzo-triazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.


Preparation of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide (23): 3-[2-[2-cyclopropylmehtyl-4-(1-methylcarbamoyl-2-naphthylen-2-yl-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 22, (50 mg, 0.064 mmol) is dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 1 mL). The reaction mixture is stirred for 1 hour, concentrated in vacuo and the residue purified by reverse phase HPLC purification to afford the TFA salt of the desired compound.


Pyrrolidine-2-carboxylic acid (1R-(4-fluorobenzyl)-2-{4-[1-methylcarbamoyl-2S-(4-trifluoromethyl-phenyl)-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-2-oxo-ethyl)-amide: 1H NMR (CD3OD, 300 MHz) δ 7.60 (d, 2H, J=7.95 Hz) 7.46 (d, 2H, J=7.87 Hz) 7.34–7.18 (m, 2H) 7.08–6.94(m, 2H) 5.58 (q, 1H, J=5.61 Hz) 5.13 (t, 1H, J=7.76 Hz) 4.69 (t, 1H, J=6.58 Hz) 4.23 (t, 1H, J=6.69 Hz) 4.10–3.88 (m, 2H) 3.71–3.44 (m, 2H) 3.23–2.83 (m, 4H) 2.74 (s, 3H) 2.41–2.25 (m, 2H) 2.09–1.68 (m, 6H) 1.29–1.08 (m, 2H) 0.84–0.63 (m, 3H) MS (ESI) m/z 634 (M+H+, 100).


Pyrrolidine-2-carboxylic acid [2-{4-[1-allylcarbamoyl-2S-(4-chlorophenyl)-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-1R-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, 300 MHz) δ 7.40–6.92 (m, 8H), 5.92–5.73 (m, 1H), 5.56–5.38 (m, 2H), 5.25–4.50 (m, 3H), 4.28–2.84 (m, 1H), 2.45–2.25 (m, 2H), 2.12–1.69 (m, 4H), 1.51–0.72 (m, 7H), MS (ESI) m/z 626 (M+H+, 100).


Pyrrolidine-2-carboxylic acid [2-{4-[2S-(4-chlorophenyl)-1-phenylcarbamoyl-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-1R-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, 300 MHz) δ 8.13–6.82 (m, 13 H) 5.12–4.62 (m, 2H) 4.50–2.68 (m, 12H) 2.30–1.48 (m, 4H) 1.35–0.58 (m, 8H) MS (ESI) m/z 684 (M+H+, 100).


Pyrrolidine-2-carboxylic acid [2-{4-[2S-(4-chlorophenyl)-1-ethylcarbamoyl-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-1S-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, 300 MHz) δ 7.42–6.93 (m, 8H) 5.62–5.31 (m, 1H) 5.13 (t, 1H, J=7.77 Hz) 4.80–3.88 (m, 2H) 3.71–2.76 (m, 10H) 2.51–1.55 (m, 8H) 1.40–0.65 (m, 8H) MS (ESI) m/z 614 (M+H+, 100).


Pyrrolidine-2-carboxylic acid [2-[4-(1-allylcarbamoyl-2S-naphthalen-2-yl-ethyl)-3-oxo-2S-propyl-piperazin-1-yl]-1R-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, 300 MHz) δ 5.99–5.50 (m, 3H) 5.28–4.50 (m, 3H) 4.28–2.72 (m, 13 H) 2.41–1.62 (m, 4H) 1.20 (t, 2H, J=7.102 Hz) 1.06–0.82 (m, 2H) 0.70–0.21 (m, 3H) (ESI) m/z 642 (M+H+, 100).


Pyrrolidine-2-carboxylic acid {1R-(4-fluorobenzyl)-2-[4S-(2-naphthalen-2-yl-1-phenylcarbamoyl-ethyl)-3-oxo-2S-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide: 1H NMR (CD3OD, 300 MHz) δ 7.92–6.88 (M, 16H) 5.90–5.65 (m, 2H) 5.28–4.51 (m, 5H) 4.28–2.78(m, 7H) 2.42–2.20 (m, 2H) 2.08–1.70 (m, 4H) 1.48–0.23 (m, 5H) (ESI) m/z 678 (M+H+, 100).


Pyrrolidine-2-carboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(4-isopropoxy-phenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-2-oxo-ethyl)-amide: 1H NMR (300 MHz, CD3OD) δ 0.789 (m, 3H), 1.768 (m, 6H, CH(CH3)2), 1.789 (m, 1H), 1.974 (m, 2H), 2.333 (m, 2H),□ 2.743, 2.805 (2 singlets, 3H, CH3NHC(O), rotamers), 3.001 (m, 3H), 3.173 (m, 3H), 3.340 (m, 2H), 3.659 (m, 1H), 4.024 (m, 1H), 4.232 (m, 1H), 4.560 (m, 1H), 4.679 (m, 1H), 5.135 (t, 1H), 5.473 (m, 1H), 6.826 (m, 2H), 7.039 (m, 2H), 7.136 (m, 2H), 7.316 (m, 1H); 19F NMR (282 MHz, CD3OD with rotamers) δ 45.392; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.4, 163.6, 163.1, 162.2, 158.7, 133.9, 133.6, 132.8, 132.7, 132.5, 132.4, 131.5, 131.4, 129.8, 120.5, 117.3, 117.1, 116.7, 116.4, 71.3, 61.3, 57.9, 57.6, 52.1, 43.3, 43.0, 38.5, 36.9, 35.8, 35.3, 35.2, 31.5, 26.7, 25.3, 22.8, 20.4, 20.2, 14.6; MS m/e 724 (M+1).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(4-benzyloxy-phenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, CD3OD) δ 0.791 (m, 3H), 1.276 (m, 2H), 1.802 (m, 1H), 1.963 (m, 2H), 2.369 (m, 1H), 2.741, 2.803 (2 singlets, 3H, CH3NHC(O), rotamers), 3.029 (m, 3H), 3.147 (m, 3H), 3.454 (m, 1H), 3.653 (m, 1H), 4.228 (m, 1H), 5.060 (m, 3H), 5.463 (m, 1H), 6.949 (m, 2H), 7.045 (m, 2H), 7.179 (m, 3H), 7.329 (m, 3H), 7.429 (m, 3H); 19F NMR (282 MHz, CD3OD with rotamers) δ 45.451; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.5, 162.2, 159.7, 139.1, 133.9, 133.6, 132.8, 132.7, 132.5, 132.4, 131.6, 131.5, 130.4, 129.9, 129.3, 128.9, 117.0, 116.8, 116.5, 116.4, 71.4, 61.4, 60.1, 58.5, 58.1, 57.6, 52.7, 52.1, 43.4, 43.0, 38.5, 35.8, 35.1, 31.5, 26.7, 25.3, 20.4, 20.2, 14.6; MS m/e 673 (M+1).


Pyrrolidine-2-carboxylic acid [2-[4-(1-ethylcarbamoyl-2S-naphthalen-2-yl-ethyl)-3-oxo-2S-propyl-piperazin-1-yl]-1R-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, 300 MHz) δ 7.79–6.89 (m, 11H) 5.69–5.45 (m, 1H) 5.09 (t, 1H, J=7.87 Hz) 4.57 (t, 1H, J=6.67 Hz) 4.28–2.70 (m, 13H) 2.08–1.62 (m, 4H) 1.20–0.16 (m, 10H) (ESI) m/z 630 (M+H+, 100).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(4-chlorophenyl)-1-(2-fluoroethylcarbamoyl)-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.17 (m, 6H), 6.92 (m, 2H), 5.38 (m, 1H), 5.01 (t, 1H, J=7.9 Hz), 4.57 (t, 1H, J=6.7 Hz), 4.44 (m, 1H), 4.26 (m, 1H), 4.10 (m, 1H), 3.88 (m, 1H), 3.43–2.75 (m, 11H), 2.22 (m, 1H), 1.89–1.61 (m, 3H), 1.15 (m, 2H), 0.69 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 172.3, 172.1, 171.9, 171.7, 171.0, 169.7, 169.5, 165.5, 162.9, 162.2, 137.2, 134.2, 133.9, 133.6, 132.8, 132.7, 132.5, 132.3, 132.2, 130.0, 117.1, 116.8, 116.5, 84.6, 82.4, 61.3, 60.2, 58.1, 57.9, 57.7, 52.7, 52.1, 47.8, 43.5, 43.0, 41.6, 41.3, 39.7, 39.3, 38.5, 37.0, 35.9, 35.3, 31.6, 25.3, 20.4, 20.2, 14.6; MS m/z (ESI): 632 (M+H, 100), 634 (M+2+H, 37).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.40–4.49 (m, 2H), 7.17–7.35 (m, 3H), 6.92–7.10 (m, 2H), 5.39–5.55 (m, 1H), 5.08–5.20 (m, 1H), 4.65–4.74 (m, 1H), 4.15–4.30 (m, 1H), 3.99–4.12 (m, 1H), 3.42–3.69 (m, 1H), 2.89–3.40 (m, 7H), 2.81 (s, 0.6H), 2.74 (s, 2.4H), 2.26–2.42 (m, 1H), 1.69–2.10 (m, 3H), 1.15–1.62 (m, 2H), 0.69–1.13 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 171.00, 171.88, 171.82, 171.68, 170.92, 169.80, 169.52, 169.40, 165.47, 162.78, 162.30, 162.23, 139.44, 133.85, 133.81, 133.66, 132.82, 132.71, 132.62, 132.49, 132.38, 132.24, 132.00, 117.03, 116.79, 116.51, 61.32, 60.05, 57.59, 57.55, 52.11, 52.68, 52.11, 47.76, 43.34, 42.98, 42.90, 39.53, 39.34, 38.54, 37.08, 35.96, 35.11, 34.85, 31.59, 26.82, 25.29, 20.45, 20.25, 14.66; (ESMS) m/z 634.2, 636.2, 638.2 (M+H)+, Cl2 isotope pattern.


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, MeOD, Rotamers) □ 7.40–4.49 (m, 2H), 7.17–7.35 (m, 3H), 6.92–7.10 (m, 2H), 5.39–5.55 (m, 1H), 5.08–5.20 (m, 1H), 4.65–4.74 (m, 1H), 4.15–4.30 (m, 1H), 3.99–4.12 (m, 1H), 3.42–3.69 (m, 1H), 2.89–3.40 (m, 7H), 2.81 (s, 0.6H), 2.74 (s, 2.4H), 2.26–2.42 (m, 1H), 1.69–2.10 (m, 3H), 1.15–1.62 (m, 2H), 0.69–1.13 (m, 5H); 13C NMR (75 MHz, CDCl3) □ 171.00, 171.88, 171.82, 171.68, 170.92, 169.80, 169.52, 169.40, 165.47, 162.78, 162.30, 162.23, 139.44, 133.85, 133.81, 133.66, 132.82, 132.71, 132.62, 132.49, 132.38, 132.24, 132.00, 117.03, 116.79, 116.51, 61.32, 60.05, 57.59, 57.55, 52.11, 52.68, 52.11, 47.76, 43.34, 42.98, 42.90, 39.53, 39.34, 38.54, 37.08, 35.96, 35.11, 34.85, 31.59, 26.82, 25.29, 20.45, 20.25, 14.66; (ESMS) m/z 634.2, 636.2, 638.2 (M+H)+, Cl2 isotope pattern.


The following are non-limiting examples of compounds encompassed by the second aspect of Category II.

  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-4-chlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-methyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide;
  • Pyrrolidine-2-carboxylic acid [2-[2-allyl-4-(1-methylcarbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide; and
  • Pyrrolidine-2-carboxylic acid [2-[2-iso-propyl-4-(1-methyl-carbamoyl-3,4-dichlorophenyl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide.


The following are examples of compounds wherein R7a is hydrogen:


1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-[4-(2-naphthalen-2-yl-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.74–7.88 (m, 3H), 7.68 (s, 1H), 7.18–7.54 (m, 11H), 5.04–5.28 (m, 1H), 4.78–4.88 (m, 1H), 4.31–4.47 (m, 2H), 3.88–4.25 (m, 3H), 3.31–3.66 (m, 2H), 2.70–3.30 (m, 8H), 0.92–1.86 (m, 4H), 0.76–0.88 (m, 3H); 13C NMR (75 MHz, MeOD, Rotamers) δ 171.62, 171.43, 170.49, 169.64, 169.30, 168.78, 137.81, 137.65, 136.72, 136.15, 135.42, 135.35, 134.70, 134.51, 134.22, 132.70, 132.42, 132.05, 131.91, 130.35, 130.10, 129.77, 129.64, 129.54, 129.16, 129.10, 129.04, 128.86, 128.78, 128.09, 127.62, 127.56, 127.01, 59.98, 56.94, 56.66, 56.54, 51.82, 51.65, 49.74, 49.41, 48.28, 47.22, 45.78, 41.56, 39.92, 38.68, 37.21, 36.17, 35.42, 34.66, 34.43, 31.38, 31.29, 20.74, 20.50, 14.56; MS (ESMS) m/z 637.3, 639.3 (M+H)+, Cl isotope pattern.


2-Amino-N-{1-(4-chlorobenzyl)-2-[4-(2-naphthalen-2-yl-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-2-methyl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.74–7.88 (m, 3H), 7.67 (s, 1H), 7.36–7.54 (m, 3H), 7.14–7.35 (m, 4H), 5.07–5.18 (m, 0.7H), 4.93–5.03 (m, 0.3H), 4.73–4.84 (m, 1H), 4.30–4.41 (m, 0.3H), 3.86–4.09 (m, 2H), 3.38–3.64 (m, 2H), 2.68–3.26 (m, 6H), 0.91–1.82 (m, 10H), 0.74–0.88 (m, 3H); 13C NMR (75 MHz, MeOD, Rotamers) δ 173.35, 172.93, 171.80, 171.61, 170.49, 168.78, 137.78, 137.65, 136.84, 136.36, 135.41, 135.35, 134.61, 134.43, 134.22, 132.58, 132.29, 130.30, 130.03, 129.64, 129.53, 129.10, 128.86, 128.75, 127.62, 127.55, 127.00, 59.97, 58.48, 56.90, 52.24, 49.69, 49.24, 48.24, 47.22, 41.58, 39.36, 38.25, 37.19, 36.08, 35.45, 34.64, 34.43, 24.57, 24.42, 24.25, 20.71, 20.52, 14.56; MS (ESMS) m/z 563.3, 565.3 (M+H)+, Cl isotope pattern.

  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-dichlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl)-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3–2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3–2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide; and
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorophenyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide.


The following are non-limiting examples of analogs wherein R7a and R7b are each hydrogen and R8 units are selected from the group consisiting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and naphth-2-yl.

  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-{4-[2-(3,4-dichlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(2-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide;
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(3-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide; and
  • Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-{4-[2-(4-chlorobenzyl)-ethyl)-3-oxo-2-cyclopropylmethyl-piperazin-1-yl]-2-oxo-ethyl}-amide.


A further iteration of this aspect comprises compounds having the formula:




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wherein R is a substituted or unsubstituted aryl as defined herein above and non-limiting examples of R1, R7a, and R8 are provided herein above in Table IV, said compounds comprising Q units selected from the group consisting of —H, —OCH3, —NH2, —NHCH3, and N(CH3)2.


Non-limiting examples of this iteration of aspect two of Category II include:


[2-{4-[2S-(4-Chlorophenyl)-1-isopropylcarbamoyl-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-1R-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester: 1H NMR (MeOH, 300 MHz) δ 7.49–7.38 (m, 2H), 7.33–7.24 (m, 2H), 7.23–7.14 (m, 2H), 7.06–6.92 (m, 2H), 5.44–5.29 (m, 1H), 4.95–4.74 (m, 1H), 4.73 (t, 1H, J=6.62 Hz), 4.07–3.90 (m, 1H), 3.62 (s, 3H), 3.37–2.87 (m, 8H), 1.29–1.04 (m, 8H), 0.89–0.67 (m, 3H); MS (ESI) m/z 623 (M+H+, 100).


[2-{4-[2S-(4-Chlorophenyl)-1-isopropylcarbamoyl-ethyl]-3-oxo-2S-propyl-piperazin-1-yl}-1R-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester: 1H NMR (MeOH, 300 MHz) δ 7.19–7.03 (m, 6H), 6.94–6.80 (m, 2H), 5.26 (q, 2H, J=5.90 Hz), 4.68 (t, 1H, J=7.31 Hz), 4.58 (t, 1H, J=6.65 Hz), 3.94–3.78 (m, 4H), 3.48 (s, 3H), 3.24–2.74 (m, 4H), 1.93 (s, 6H), 1.14–1.03 (m, 2H), 1.01 (q, 2H, J=3.357 Hz), 0.63 (s, 3H); MS (ESI) m/z 589 (M+H+, 100).


A third aspect of Category II comprises analogs with a scaffold having the formula:




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wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R5b, R7a, R8 and Q are defined herein below in Table V.














TABLE V





No.
R1
R5b
Q
R7a
R8







428
methyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


429
ethyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


430
propyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


431
iso-propyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


432
cyclopropyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


433
cyclopropylmethyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


434
allyl
—H
—H
—C(O)NH2
naphthylen-2-ylmethyl


435
methyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


436
ethyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


437
propyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


438
iso-propyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


439
cyclopropyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


440
cyclopropylmethyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


441
allyl
—H
—CH3
—C(O)NH2
naphthylen-2-ylmethyl


442
methyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


443
ethyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


444
propyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


445
iso-propyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


446
cyclopropyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


447
cyclopropylmethyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


448
allyl
—H
—H
—C(O)NH2
(3,4-dichlorophenyl)methyl


449
methyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


450
ethyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


451
propyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


452
iso-propyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


453
cyclopropyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


454
cyclopropylmethyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


455
allyl
—H
—CH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


456
methyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


457
ethyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


458
propyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


459
iso-propyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


460
cyclopropyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


461
cyclopropylmethyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


462
allyl
—H
—H
—C(O)NHCH3
naphthylen-2-ylmethyl


463
methyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


464
ethyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


465
propyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


466
iso-propyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


467
cyclopropyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


468
cyclopropylmethyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


469
allyl
—H
—CH3
—C(O)NHCH3
naphthylen-2-ylmethyl


470
methyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


471
ethyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


472
propyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


473
iso-propyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


474
cyclopropyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


475
cyclopropylmethyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


476
allyl
—H
—H
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


477
methyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


478
ethyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


479
propyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


480
iso-propyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


481
cyclopropyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


482
cyclopropylmethyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


483
allyl
—H
—CH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


484
methyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


485
ethyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


486
propyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


487
iso-propyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


488
cyclopropyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


489
cyclopropylmethyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


490
allyl
—H
—CH3
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


491
methyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


492
ethyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


493
propyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


494
iso-propyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


495
cyclopropyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


496
cyclopropylmethyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


497
allyl
—H
—H
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


498
methyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


499
ethyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


500
propyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


501
iso-propyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


502
cyclopropyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


503
cyclopropylmethyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


504
allyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


505
methyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


506
ethyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


507
propyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


508
iso-propyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


509
cyclopropyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


510
cyclopropylmethyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


511
allyl
—H
—CH3
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl









The compounds which comprise the third aspect of Category II can be suitably prepared according to Scheme VI below from final analogs which comprise Category I, for example, utilizing as starting materials compounds such as 18 which corresponds to analog 9 from Table I.




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EXAMPLE 6
2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide (24)

Preparation of 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-cyclopropyl-methyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide (24): To a solution of 2-[4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (100 mg, 0.155 mmol) and triethylamine (20 mg, 0.2 mmole) in CH2Cl2 (5 mL) at 0° C. is added dropwise acetyl chloride (13.4 mg, 0.17 mmole). The reaction is allowed to warm to room temperature and stirred 1 hour. The reaction is diluted with CH2Cl2 (10 mL) and extracted with water then brine, dried and concentrated in vacuo to afford a residue which is purified over silica gel to afford the desired product. 13C NMR (CDCl3, 75 MHz), 170.12, 169.90, 169.82, 169.49, 169.35, 167.70, 134.07, 133.67, 132.57, 131.64, 128.65, 127.83, 127.80, 127.70, 127.51, 127.23, 127.15, 126.64, 126.15, 115.87, 115.79, 115.60, 115.51, 58.65, 57.40, 56.61, 56.43, 50.61, 50.09, 42.76, 41.96, 41.55, 39.84, 38.39, 37.77, 36.89, 34.65, 34.09, 26.59, 23.26, 23.07, 7.20, 7.12, 4.83, 4.69, 4.45; MS, (ES-MS) m/z 573 (M+1).


Other non-limiting examples of this aspect of Category II include:


2-{4-[2-Acetylamino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl-N-methyl-3-naphthalen-2-yl-propionamide. 1H-NMR (CDCl3, 300 MHz) 7.82˜7.90 (m, 3H), 7.2˜7.55 (m, 6H), 7.00˜7.14 (m, 2H), 5.12˜5.18 (m, 1H), 2.80˜3.45 (m, 8H), 2.60˜2.70 (m, 3H), 2.10˜2.15 (m, 5H), 1.75˜1.90 (m, 3H), 1.59˜1.70 (m, 2H), 1.0˜1.30 (m, 2H), 0.80˜0.90 (m, 3H); MS (ES-MS) m/z 547 (M+1).


2-{4-[3-(4-Chlorophenyl)-2-(2-methylamino-acetylamino)-propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) 7.00˜8.00 (m, 11H), 5.01 (m, 1H), 4.64 (t, 1H, J=6.6 Hz), 2.60–3.80 (m, 17H), 1.20˜1.40 (m, 2H), 0.31 (t, J=7.2 Hz, 3H); MS (ES-MS) m/z 592 (M+1).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-cyclopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.84–7.71 (m, 3H), 7.56 (s, 1H), 7.51–7.39 (m, 3H), 7.15–7.04 (m, 2H), 6.99–6.88(m, 2H) 6.50 (t, 1H, J=11.67 Hz) 6.29 (d, 1H, J=2.37 Hz) 5.32 (q, 1H, J=6.70 Hz) 5.04–4.87 (m, 1H) 4.73 (t, 1H, J=6.65 Hz) 3.53–3.14 (m, 4H) 2.97–2.63 (m, 4H) 1.99 (s, 1H) 1.95 (s, 3H) 1.14 (p, 3H, J=18.236 Hz) 0.88–0.58(m, 4H) 0.49 (q, 4H, J=10.755 Hz).


2-{3-Cyclopropylmethyl-4-[3-(R)-(4-fluorophenyl)-2-(S)-(2-methylamino-acetylamino)-propionyl]-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, 1H, J=7.40) 7.78–7.61 (m, 3H) 7.53 (s, 1H) 7.46–7.33 (m, 3H) 7.06 (q, 2H, J=5.33 Hz) 6.97(q, 2H, J=3.14 Hz) 6.91–6.79 (m, 1H) 6.33–6.18 (m, 1H) 5.42 (q, 1H, J=6.86 Hz) 5.29 (q, 1H, J=6.88 Hz) 5.03 (d, 1H, J=7.75 Hz) 4.92 (d, 1H, J=7.49 Hz) 4.73 (t, 1H, 5.32) 3.37–2.94 (m, 2H) 2.60–2.70 (m,2H) 2.63(d, 3H, J=6.07 Hz) 1.32–1.21 (m, 1H) 1.08 (d, 2H, J=6.59 Hz) 1.00 (q, 4H, J=6.570 Hz) 0.21–0.18 (m, 4H) MS (ESI) m/z 629 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-butyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.61–7.46 (m, 3H) 7.38–7.32 (m, 1H) 7.28–7.17 (m, 2H) 7.09–7.04 (m, 1H) 6.89–6.79 (m, 2H) 6.72–6.64 (m, 2H) 5.13–5.02 (m, 1H) 4.79–4.63 (m, 1H) 4.53 (t, 1H, J=6.64 Hz) 3.47–3.31 (m, 2H) 3.25–2.84 (m, 4H) 2.69–2.46 (m, 4H) 1.67 (s, 3H) 1.26–1.12 (m, 2H) 1.07–0.89 (m, 4H) 0.67–0.58 (m, 3H) 0.53–0.40 (m, 2H) 0.31–0.23 (m, 3H) MS (ESI) m/z 602 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-benzyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.78–7.61 (m, 3H) 7.53–7.46 (m, 1H) 7.42–7.32 (m, 2H) 7.16–7.08 (m, 3H) 7.03–6.98 (m, 3H) 6.33–6.25 (m, 1H) 6.00 (d, 1H, J=8.24) 5.32–5.21 (m, 2H) 4.70 (t, 1H, J=6.70 Hz) 4.42–4.08 (m, 2H) 3.61–3.05 (m, 6H) 2.82 (d, 2H, J=7.21 Hz) 1.79 (s, 3H) 1.21–1.08 (m, 2H) 0.73–0.58 (m, 2H) 0.49–0.38 (m, 3H) MS (ESI) m/z 636 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.69–7.58 (m, 3H) 7.46 (s, 1H) 7.38–7.29 (m, 2H) 7.01–6.89 (m, 3H) 6.84–6.75 (m, 2H) 6.13 (d, 1H, J=8.85 Hz) 5.70 (d, 1H, J=7.29 Hz) 4.98–4.82 (m, 2H) 4.74 (t, 1H, J=5.82 Hz) 3.99–3.83 (m, 2H) 3.78–3.59 (m, 2H) 3.33–3.09 (m, 4H) 2.95–2.72 (m, 2H) 1.75 (s, 3H) 1.48 (s, 6H) 1.06–0.92 (m, 5H) MS (ESI) m/z 600 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-chlorophenyl)-propionyl]-3-(S)-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.68–7.52 (m, 3H) 7.43 (s, 1H) 7.36–7.24 (m, 3H) 6.92 (d, 2H, J=19.21 Hz) 6.83 (d, 2H, J=14.83 Hz) 6.07 (d, 1H, J=7.72 Hz) 5.72 (d, 1H, J=6.89 Hz) 5.17–5.09 (m, 2H) 4.69 (t, 1H, J=5.92 Hz) 3.94–3.70 (m, 1H) 3.33–3.01 (m, 4H) 2.92–2.58 (m, 4H) 1.75 (s, 2H) 1.71 (s, 3H) 1.43 (s, 6H) 1.08–0.83 (m, 5H) MS (ESI) m/z 617 (M+H+, 100).


Preparation of 2-{4-[2-Acetylamino-3-(R)-(4-chlorophenyl)-propionyl]-3-(S)-isobutyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.83–7.71 (m, 3H) 7.58 (s, 1H) 7.53–7.41 (m, 3H) 7.33–7.19 (m, 2H) 7.10–6.98 (m, 2H) 6.05 (d, 1H, J=8.20 Hz) 5.94 (d, 1H, J=7.75 Hz) 5.37–5.19 (m, 1H) 4.12–3.98 (m, 2H) 3.62–3.49 (m, 1H) 3.38–3.04 (m, 4H) 2.91 (d, 2H, J=7.22 Hz) 2.84–2.74 (m, 2H) 1.94 (s, 1H) 1.89 (s, 2H) 1.18–1.04 (m, 6H) MS (ESI) m/z 618 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-chlorophenyl)-propionyl]-3-(S)-isopropyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.71 (m, 3H) 7.58 (s, 1H) 7.49–7.41 (m, 2H) 7.28–7.18 (m, 3H) 7.14–7.06 (m, 2H) 6.07–5.94 (m, 2H) 5.14–4.99 (m, 1H) 5.09–4.99 (m, 1H) 4.68 (d, 1H, J=7.050 Hz) 4.08–3.96 (m, H) 3.78–3.57 (m, 2H) 3.49–3.21 (m, 4H) 3.09–2.84 (m, 2H) 2.76–2.68 (m, 1H) 1.86 (s, 3H) 1.64 (s, 6H) 1.09 (t, 6H, J=6.577 Hz) MS (ESI) m/z 605 (M+H+, 100).


2-Amino-N-[2-[2-(S)-cyclopropylmethyl-4-(1-isopropylcarbamoyl-2-(S)-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1R-(4-fluorobenzyl)-2-oxo-ethyl]-2-ethyl-butyramide: 1H NMR (CDCl3, 300 MHz) δ 7.81–7.67 (m, 3H) 7.58 (s, 1H) 7.49–7.38 (m, 2H) 7.22–7.12 (m, 1H) 7.08–7.00 (m, 1H)6.99–6.87 (m, 3H) 6.32 (t, 1H, J=9.62 Hz) 5.5 (q, 1H, J=6.23 Hz) 5.38 (q, 1H, J=6.89 Hz) 4.81 (t, 1H, J=5.31 Hz) 4.11–3.89 (m, 1H) 3.61–3.04 (m, 4H) 3.00–2.91 (m, 2H) 2.89–2.78 (m, 2H) 2.03–1.74 (m, 6H) 1.42–1.30 (m, 1H) 1.22–0.98 (m, 6H) 0.95–0.75 (m, 6H) 0.10–0.03 (m, 5H) MS (ESI) m/z 671 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-3-(S)-(1H-indol-2-yl)-N-methyl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 7.56 (d, 1H, J=7.72 Hz), 7.49–6.86 (m, 8H), 6.47 (d, 1H, J=8.02 Hz), 5.37–5.24 (m, 1H), 5.02–4.91 (m, 1H), 4.79 (t, 1H, J=6.53 Hz), 3.32–3.08 (m, 4H), 2.93 (d, 2H, J=7.31 Hz), 2.84 (d, 2H, J=4.76 Hz), 2.76 (d, 3H, J=4.61 Hz), 1.95 (s, 3H), 1.39–1.22 (m, 2H), 0.94–0.80 (m, 2H), 0.78–0.68 (m, 3H).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.84–7.68 (m, 3H), 7.56 (s, 1H), 7.52–7.41 (m, 2H), 7.16–6.88 (m, 5H), 6.37–6.20 (m, 1H), 6.01–5.80 (m, 1H), 5.34–5.23 (m, 1H), 5.03–4.72 (m, 2H), 4.16–3.94 (m, 1H), 3.50–3.07 (m, 4H), 2.91 (d, 2H, J=7.50 Hz), 2.85 (d, 2H, J=6.95 Hz), 1.92 (s, 3H), 1.18–1.02 (m, 10H), 0.54–0.45 (m, 3H); MS (ESI) m/z 589 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-isobutyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.83–7.70 (m, 3H) 7.56 (s, 1H) 7.52–7.40 (m, 2H) 7.14–7.02 (m, 3H) 6.98–6.86 (m, 2H) 6.05 (d, 1H, J=8.30 Hz) 5.94 (d, 1H, J=7.57 Hz) 5.35–5.20 (m, 2H) 5.00–4.82 (m, 1H) 4.10–3.85 (m, 1H) 3.58–3.05 (m, 4H) 2.94–2.83 (m, 2H) 2.79–2.68 (m, 2H) 1.88 (s, 3H) 1.61 (s, 6H) 1.17–0.59 (m, 9H) MS (ESI) m/z 603 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-isopropyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.70 (m, 3H) 7.58 (s, 1H) 7.49–7.41 (m, 2H) 7.17–7.08 (m, 2H) 7.02–6.88 (m, 3H) 6.29 (d, 1H, J=7.65 Hz) 6.03 (t, 1H, J=9.05 Hz) 5.34–5.19 (m, 1H) 5.09–4.98 (m, 1H) 4.67 (d, 1H, J=6.97 Hz) 4.24–3.93 (m, 2H) 3.78–3.53 (m, 2H) 3.41–3.13 (m, 2H) 3.09–2.69 (m, 2H) 2.02–1.83 (m, 4H) 1.66 (s, 6H) 1.12–1.02 (m, 6H) MS (ESI) m/z 589 (M+H+, 100).


Cyclopropanecarboxylic acid [2-[2-(S)-cyclopropylmethyl-4-(S)-(1-isopropylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(R)-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CDCl3, 300 MHz) δ 7.812–7.68 (m, 3H) 7.58 (s, 1H) 7.52–7.39 (m, 3H) 7.34–7.28 (m, 2H) 7.14–7.01 (m, 2H) 6.97–6.87 (m, 2H) 6.18 (d, 1H, J=8.36 Hz) 5.86 (d, 1H, J=7.37) 5.12–4.95 (m, 1H) 4.87 (t, 1H, J=5.87) 4.10–3.92 (m, 1H) 3.84–3.70 (m, 1H) 3.42–2.97 (m, 4H) 3.05–2.94 (m, 2H) 2.90–2.79 (m, 2H) 1.73 (s, 8H) 1.24–1.02 (m, 5H) 0.92–0.81 (m, 1H) 0.78–0.66 (m, 2H) MS (ESI) m/z 627 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-chlorophenyl)-propionyl]-3-(S)-cyclohexylmethyl-2-oxo-piperazin-1-yl}-N-isopropyl-3S-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.70 (m, 3H) 7.58 (s, 1H) 7.54–7.39 (m, 2H) 7.36–7.19 (m, 3H) 7.12–7.05 (m, 2H) 6.06 (d, 1H, J=8.17 Hz) 5.97 (d, 1H, J=7.55 Hz) 5.36–5.17 (m, 2H) 5.00–4.84 (m, 1H) 4.10–3.92 (m, 1H) 3.39–3.02 (m, 4H) 2.91 (d, 2H, J=7.13 Hz) 2.88–2.75 (m, 2H) 1.87 (s, 3H) 1.73–1.40 (m, 11H) 1.18–0.87 (m, 11H) MS (ESI) m/z 660 (M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-butyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.75–6.70 (m, 11H) 6.14 (d, 1H, J=7.56 Hz) 5.94 (d, 1H, J=8.13 Hz) 5.29–5.10 (m, 1H) 4.95–4.60 (m, 2H) 4.09–3.82 (m, 1H) 3.60–3.04 (m, 4H) 2.91–2.58 (m, 4H) 1.89–1.41 (m, 5H) 1.22–0.46 (m, 13H) MS (ESI) m/z 603(M+H+, 100).


2-{4-[2-Acetylamino-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-3-(S)-propyl-piperazin-1-yl}-N-methyl-3-(S)-naphthalen-1-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 8.04–6.70 (m, 11H) 6.65 (d, 1H, J=11.0 Hz) 6.34 (d, 1H, J=8.21 Hz) 5.46–5.32 (m, 1H) 5.01–4.88 (m, 1H) 4.62 (t, 1H, J=6.86 Hz) 3.70–3.42 (m, 4H) 3.32–3.12 (m, 4H) 2.92 (d, 3H, J=7.74 Hz) 2.86–2.72 (m, 3H) 2.66 (d, 2H, J=4.60 Hz) 1.28–0.78 (m, 4H).


2-{3-(S)-Cyclopropylmethyl-4-[3-(R)-(4-fluorophenyl)-2-(2-methoxy-acetylamino)-propionyl]-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.80–7.68 (m, 3H) 7.58 (s, 1H) 7.48–7.41 (m, 2H) 7.17–7.05 (m, 3H) 6.98–6.88 (m, 2H) 5.89 (t, 2H, J=9.03 Hz) 5.44 (q, 1H, J=12.67 Hz) 5.32–5.23 (m, 1H) 5.11–5.01 (m, 2H) 4.86 (t, 1H, J=5.82 Hz) 4.12–3.98 (m, 2H) 3.87–3.72 (m, 2H) 3.37 (d, 3H, J=7.07 Hz) 3.08–2.98 (m, 2H) 2.91–2.82 (m, 2H) 2.04 (s, 6H) 1.41–1.29 (m, 2H) 1.17 (d, 4H, J=6.083 Hz) 1.09 (t, 1H, J=5.435 Hz) MS (ESI) m/z 630 (M+H+, 100).


2-{3-(S)-Cyclopropylmethyl-4-[2-(2,2-difluoro-acetylamino)-3-(R)-(4-fluorophenyl)-propionyl]-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.81–7.68 (m, 3H) 7.58(s, 1H) 7.49–7.41 (m, 2H) 7.14–7.02 (m, 3H) 6.98–6.89 (m, 2H) 5.98(d, 1H, J=1.22 Hz) 5.81 (d, H, J=1.09 Hz) 5.63 (d, 1H, J=1.06 Hz) 5.38 (q, 1H, J=6.63 Hz) 5.28 (q, 1H, J=7.00 Hz) 5.12–4.93 (m, 1H) 4.84 (t, 1H, J=5.96 Hz) 3.54–3.15 (m, 4H) 3.07–2.98 (m, 2H) 2.97–2.84 (m, 2H) 1.16 (d, 2H, J=6.552 Hz) 1.08 (t, 6H, J=5.804 Hz) 0.18–0.12 (m, 5H) MS (ESI) m/z 636 (M+H+, 100)


2-{4-[2-(2-Cyano-acetylamino)-3-(R)-(4-fluorophenyl)-propionyl]-3-(S)-cyclopropyl-methyl-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.76–7.58 (m, 3H) 7.53 (s, 1H) 7.44–7.30 (m, 3H) 7.28–7.18 (m, 2H) 7.03(q, 2H, J=5.31 Hz) 6.95–6.78 (m, 1H) 6.28(d, 1H, J=7.72 Hz) 6.18 (d, 1H, J=7.56 Hz) 5.45 (q, 1H, J=6.84 Hz) 5.12–4.98 (m, 1H) 4.72 (t, 1H, J=5.55 Hz) 3.94–3.77 (m, 2H) 3.48–2.65 (m, 6H) 1.49(s, 6H) 1.38 (s, 6H) 1.05 (t, 1H, J=6.552 Hz) 0.97 (q, 4H, J=3.723 Hz) MS (ESI) m/z 643 (M+H+, 100).


2-{3-Cyclopropylmethyl-4-[3-(R)-(4-fluorophenyl)-2S-(2-methylamino-acetylamino)-propionyl]-2-oxo-piperazin-1-yl}-N-isopropyl-3-(S)-naphthalen-2-yl-propionamide: 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, 1H, J=7.40) 7.78–7.61 (m, 3H) 7.53 (s, 1H) 7.46–7.33 (m, 3H) 7.06 (q, 2H, J=5.33 Hz) 6.97(q, 2H, J=3.14 Hz) 6.91–6.79 (m, 1H) 6.33–6.18 (m, 1H) 5.42 (q, 1H, J=6.86 Hz) 5.29 (q, 1H, J=6.88 Hz) 5.03 (d, 1H, J=7.75 Hz) 4.92 (d, 1H, J=7.49 Hz) 4.73 (t, 1H, 5.32) 3.37–2.94 (m, 2H) 2.60–2.70 (m, 2H) 2.63(d, 3H, J=6.07 Hz) 1.32–1.21 (m, 1H) 1.08 (d, 2H, J=6.59 Hz) 1.00 (q, 4H, J=6.570 Hz) 0.21–0.18 (m, 4H) MS (ESI) m/z 629 (M+H+, 100).


The fourth aspect of Category II comprises analogs with a scaffold having the formula:




embedded image



wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R4, R5b, R8 and Q are defined herein below in Table VI.















TABLE VI





No.
R1
R7a
R5a
R5b
Q
R8







511
methyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


512
ethyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


513
propyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


514
iso-propyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


515
cyclopropyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


516
cyclopropylmethyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


517
allyl
—CO2H
—H
—H
—NH2
naphthylen-2-ylmethyl


518
methyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


519
ethyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


520
propyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


521
iso-propyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


522
cyclopropyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


523
cyclopropylmethyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


524
allyl
—CO2H
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


525
methyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


526
ethyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


527
propyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


528
iso-propyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


529
cyclopropyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


530
cyclopropylmethyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


531
allyl
—CO2H
—H
—H
—NH2
(4-chlorophenyl)methyl


532
methyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


533
ethyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


534
propyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


535
iso-propyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


536
cyclopropyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


537
cyclopropylmethyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


538
allyl
—CO2CH3
—H
—H
—NH2
naphthylen-2-ylmethyl


539
methyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


540
ethyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


541
propyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


542
iso-propyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


543
cyclopropyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


544
cyclopropylmethyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


545
allyl
—CO2CH3
—H
—H
—NH2
(3,4-dichlorphenyl)methyl


546
methyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


547
ethyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


548
propyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


549
iso-propyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


550
cyclopropyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


551
cyclopropylmethyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


552
allyl
—CO2CH3
—H
—H
—NH2
(4-chlorophenyl)methyl


553
methyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


554
ethyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


555
propyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


556
iso-propyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


557
cyclopropyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


558
cyclopropylmethyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


559
allyl
—CO2H
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


560
methyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


561
ethyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


562
propyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


563
iso-propyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


564
cyclopropyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


565
cyclopropylmethyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


566
allyl
—CO2H
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


567
methyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


568
ethyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


569
propyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


570
iso-propyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


571
cyclopropyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


572
cyclopropylmethyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


573
allyl
—CO2H
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


574
methyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


575
ethyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


576
propyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


577
iso-propyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


578
cyclopropyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


579
cyclopropylmethyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


580
allyl
—CO2CH3
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


581
methyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


582
ethyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


583
propyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


584
iso-propyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


585
cyclopropyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


586
cyclopropylmethyl
—CO2CH3
—CH3
—CH3
—NH2
(3,4-dichlorphenyl)methyl


587
methyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


588
ethyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


589
propyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


590
iso-propyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


591
cyclopropyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


592
cyclopropylmethyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


593
allyl
—CO2CH3
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl









The compounds which comprise the fourth aspect of Category II can be suitably prepared starting with intermediate compounds such as 15 as outlined in Scheme VII herein below.




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EXAMPLE 7
2-{4-[2-(2-Amino-2-mmethyl-propionylamino)-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (27)

Preparation of 2-{4-[2-amino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester (25): To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 15, (531 mg, 0.842 mmol) is dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 10 mL). The reaction mixture was stirred for 3 minutes, concentrated in vacuo and the residue purified by reverse phase HPLC to afford the TFA salt of the desired compound.


Preparation of 2-{4-[2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester (26): To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester, 25, (37 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (202 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.


Preparation of 2-{4-[2-(2-amino-2-mmethyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (27): To a solution of 2-{4-[2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 26, (45 mg, 0.063 mmol) is dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 2 mL). The reaction mixture is stirred for 3 minutes, concentrated in vacuo and the residue purified by reverse phase HPLC to afford the TFA salt of the desired compound.


A further iteration of the fourth aspect of Category II relates to R7a units which are carboxy, which can be prepared from the corresponding esters as outlined in Scheme VIII.




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EXAMPLE 8
2-{4-[2-(2-Amino-2-mmethyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (28)

Preparation of 2-{4-[2-(2-amino-2-mmethyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (28): To a solution of 2-{4-[2-(2-amino-2-mmethyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 27, (518 mg, 0.842 mmol) in a mixture of THF (5 mL)/CH3OH (1 mL)/H2O (2 mL) is added LiOH (100 mg, 4.17 mol). The reaction mixture is stirred for 4 hours, acidified with 1N HCl to pH 3 and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give the free acid in quantitative yield.


A fifth aspect of Category II melanocortin receptor ligands relate to compounds wherein R5a and R5b are taken together to form a carbocyclic or heterocyclic ring having from 3 to 10 atoms, said compounds having the general scaffold with the formula:




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wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R5a/R5b ring, R7a, R8 and Q are defined herein below in Table VII. 1,2,3,4-THN-2-yl stands for 1,2,3,4-tetrahydronaphthylen-2-yl.














TABLE VII





No.
R1
R5a/R5b ring
Q
R7a
R8







594
—CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


595
—CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


596
—CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


597
—CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


598
—CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


599
—CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


600
—CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


601
—CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


602
—CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


603
—CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


604
—CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


605
—CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


606
—CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


607
—CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


608
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


609
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


610
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


611
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


612
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


613
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


614
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


615
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


616
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


617
—CH2CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


618
—CH2CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


619
—CH2CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


620
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


621
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


622
—CH2(C3H5)
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


623
—CH2(C3H5)
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


624
—CH2(C3H5)
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


625
—CH2(C3H5)
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


626
—CH2(C3H5)
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


627
—CH2(C3H5)
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


628
—CH2(C3H5)
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


629
—CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


630
—CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


631
—CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


632
—CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


633
—CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


634
—CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


635
—CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


636
—CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


637
—CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


638
—CH2CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


639
—CH2CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


640
—CH2CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


641
—CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


642
—CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


643
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


644
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


645
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


646
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


647
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


648
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


649
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


650
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


651
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


652
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


653
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


654
—CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


655
—CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


656
—CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


657
—CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


658
—CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


659
—CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


660
—CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


661
—CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


662
—CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


663
—CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


664
—CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


665
—CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


666
—CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


667
—CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


668
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


669
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


670
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


671
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


672
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


673
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


674
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


675
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


676
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


677
—CH2CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


678
—CH2CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


679
—CH2CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


680
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


681
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


682
—CH2(C3H5)
cyclopropyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


683
—CH2(C3H5)
cyclobutyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


684
—CH2(C3H5)
cyclopentyl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


685
—CH2(C3H5)
azetidin-2-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


686
—CH2(C3H5)
azetidin-3-yl
—NH2
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


687
—CH2(C3H5)
cyclopropyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


688
—CH2(C3H5)
cyclobutyl
—NHCH3
—C(O)NHCH3
(3.4-dichlorophenyl)methyl


689
—CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


690
—CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


691
—CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


692
—CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


693
—CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


694
—CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


695
—CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


696
—CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


697
—CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


698
—CH2CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


699
—CH2CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


700
—CH2CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


701
—CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


702
—CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


703
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


704
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


705
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


706
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


707
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


708
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


709
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


710
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


711
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


712
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl


713
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3.4-dichlorophenyl)methyl









The compounds which comprise the fifth aspect of Category II melanocortin receptor ligands can be suitably prepared starting with intermediate compound 18 as outline in Scheme IX herein below.




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EXAMPLE 9
1-Amino-cyclopropane carboxylic acid [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazin-1-yl]-1-(4fluorobenzyl)-2-oxo-ethyl]-amide (30)

Preparation of {1-[2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]cyclopropyl}-carbamic acid tert-butyl ester (29): To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (62 mg, 0.12 mmol) in DMF (2 mL) are added tert-butoxycarbonylamino-cyclopropanecarboxylic acid (28.5 mg, 0.14 mmol), 1-hydroxybenzotriazole (36 mg, 0.266 mmol), N-methylmorpholine (74 mg, 0.74 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (29 mg, 0.15 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.


Preparation of 1-amino-cyclopropane carboxylic acid [2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazin-1-yl]-1-(4fluorobenzyl)-2-oxo-ethyl]-amide (30): {1-[2-[2-cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]cyclopropyl}-carbamic acid tert-butyl ester, 29, (63 mg, 0.09 mmol) was dissolved into a mixture of TFA/anisole/CH2Cl2 (45:5:50, 2 mL). The reaction mixture is stirred for 1 hour, concentrated in vacuo and the residue purified by reverse phase HPLC purification to afford the TFA salt of the desired compound.


N-[2-{4-[2-(4-Chlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide HCl: 1H NMR (CD3OD, with rotamers) δ 9.01 (br s, 2H), 8.32 (d, 2H, J=5.7 Hz), 7.39–7.31 (m, 6H), 7.04 (m, 2H), 5.44 (m, 1H), 5.31 (m, 1H), 4.75 (m, 1H), 4.05 (m, 1H), 3.77–3.51 (m, 2H), 3.30–3.00 (m, 5H), 2.83, 2.74 (2 singlets, 3H, CH3NHC(O), rotamers), 1.44–0.83 (m, 7H); 13C NMR (CD3OD, with rotamers) δ 172.0, 171.9, 171.4, 171.3, 170.7, 169.0, 165.0, 164.4, 162.8, 150.6, 145.0, 137.1, 137.0, 133.9, 133.7, 133.5, 133.3, 132.6, 132.5, 132.1, 132.0, 131.7, 129.8, 126.5, 126.0, 116.8, 116.7, 116.5, 116.4, 73.7, 72.6, 62.3, 59.8, 58.0, 57.4, 53.4, 52.8, 49.7, 48.1, 43.9, 43.3, 42.7, 42.6, 39.5, 38.8, 38.1, 36.7, 35.5, 35.3, 34.7, 26.6, 20.2, 20.0, 19.7, 14.3, 9.4; MS m/z (ESI): 608 (M+H, 60), 610 (M+2+H, 20), 630 (M+Na+H, 100).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.26 (m, 6H), 7.03 (m, 2H), 5.48 (m, 1H), 5.06 (m, 1H), 4.67 (m, 1H), 3.99 (m, 1H), 3.61 (m, 1H), 3.26–2.93 (m, 6H), 2.80, 2.74 (2 singlets, 3H, CH3NHC(O), rotamers), 1.62 (m, 1H), 1.39–1.20 (m, 5H), 0.79 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 171.9, 171.7, 171.5, 170.7, 170.5, 169.0, 164.2, 162.6, 162.5, 136.8, 133.8, 133.6, 132.3, 131.9, 131.8, 129.6, 116.6, 116.5, 116.3, 116.2, 59.6, 57.5, 57.4, 57.2, 52.6, 52.1, 42.9, 42.5, 39.3, 38.3, 37.6, 36.5, 36.3, 35.5, 35.0, 34.8, 26.4, 20.1, 19.8, 14.2, 13.5, 13.3, 13.2; MS m/z (ESI): 586 (M+H, 80), 588 (M+2+H, 28), 338 (100).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.16 (m, 6H), 6.90 (m, 2H), 5.36 (m, 1H), 4.98 (m, 1H), 4.55 (m, 1H), 3.88 (m, 1H), 3.48 (m, 1H), 3.15–2.83 (m, 6H), 2.68, 2.62 (2 singlets, 3H, CH3NHC(O), rotamers), 2.58, 2.55 (2 singlets, 3H, CH3NHC(CH2—CH2)C(O), rotamers), 1.52 (m, 1H), 1.36 (m, 3H), 1.11 (m, 2H), 0.68 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 171.9, 171.8, 171.6, 171.4, 170.5, 169.5, 164.2, 162.6, 162.4, 162.1, 136.8, 133.8, 133.7, 132.4, 132.3, 131.9, 131.8, 129.6, 116.6, 116.4, 116.3, 116.1, 59.7, 57.4, 57.2, 52.6, 52.0, 43.6, 43.0, 42.5, 39.2, 38.3, 37.6, 36.5, 35.5, 35.0, 34.8, 32.8, 32.7, 26.4, 20.1, 19.8, 14.2, 13.4, 13.2; MS m/z (ESI): 600 (M+H, 80), 602 (M+2+H, 37).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(2,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, 300 MHz, with rotamers) δ 7.28 (m, 1H), 7.11 (m, 4H), 6.87 (m, 2H), 5.43 (m, 1H), 4.92 (m, 1H), 4.53 (m, 1H), 3.88 (m, 1H), 3.38 (m, 1H), 3.26–3.06 (m, 3H), 2.83 (m, 3H), 2.63, 2.58 (2 singlets, 3H, CH3NHC(O), rotamers), 1.45 (m, 1H), 1.23–1.17 (m, 5H), 0.65 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 171.7, 171.5, 171.3, 171.2, 170.7, 170.4, 168.9, 164.2, 162.7, 162.6, 162.5, 136.4, 136.3, 134.8, 134.7, 133.9, 133.7, 133.6, 133.5, 132.3, 131.9, 130.3, 128.4, 119.0, 116.5, 116.4, 116.3, 116.2, 134.1, 1332.7, 132.6, 132.3, 130.7, 128.8, 117.0, 116.8, 116.5, 59.6, 57.1, 56.0, 52.6, 52.1, 43.3, 42.9, 42.3, 38.9, 38.2, 37.6, 36.6, 36.3, 35.4, 32.7, 32.3, 26.5, 20.1, 19.9, 14.2, 13.6, 13.4, 13.3; MS m/z (ESI): 620 (M+H, 60), 602 (M+2+H, 40).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(2,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-3-oxo-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.22 (m, 1H), 7.04 (m, 4H), 6.81 (m, 2H), 5.35 (m, 1H), 4.88 (m, 1H), 4.46 (m, 1H), 3.76 (m, 1H), 3.29–3.00 (m 4H), 2.77 (m, 3H), 2.73, 2.57 (2 singlets, 3H, CH3NHC(O), rotamers), 2.51, 2.46 (2 singlets, 3H, CH3NHC(CH2—CH2)C(O), rotamers), 1.41 (m, 1H), 1.25 (m, 3H), 1.08 (m, 2H), 0.59 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 172.0, 171.0, 170.0, 165.5, 162.2, 136.7, 135.2, 135.1, 134.1, 132.8, 132.7, 130.7, 128.8, 116.8, 116.5, 60.1, 57.5, 56.5, 52.9, 52.4, 44.143.8, 42.7, 38.1, 37.0, 35.9, 33.3, 32.7, 26.9, 20.5, 20.3, 14.6, 13.8; MS m/z (ESI): 634 (M+H, 100), 606 (M+2+H, 70).


2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) 7.00˜8.00 (m, 11H), 4.57 (m, 1H), 4.10˜4.30 (m, 2H), 2.60˜3.75 (m, 12H), 1.85 (bs, 2H), 1.25˜1.50 (m, 2H), 0.40˜0.60 (m, 3H); MS (ES-MS) m/z 592 (M+1).


The following are non-limiting examples of analogs according to Category II of the melanocortin receptor ligands of the present invention.


N-(2-Fluoroethyl)-2-{4-[3-(4-fluorophenyl)-2-methylamino-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, MeOD, Rotamers) δ 8.38–8.86 (m, 0.3H), 7.77–7.89 (m, 3H), 7.62–7.72 (m, 1H), 7.38–7.58 (m, 3H), 7.15–7.30 (m, 2H), 6.94–7.11 (m, 2H), 5.52–5.65 (m, 1H), 4.20–4.68 (m, 4H), 3.16–3.68 (m, 8H), 2.56–3.04 (m, 5H), 0.72–1.14 (m, 2H), 0.18–0.66 (m, 5H); 13C NMR (75 MHz, MeOD, Rotamers) δ 172.23, 169.85, 167.14, 162.39, 135.65, 135.03, 134.10, 132.90, 132.79, 130.66, 129.45, 128.91, 128.83, 128.63, 128.32, 127.57, 127.04, 117.10, 116.81, 84.29, 82.07, 59.79, 58.32, 57.87, 43.58, 42.84, 41.42, 41.14, 39.31, 37.13, 36.63, 35.69, 35.47, 32.34, 19.78, 13.86; MS (ESMS) m/z 565.4 (M+H)+.


N-(2-Fluoroethyl)-2-{4-[3-(4-fluorophenyl)-2-isopropylamino-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 8.36–8.46 (m, 0.6H), 7.70–7.92 (m, 3H), 7.34–7.65 (m, 4H), 7.16–7.33 (m, 2H), 6.94–7.10 (m, 2H), 5.57 (dd, J=12.3, 5.1 Hz, 1H), 4.71 (dd, J=10.8, 5.1 Hz, 1H), 4.46–4.60 (m, 2H), 4.32–4.44 (m, 1H), 3.36–3.37 (m, 5H), 3.09–3.32 (m, 4H), 2.90–3.04 (m, 1H), 2.50–2.64 (m, 1H), 1.23–1.36 (m, 6H), 0.60–1.14 (m, 2H), 0.14–0.58 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 172.49, 170.00, 167.27, 165.92, 162.65, 135.88, 135.28, 134.36, 133.28, 133.18, 132.65, 132.54, 130.90, 129.71, 129.18, 129.04, 128.88, 128.54, 127.85, 127.32, 117.81, 117.30, 117.01, 84.56, 82.34, 58.54, 58.36, 56.22, 51.53, 43.77, 43.26, 41.67, 41.40, 38.02, 35.96, 35.77, 20.62, 20.02, 19.24, 14.10; MS (ESMS) m/z 593.3 (M+H)+.


2-{4-[2-Ethylamino-3-(4-fluorophenyl)-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-N-(2-fluoroethyl)-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 8.60–8.70 (m, 0.15H), 8.37–8.48 (m, 0.75H), 7.75–7.89 (m, 3H), 7.61–7.74 (m, 1H), 7.36–7.59 (m, 3H), 7.14–7.30 (m, 2H), 6.94–7.11 (m, 2H), 5.60 (dd, J=11.8, 5.0 Hz, 1H), 4.17–4.72 (m, 4H), 3.12–3.70 (m, 7H), 2.74–3.08 (m, 3H), 2.50–2.64 (m, 1H), 1.30 (t, J=7.4 Hz, 3H), 0.12–1.16 (m, 7H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 172.48, 170.06, 168.18, 167.47, 165.91, 163.15, 162.65, 135.85, 135.28, 134.37, 133.16, 133.06, 132.56, 132.46, 131.03, 130.99, 129.69, 129.16, 129.06, 128.87, 128.56, 127.82, 127.30, 117.83, 117.55, 117.34, 117.05, 84.55, 82.34, 59.48, 59.35, 58.64, 58.32, 58.20, 57.36, 43.57, 43.34, 43.21, 41.67, 41.39, 39.72, 37.81, 37.63, 37.01, 35.97, 35.74, 20.00, 14.10, 12.07; MS (ESMS) m/z 579.3 (M+H)+.

  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-methyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-chlorophenyl)propionyl]-3-methyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-chlorophenyl)propionyl]-3-ethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-propyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-(1-methylethyl)-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-fluorophenyl)propionyl]-3-(1-methylethyl)-2-oxo-piperazin-1-yl}-N-cyclopropyl-3-naphthalen-2-yl propionamide;
  • 2-{4-[2-Acetylamino-3-(4-chlorophenyl)propionyl]-3-propyl-2-oxo-piperazin-1-yl}-N-cyclopropyl-3-naphthalen-2-yl propionamide;


The Category III melanocortin receptor ligands according to the present invention comprises the 2-hydrocarbyl-piperazines having the general scaffold with the formula:




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the first aspect of which comprises compounds having the formula:




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wherein R is a substituted phenyl unit as described herein above and non-limiting examples of R1, R7a, R8 are defined herein below in Table VIII and in the examples which follow.












TABLE VIII





No.
R1
R7a
R8







714
methyl
—C(O)NH2
naphthylen-2-ylmethyl


715
ethyl
—C(O)NH2
naphthylen-2-ylmethyl


716
propyl
—C(O)NH2
naphthylen-2-ylmethyl


717
iso-propyl
—C(O)NH2
naphthylen-2-ylmethyl


718
cyclopropyl
—C(O)NH2
naphthylen-2-ylmethyl


719
cyclopro-
—C(O)NH2
naphthylen-2-ylmethyl



pylmethyl


720
allyl
—C(O)NH2
naphthylen-2-ylmethyl


721
methyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


722
ethyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


723
propyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


724
iso-propyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


725
cyclopropyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


726
cyclopro-
—C(O)NH2
(3,4-dichlorophenyl)methyl



pylmethyl


727
allyl
—C(O)NH2
(3,4-dichlorophenyl)methyl


728
methyl
—C(O)NH2
(2-chlorophenyl)methyl


729
ethyl
—C(O)NH2
(2-chlorophenyl)methyl


730
propyl
—C(O)NH2
(2-chlorophenyl)methyl


731
iso-propyl
—C(O)NH2
(2-chlorophenyl)methyl


732
cyclopropyl
—C(O)NH2
(2-chlorophenyl)methyl


733
cyclopro-
—C(O)NH2
(2-chlorophenyl)methyl



pylmethyl


734
allyl
—C(O)NH2
(2-chlorophenyl)methyl


735
methyl
—C(O)NHCH3
naphthylen-2-ylmethyl


736
ethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


737
propyl
—C(O)NHCH3
naphthylen-2-ylmethyl


738
iso-propyl
—C(O)NHCH3
naphthylen-2-ylmethyl


739
cyclopropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


740
cyclopro-
—C(O)NHCH3
naphthylen-2-ylmethyl



pylmethyl


741
allyl
—C(O)NHCH3
naphthylen-2-ylmethyl


742
methyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


743
ethyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


744
propyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


745
iso-propyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


746
cyclopropyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


747
cyclopro-
—C(O)NHCH3
(3,4-dichlorophenyl)methyl



pylmethyl


748
allyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


749
methyl
—C(O)NHCH3
(2-chlorophenyl)methyl


750
ethyl
—C(O)NHCH3
(2-chlorophenyl)methyl


751
propyl
—C(O)NHCH3
(2-chlorophenyl)methyl


752
iso-propyl
—C(O)NHCH3
(2-chlorophenyl)methyl


753
cyclopropyl
—C(O)NHCH3
(2-chlorophenyl)methyl


754
cyclopro-
—C(O)NHCH3
(2-chlorophenyl)methyl



pylmethyl


755
allyl
—C(O)NHCH3
(2-chlorophenyl)methyl


756
methyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


757
ethyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


758
propyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


759
iso-propyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


760
cyclopropyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


761
cyclopro-
—C(O)N(CH3)2
naphthylen-2-ylmethyl



pylmethyl


762
allyl
—C(O)N(CH3)2
naphthylen-2-ylmethyl


763
methyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


764
ethyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


765
propyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


766
iso-propyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


767
cyclopropyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


768
cyclopro-
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl



pylmethyl


769
allyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


770
methyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


771
ethyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


772
propyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


773
iso-propyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


774
cyclopropyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


775
cyclopro-
—C(O)N(CH3)2
(2-chlorophenyl)methyl



pylmethyl


776
allyl
—C(O)N(CH3)2
(2-chlorophenyl)methyl


777
methyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


778
ethyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


779
propyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


780
iso-propyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


781
cyclopropyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


782
cyclopro-
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl



pylmethyl


783
allyl
—C(O)NH(CH2CH2F)
naphthylen-2-ylmethyl


784
methyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


785
ethyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


786
propyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


787
iso-propyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


788
cyclopropyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


789
cyclopro-
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl



pylmethyl


790
allyl
—C(O)NH(CH2CH2F)
(3,4-dichlorophenyl)methyl


791
methyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


792
ethyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


793
propyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


794
iso-propyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


795
cyclopropyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


796
cyclopro-
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl



pylmethyl


797
allyl
—C(O)NH(CH2CH2F)
(2-chlorophenyl)methyl


798
methyl
—C(O)NHCH3
(3-chlorophenyl)methyl


799
ethyl
—C(O)NHCH3
(3-chlorophenyl)methyl


800
propyl
—C(O)NHCH3
(3-chlorophenyl)methyl


801
methyl
—C(O)N(CH3)2
(3-chlorophenyl)methyl


802
ethyl
—C(O)N(CH3)2
(3-chlorophenyl)methyl


803
propyl
—C(O)N(CH3)2
(3-chlorophenyl)methyl


804
methyl
—C(O)NHCH3
(4-chlorophenyl)methyl


805
ethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


806
propyl
—C(O)NHCH3
(4-chlorophenyl)methyl


807
methyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


808
ethyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


809
propyl
—C(O)N(CH3)2
(4-chlorophenyl)methyl


810
methyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


811
ethyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


812
propyl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


813
methyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


814
ethyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


815
propyl
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl









The compounds of the first aspect of Category II can be suitably prepared by the procedure outlined herein below in Scheme X.




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EXAMPLE 10
2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl (38)

Preparation of 3-naphthalen-2-yl-2-[2-(2-nitro-benzenesulfonylamino)-butyryl-amino]-propionic acid methyl ester (31): 2-Amino-3-naphthen-2-yl-propionic acid methyl ester hydrochloride (1401 g, 53.2 mmol) and 2-(2-nitrobenzenesulfonyl-amino)-butyric acid (19.7 g, 68.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (13.4 g, 106.4 mmol) and 1-hydroxybenzotriazole (12.3 g, 63.9 mmol) are dissolved in anhydrous DMF (75 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (17.5 mL, 160.0 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (100 mL) and water (800 mL) are added and the organic layer is decanted. The aqueous layer is extracted with EtOAc (3×200 mL), the organic layers combined, washed with water (200 mL), dried over Na2SO4, and concentrated in vacuo to afford 26.6 g, (quantitative yield) of the desired product. 1H NMR (CDCl3, δ): 7.90 (d, J=10.2 Hz, 1H), 7.76–7.65 (m, 4H), 7.55–7.38 (m, 5H), 7.12–7.08 (m, 1H), 6.67 (d, J=11.7 Hz, 1H), 6.05 (d, J=11.7 Hz, 1H), 4.72 (quartet, J=7.3 Hz, 1H), 3.88–3.79 (m, 1H), 3.60 (s, 3H), 3.20 (double quartet, J=14.6, 7.3 Hz, 1H), 1.75–1.45 (m, 2H), 0.070 (t, J=11.7 Hz, 3H); 13C NMR, δ 175.0, 171.0,148.0, 134.0, 133.8, 133.6, 133.2, 132.9, 130.9, 130.3, 128.7, 128.4, 128.0, 127.6, 126.7, 126.3, 125.8, 59.3, 53.8, 52.9, 38.4, 36.9, 31.9, 26.8, 9.8.


Preparation of 2-[3-ethyl-4-(2-nitrobenzenesulfonyl)-2-oxo-piperazin-1yl]-3-naphthalen-2-yl-propionic acid methyl ester (32): To a solution of 3-naphthalen-2-yl-2-[2-(2-nitrobenzenesulfonylamino)-butyryl amino]-propionic acid methyl ester, 31, (26.6 g, 53.2 mmol) in anhydrous DMF (100 mL) is added 1,2-dibromoethane (100.0 g, 532.0 mmol) and potassium carbonate (66.1 g, 479.0 mmol). The reaction mixture is heated at 60° C. over night. The reaction mixture is cooled in an ice bath and the pH is adjusted to ˜3 with 1M KHSO4. The reaction mixture is extracted with EtOAc (3×300 mL). The organic layers are combined and washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo and the resulting residue is purified over silica (Hexane: EtOAc 1:1; 5% MeOH in EtOAc) to afford 27.4 g (98% yield) of the desired product. 1H NMR (CDCl3, δ): 8.02–7.90 (m, 1H), 7.84–7.70 (m, 3H), 7.64–7.58 (m, 3H), 7.55–7.50 (m, 1H), 7.50–7.40 (m, 2H), 7.30 (d, J=6.0 Hz, 1H), 5.35 (dd, J−12.0, 4.8 Hz, 1H), 4.25 (t, J=7.2 Hz, 1H, 3.78–3.68 (m, 1H), 3.65 (s, 3H), 3.52 (dd, J=15.0, 6.0 Hz, 1H), 3.30–3.10 (m, 4H), 1.58–1.50 (m, 1H), 1.42–1.38 (m, 1H), 0.56 (t, J=7.2 Hz, 3H); 13C NMR, δ 170.5, 167.8, 148.0, 134.2, 134.0, 133.6, 133.1, 132.6, 132.3, 130.9, 128.5, 127.9, 127.7, 127.5, 126.9, 126.5, 126.0, 124.6.


Preparation of 2-[3-ethyl-4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester (33): To a solution of 2-[3-ethyl-4-(2-nitrobenzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 32, (5.3 g, 10. mmol) in anhydrous THF (10 mL) is added 1.0 M borane-tetrahydrofuran complex (32.0 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and the solution is allowed to stir for twenty minutes. Additional methanol (6 mL) is added and the reaction mixture is allowed to warm to room temperature. The solvent is removed in vacuo and the product is purified over silica (EtOAc/Hexane: 1:1) to afford 4.1 g (68% yield) of the desired product. 1H NMR (CDCl3, δ): 8.04–7.98m, (1H), 7.80–7.72 (m, 3H), 7.61–7.52 (m, 4H), 7.45–7.38 (m, 2H), 7.28 (d, J=9.6 Hz, 1H), 3.78 (t, J=6.0 Hz, 1H), 3.64 (d, J=11.0 Hz, 1H), 3.50 (s, 3H), 3.48 (t, J=7.2 Hz, 1H), 3.24–3.10 (m, 2H), 3.10–2.95 (m, 1H), 2.90 (t, J=11.0 Hz, 1H), 2.66 (d, J=2.4 Hz), 2.38–2.20 (m, 1H), 1.61–1.48 (m, 1H), 1.48–1.32 (m, 1H), 0.58 (t, J=9.6 Hz, 3H); ); 13C NMR, δ 171.7, 148.0, 135.9, 134.2, 133.7, 132.4, 132.0, 130.9, 128.0, 127.7, 127.6, 126.2, 125.6, 124.4, 69.0, 56.4, 53.8, 51.3, 47.0, 41.9, 35.2, 22.2, 10.7.


Preparation of 2-(3-ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester (34): To a solution of 2-[3-ethyl-4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 33, (4.1 g, 8.0 mmol) in anhydrous DMF (40 mL) is added potassium carbonate (6.7 g, 48.2 mmol) and 4-mercaptophenol (3.0 g, 24.1 mmol). The reaction mixture is stirred for six hours at room temperature, cooled in a ice bath and the pH adjusted to ˜3 with 1M HCl. The reaction mixture is extracted with Et2O (4×100 mL), the organic layers combined and extracted with 1M HCl (100 mL). The organic layers are then discarded. The aqueous layers were combined and cooled in ice bath and pH was adjusted to ˜10 with K2CO3. The aqueous layer is extracted with EtOAc (4×125 mL) and dried over Na2SO4. The combined organic layers are concentrated in vacuo to afford 2.1 g (80% yield) of the desired product. 1H NMR (CDCl3, δ): 7.84–7.75 (m, 3H), 7.70 (s, 1H), 7.50–7.38 (m, 2H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 3.60(s, 3H), 3.55–3.50 (m, 1H), 3.30–3.24 (m, 1H), 3.18–3.08 (m, 1H), 3.05–2.75 (m, 5H), 2.70–2.55 (m, 1H), 2.50 (dd, J=10.4, 4.1 Hz, 1H), 2.04 (t, J=10.4 Hz, 1H), 1.52–1.32 (M, 2H), 1.00 (t, J=8.3 Hz, 3H); 13C NMR, δ 171.8, 135.9, 133.7, 132.4, 128.1, 128.0, 127.9, 127.8, 126.1, 125.6, 120.8, 70.0, 57.3, 54.3, 52.9, 51.3, 46.4, 35.7, 27.5, 10.6.


Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (35): 2-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (2.1 g, 6.4 mmol) and N-Boc-D-4-fluorophenylalanine (1.9 g, 6.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (4.9 g, 12.9 mmol) are dissolved in anhydrous DMF (20 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.75 mL, 6.8 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (300 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×150 mL). The combined organic layers are washed with water (100 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue is purified over silica (EtOAc/Hexane, 1:2) to afford 3.5 g (91% yield) of the desired product. 1H NMR (CDCl3, δ): 7.82–7.75 (m, 3H), 7.62 (s, 1H), 7.52–7.40 (M, 2H), 7.34 (m, 1H), 7.22–7.25 (m, 2H), 7.02–6.92 (m2H), 5.75–5.62 (M, 1H), 5.18 (d, J=7.7 Hz, 0.5H), 4.90 (quartet, J=7.7 Hz, 1H), 4750–4.62 (m, 0.5H), 4.50–4.25 (m, 1H), 3.64 (d, J=9.7 Hz, 3H), 3.58–3.38 (m, 1.5H), 3.30–2.90 (m, 6H), 2.90–2.70 (m, 1H), 2.62–2.25 (d, J=11.6 Hz, 1H), 2.15–2.00 (m, 1H), 1.78–1.50 (m, 1.5H), 1.42 (s, 9H), 1.35–1.20 (m, 1H), 0.6 (t, J=9.7 Hz, 2H); 13C NMR, δ 174.2, 171.6, 171.0, 170.2, 164.0, 160.2, 156, 135.7, 133.7, 132.4, 131.4, 131.3, 128.1, 127.8, 127.6, 127.5, 126.2, 125.7, 115.7, 115.5, 115.4, 115.3, 79.9, 68.9, 68.7, 55.9, 54.1, 53.7, 51.4, 51.2, 51.0, 47.5, 46.6, 40.1, 39.1, 38.1, 35.4, 28.5, 22.9, 21.9, 10.6, 10.0


Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (36): LiOH (0.61 g, 25.5 mmol) is added to a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 35, (3.5 g, 5.9 mmol) in THF/H2O (2:1, 36 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in a ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The organic layers are combined and concentrated in vacuo to afford 3.4 g (98% yield) of the desired product.


Preparation of [2-[4-(1-carbamoyl-2-naphthalen-2-yl-ethyl)-2-ethyl-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (37): To solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 36, (0.3 g, 0.5 mmol) and 2-(1-oxy-pyridine-2-yl)-1,1,3,3-tetramethylisothiouronium tetrafluoroborate (TOTT) (0.24 g, 0.8 mmol) in DMF (2.0 mL) are added ammonium chloride (0.06 g, 1.0 mmol) and DIEA (0.2 mL, 1.0 mmol). The reaction mixture is stirred at room temperature for 1 hour then a saturated solution of ammonium chloride (30 mL) is added. The reaction mixture is extracted with EtOAc (3×30 mL), then the combined organic layers are washed with 2M HCl (2×10 mL), water (2×10 mL), a saturated solution of sodium bicarbonate (2×10 mL), water (2×10 mL) and dried over Na2SO4. The solution is concentrated in vacuo to afford 0.26 g (87% yield) of the desired product. 1H NMR (CDCl3, δ): 7.75–7.55 (m, 4H), 7.38–7.20 (m ,3H), 7.10–7.00 (m, 2H), 6.90–6.80 (m, 2H), 6.40–6.00 (m, 1H), 5.55–5.25 (m, 1H), 4.45–4.18 (m, 1H), 3.60–2.00 (m, 10H), 1.80–1.32 (m, 2H), 1.32–1.18 (m, 11H), 0.70–0.55 (m, 3H); 13C NMR, δ 175.0, 172.0, 171.0, 170.0, 164.0, 160.0, 155.2, 137.3, 133.8, 132.6, 132.4, 131.5, 131.4, 131.3, 131.2, 131.1, 128.4, 128.0, 127.8, 126.4, 125.8, 116.0, 115.8, 115.7, 115.6, 115.4, 80.4, 80.0, 70.6, 70.3, 60.7, 55.5, 51.8, 51.4, 51.1, 50.8, 50.4, 41.9, 40.2, 39.2, 38.0, 37.9, 32.6, 28.6, 23.3, 22.4, 21.4, 14.5, 10.9, 10.3.


Preparation of 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl (38): [2-[4-(1-carbamoyl-2-naphthalen-2-yl-ethyl)-2-ethyl-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 37, (0.26 g, 0.5 mmol) is dissolved in 4M HCl in dioxane (7 mL). The reaction mixture is stirred for 60 minutes, then 1,2-dichloroethane (7 mL) is added. The solution is concentrated in vacuo to afford 0.24 g (quantitative yield) of the desired product.


Other iterations of R7a can be obtained from Intermediate 36 as outlined in Scheme XI.




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EXAMPLE 11
2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide Hydrochloride (41)

Preparation of [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (40): To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 36, (1.7 g, 3.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (2.0 g, 3.8 mmol) in anhydrous dichloromethane (10 mL) are added 2 M methyl amine solution in THF (1.5 mL, 3.0 mmol) and triethyl amine (1.0 mL, 7.4 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (200 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product is purified over silica (EtOAc/hexane, 1:1) to afford 1.3 g (73% yield) of the desired product. 1H NMR (CDCl3, 300 MHz, δ): 7.75–7.65 (m, 3H), 7.55 (s, 1H), 7.39–7.29 (m, 2H), 7.29–7.2 (m, 1H), 7.10–7.02 (m, 2H), 6.90–6.82 (m, 2H), 6.51–6.30 (m, 1H), 5.31 (d, J=10.4 Hz, 1H), 4.85–4.15 (m, 2.5H), 3.55–3.12 (m, 3H), 3.00–2.05 (m, 10H), 1.85–1.45 (m, 10H), 0.7 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.0, 172.0, 171.0, 170.0, 163.9, 160.6, 155.2, 137.4, 133.8, 132.4, 131.5, 131.4, 131.3, 131.2, 128.4, 128.0, 127.8, 126.4, 125.8, 116.0, 115.7, 115.4, 80.0, 70.9, 70.7, 60.7, 55.4, 52.1, 51.2, 51.0, 50.5, 49.8, 41.9, 40.2, 39.4, 38.0, 32.4, 28.6, 26.3, 23.3, 22.3, 21.4, 14.5, 10.8, 10.3.


Preparation of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide Hydrochloride (41): [2-[2-Ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 40, is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 1 hour, then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1.1 g (99% yield) of the desired product.


Scheme XII illustrates the replacement of 4-fluorophenyl as the R unit with 4-chlorophenyl.




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EXAMPLE 12
2-{4-[2-amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl (45)

Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (42): 2-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (0.52 g, 1.6 mmol) and Boc-D-4-chlorophenylalanine (0.5 g, 1.7 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.2 g, 3.2 mmol) are dissolved in anhydrous DMF (20 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.35 mL, 3.2 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×50 mL). All organic layers are combined and washed with water (20 mL), and dried over Na2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product. 1H NMR (CDCl3, δ): 7.70–7.65 (m, 3H), 7.52 (s, 1H), 7.35–7.32 (m, 2H), 7.22–7.13 (m, 4H), 7.07–7.02 (m, 2H), 5.59 (dd, J=13.5, 8.7 Hz, 1H), 4.74 (q, J=7.5 Hz, 1H), 2.28–4.21 (m, 1H), 3.53 (d, J=12.3 Hz, 3H), 3.42–3.08 (m, 2H), 3.04–2.81 m, 4H), 2.80 (s, 1H), 2.75 (s, 3H), 2.64–2.60 (m, 1H), 2.46 (t, J=10.5 Hz, 1H), 2.20–2.05 (m, 1H), 1.55–1.40 (m, 1H), 1.18 (s,9H), 0.54–0.47 (m, 2H); 13C NMR, δ 171.6, 170.5, 170.0, 162.9, 155.0, 150.7, 135.8, 135.2, 133.6, 132.8, 132.4, 131.1, 131.2, 128.9, 128.7, 128.6, 128.0, 127.7, 127.6, 126.2, 125.6, 124.5, 120.4, 79.7, 68.9, 60.5, 55.8, 53.7, 51.4, 51.0, 47.4, 47.0, 41.5, 40.0, 39.0, 38.7, 38.0, 36.6, 35.3, 35.0, 31.6, 28.4, 22.8, 21.8, 21.1, 14.3,10.5, 10.0.


Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl}-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid (43): LiOH (0.2 g, 7.9 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 42, (1.0 g, 1.6 mmol) in THF/H2O (2/1, 30 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×75 mL) and dried over Na2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product.


Preparation of {1-(4-chlorobenzyl)-2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl]-carbamic acid tert-butyl ester (44): To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 43, (1.0 g, 1.6 mmol) and PyBOP (1.1 g, 2.0 mmol) in anhydrous dichloromethane (10 mL) are added 2 M methyl amine solution in THF (0.9 mL, 1.6 mmol) and triethyl amine (0.6 mL, 3.9 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (100 mL) are added, the organic layer is decanted and the aqueous layer is extracted with EtOAc (3×75 mL). All organic layers are combined and washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo and purified over silica (EtOAc/Hexane, 1:1) to provide 1.0 g (quantitative yield) of the desired product. 1H NMR (CDCl3, 300 MHz): δ 7.72–7.50 (m, 4H), 7.29–7.14 (m, 4H), 7.10–7.04 (m, 2H), 7.00–6.97 (m, 3H), 5.60–5.51 (m, 1H), 4.73–4.66 (m, 1H), 4.30–4.11 (m, 1H), 3.45–3.26 (m, 2H), 3.15–3.05 (m, 1H), 2.86–2.79 (m, 3H), 2.75–2.59 (m, 5H), 2.56–2.47 (m, 1H), 2.43–2.29 (m, 1H), 2.05–2.01 (m,1H), 1.61 (s, 9H), 0.64–0.54 (m, 2); 13C NMR, (CDCl3, 75 MHz): δ 171.9, 170.3, 170.0, 155.0, 137.4, 137.2 135.3, 135.1, 133.6, 132.8, 132.2, 131.2, 131.1, 131.0, 128.7, 128.6, 128.4, 127.9, 127.8, 127.6, 127.5, 126.4, 126.0, 125.4, 124.7, 118.6, 110.4, 79.6, 69.9, 55.4, 50.9, 50.2, 46.4, 39.8, 37.9, 32.0, 32.6, 28.4, 26.5, 26.1, 23.0, 22.0, 10.6, 10.0.


Preparation of 2-{4-[2-amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl (45): {1-(4-Chlorobenzyl)-2-[2-ethyl-4-(1-methylcarbamo yl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl]-carbamic acid tert-butyl ester, 44, (1.0 g, 1.6 mmol) is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 60 minutes then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1 g (quantitative yield) of the desired product.


The following are non-limiting examples of analogs which comprise the first aspect of Category III according to the present invention.


2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, ppm, CD3OD), rotamers: δ 7.78–7.76, m, 3H; 7.65, s, 1H; 7.43–7.31, m, 5H; 7.11–7.15, m, 2H; 4.72–4.67, m, 0.5H, 4.54–4.49, m, 1H; 4.34–4.29, m, 0.5H; 3.64–3.54, m, 1H; 3.42–3.31, m, 3H; 3.26–2.98, m, 7H; 2.88–2.81, m, 1H; 2.71–2.58, m, 5H; 1.58–1.23, m, 2H; 1.08, m, 2H; 0.78–0.72, m, 3H. Carbon 13NMR (300 MHz, ppm, CD3OD), rotamers: δ 171.10, 170.57, 166.91, 164.36, 161.12, 135.57, 135.05, 133.79, 132.66, 131.78, 131.66, 131.54, 131.44, 130.00, 127.82, 127.74, 127.42, 127.29, 125.95, 125.89, 125.48, 125.37, 116.01, 115.80, 115.51, 54.31, 52.91, 52.08, 50.90, 50.60, 49.84, 40.98, 37.92, 37.11, 36.31, 34.33, 34.29, 31.86, 30.99, 24.70, 19.17, 18.99, 12.80, 12.86. MS(ESI) m/e 505 [M+1].


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz): δ with rotamers 7.34–7.08 (m, 8H), 4.72–4.37 (m, 2H), 3.68–3.41 (m, 2H), 3.23–2.84 (m, 8H), 2.67, 2.62 (2 singlets, 3H, CH3NHC(O), rotamers), 2.40–1.68 (m, 1H), 1.49 (m, 2H), 1.17 (m, 2H), 0.90 (m, 3H); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.0, 172.0, 169.0, 166.0, 162.8, 162.7, 162.3, 138.3, 137.6, 134.1, 133.8, 133.4, 133.3, 133.2, 133.1, 132.3, 131.6, 129.9, 129.8, 117.6, 117.4, 117.3, 117.1, 112.3, 71.1, 70.9, 55.8, 54.3, 53.6, 52.5, 52.2, 51.2, 50.3, 38.7, 37.9, 34.9, 33.5, 32.6, 26.3, 20.8, 20.6, 14.6, 14.5; MS m/z (ESI): 489 (M+H, 100), 491 (M+2+H, 37).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2-chlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.21–6.94 (m, 8H), 4.53–4.13 (m, 2H), 3.39–3.26 (m, 1H), 3.04–2.57 (m, 7H), 2.51, 2.49 (2 singlets, 3H, CH3NHC(O), rotamers), 2.36 (m, 2H), 1.98–1.47 (m, 1H), 1.31–1.11 (m, 2H), 0.95 (m, 2H), 0.67 (t, 3H, J=7.1 Hz); 13C NMR (CD3OD, 5 MHz with rotamers) δ 173.2, 173.0, 168.3, 166.0, 162.7, 137.8, 137.6, 135.6, 133.4, 133.3, 133.2, 133.1, 131.6, 130.9, 129.7, 129.6, 128.3, 117.6, 117.4, 117.3, 117.1, 114.1, 69.4, 69.2, 56.2, 54.6, 53.6, 52.5, 52.1, 51.9, 43.2, 39.9, 38.8, 38.0, 33.5, 32.5, 26.2, 20.8, 20.6, 14.7; MS m/z (ESI): 489 (M+H, 100), 491 (M+2+H, 37).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3-chlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.22–6.96 (m, 8H), 4.93–4.21 (m, 2H), 3.50–3.13 (m, 2H), 2.97–2.79 (m, 6H), 2.57, 2.53 (2 singlets, 3H, CH3NHC(O), rotamers), 2.45 (m, 2H), 2.12–1.55 (m, 1H), 1.37(m, 2H), 1.03 (m, 2H), 0.79 (t, 3H, J=7.1 Hz); 13C NMR (CD3OD, 75 MHz with rotamers) δ 172.7, 172.4, 168.5 166.0, 162.7, 142.5, 142.0, 135.5, 135.4, 133.4, 133.3, 133.1, 133.0, 131.6, 131.2, 130.8, 129.1, 128.1, 127.9, 117.6, 117.4, 117.3, 117.1, 71.0, 70.8, 56.0, 54.6, 53.7, 52.5, 52.2, 51.7, 42.9, 39.7, 38.7, 37.9, 35.4, 35.2, 33.5, 32.6, 26.2, 20.8, 20.6, 14.7, 14.6; MS m/z (ESI): 489 (M+H, 100), 491 (M+2+H, 37).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2,4-dichlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.44 (m, 1H), 7.33–7.14 (m, 4H), 7.12 (m, 2H), 4.69–4.25 (m, 2H), 3.56–3.40 (m, 1H), 3.29–2.78 (m, 7H), 2.70, 2.67 (2 singlets, 3H, CH3NHC(O), rotamers), 2.55–2.38 (m, 2H), 2.12–1.60 (m, 1H), 1.42–1.25 (m, 2H), 1.10 (m, 2H), 0.87 (t, 3H, J=7.3 Hz); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.0, 172.9, 168.5, 166.0, 162.7, 136.9, 136.6, 136.4, 134.5, 134.4, 133.4, 133.3, 133.2, 133.1, 131.6, 130.5, 128.5, 117.6, 117.4, 117.3, 117.2, 69.2, 68.9, 56.2, 54.7, 53.8, 52.5, 52.1, 51.9, 43.1, 39.8, 38.8, 38.0, 33.5, 32.9, 32.8, 32.6, 26.2, 20.8, 20.6, 14.7,14.6; MS m/z (ESI): 523 (M+H, 100), 525 (M+2+H, 70).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-(2-fluoroethyl)-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.40–7.17 (m, 8H), 4.76–4.29 (m, 4H), 3.69–3.37 (m, 4H), 3.25–2.88 (m, 4H), 2.75–2.34 (m, 2H), 1.92 (m, 2H), 1.63–1.18 (m, 3H), 1.24 (m, 2H), 0.96 (t, 3H, J=7.2 Hz); 13C NMR (CD3OD, 75 MHz with rotamers) δ 172.6, 172.0, 168.5, 166.0, 162.7, 162.4, 138.6, 138.2, 133.9, 133.7, 133.3, 133.1, 132.3, 131.6, 129.8, 117.6, 117.4, 117.1, 84.5, 82.3, 71.0, 70.9, 55.9, 54.6, 53.6, 52.5, 51.6, 47.8, 42.8, 41.3, 41.0, 39.6, 38.6, 37.9, 35.1, 34.7, 33.6, 32.7, 27.8, 27.7, 20.8, 20.7, 14.7, 14.6; MS m/z (ESI): 521 (M+H, 60), 523 (M+2+H, 20), 258 (100).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.865 (t, 3H, J=6.9 Hz), 1.128 (m, 2H), 1.411 (m, 2H), 2.681, 2.719 (2 singlets, 3H, CH3NHC(O), rotamers), 2.856 (m, 3H), 3.072 (m, 5H), 3.338 (m, 3H), 3.529 (d, 1H, J=12.9), 4.465 (d, 1H, J=12.9), 4.515 (m, 2H), 4.705 (t, 1H, J=7.2), 7.103 (m, 4H), 7.300 (m, 4H); 19F NMR (282 MHz, CD3OD with rotamers) δ 42.462, 46.229, 46.726; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.9, 164.8, 162.7, 161.4, 133.3, 133.1, 133.0, 129.8, 125.5, 117.5, 117.3, 117.2, 117.0, 116.5, 116.2, 69.9, 69.6, 56.2, 54.6, 53.7, 52.4, 52.1, 52.0, 43.3, 40.0, 38.7, 33.4, 32.5, 29.2, 29.0, 26.3, 26.2, 20.7, 20.6, 14.7, 14.6; MS m/e 473 (M+1).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.921 (t, 3H), 1.200 (m, 2H), 1.511 (m, 2H), 2.643, 2.687 (2 singlets, 3H, CH3NHC(O), rotamers), 2.948 (m, 3H), 3.056 (m, 5H), 3.334 (m, 3H), 3.650 (d, 1H), 4.349 (d, 1H), 4.518 (m, 2H), 4.732 (t, 1H), 6.993 (m, 3H), 7.140 (m, 1H), □7.325 (m, 4H); 19F NMR (282 MHz, CD3OD with rotamers) δ 42.462, 46.229, 46.726; 13C NMR (75 MHz, CD3OD with rotamers) δ 166.2, 165.9, 162.7, 142.9, 133.3, 133.2, 133.1, 133.0, 131.6, 131.4, 131.3, 126.5, 117.6, 117.4, 117.3, 117.1, 117.0, 114.7, 114.6, 114.4, 114.3, 71.1, 70.9, 56.0, 54.5, 53.6, 52.5, 52.1, 51.8, 43.1, 39.8, 37.9, 35.5, 33.5, 32.6, 26.2, 20.8, 20.6, 14.6, 14.5; MS m/e 473 (M+1).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.91 (t, 3H, J=6.9), 1.16 (m, 2H), 1.48 (m, 2H), 2.63, 2.67 (2 singlets, 3H, CH3NHC(O), rotamers), 2.88 (m, 3H), 3.08 (m, 5H), 3.36 (m, 3H), 3.60 (d, 1H), 4.31 (d, 1H, J=12.9), 4.54 (m, 2H), 4.711 (t, 1H), 7.01 (m, 2H), 7.15 (m, 4H), 7.32 (m, 2H); 19F NMR (282 MHz, CD3OD with rotamers) δ 46.718, 47.167, 47.378; 13C NMR (75 MHz, CD3OD with rotamers) δ 166.2, 165.9, 162.7, 142.9, 133.3, 133.2, 133.1, 133.0, 131.6, 131.4, 131.3, 126.5, 117.6, 117.5, 117.4, 117.2, 117.1, 114.7, 114.6, 114.4, 114.3, 71.1, 70.9, 56.1, 54.5, 53.6, 52.5, 52.2, 51.8, 50.3, 43.0, 39.9, 37.9, 35.5, 33.5, 32.7, 26.2, 20.8, 20.6, 14.7, 14.6; MS m/e 473 (M+1).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-difluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.918 (t, 3H, J=7.2), 1.154 (m, 2H), 1.439 (m, 2H), 2.66, 2.70 (2 singlets, 3H, CH3NHC(O), rotamers), 2.871 (m, 3H), 3.160 (m, 5H), 3.34 (m, 3H), 3.590 (d, 1H, J=13.2), 4.30 (d, 1H, J=13.8), 4.52 (m, 2H), 4.713 (t, 1H), 7.00 (m, 1H), 7.155 (m, 4H), 7.32 (m, 2H); 13C NMR (75 MHz, CD3OD with rotamers) δ 165.9 162.7, 150.1, 137.9, 137.6, 133.3, 133.2, 133.1, 133.0, 131.6, 127.1, 119.5, 119.3, 118.4, 118.2, 117.6, 117.3, 117.2, 117.1, 71.1, 70.9, 56.1, 54.6, 53.7, 52.5, 52.2, 51.8, 50.2, 43.2, 38.8, 37.9, 34.9, 33.6, 32.7, 26.2, 20.8, 20.6, 14.7, 14.6; MS m/e 491 (M+1).


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.37–7.46 (m, 2H), 7.28–7.37 (m, 2H), 7.07–7.18(m, 3H), 4.73 (t, J=7.4 Hz, 1H), 4.50–4.61 (m, 1.5H), 4.26–4.38 (m, 0.5H), 3.58–3.68 (m, 0.5H), 3.38–3.47 (m, 0.5H), 3.14–3.28 (m, 1H), 2.78–3.14 (m,6H), 2.71 (s, 1.33H), 2.66 (s, 1.66H), 2.50–2.65 (m, 2H), 1.26–1.72 (m, 2H), 1.01–1.26 (m, 2H), 0.85–0.94 (m, 3H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 170.79, 170.35, 167.04, 166.95, 164.40, 161.14, 161.04, 131.89, 131.28, 131.72, 131.59, 131.49, 131.32, 130.28, 130.19, 130.14, 129.14, 116.02, 115.81, 115.72, 115.53, 69.30, 69.02, 54.46, 53.04, 52.25, 50.89, 50.57, 50.01, 41.14, 38.07, 37.20, 36.39, 33.13, 33.06, 31.94, 31.08, 24.73, 19.25, 19.06, 13.11, 13.04; MS (ESMS) m/z 523.4, 525.4, 527.6 (M+H)+, Cl2 isotope pattern.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-(2-fluoroethyl)-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.38–7.47 (m, 2H), 7.28–7.38 (m, 2H), 7.06–7.19 (m, 3H), 4.73 (t, J=7.5 Hz, 1H), 4.19–4.62 (m, 4H), 3.36–3.70 (m, 3H), 2.75–3.24 (m, 7H), 2.56–2.71 (m, 2H), 1.28–1.76 (m, 2H), 1.03–1.25 (m, 2H), 0.91 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 170.49, 169.86, 167.06, 166.98, 164.38, 161.13, 160.82, 160.32, 139.16, 138.68, 131.92, 131.78, 131.67, 131.60, 131.48, 131.34, 130.38, 130.23, 130.04, 129.17, 116.02, 115.82, 115.74, 115.53, 82.90, 80.67, 69.14, 68.95, 54.35, 53.06, 52.18, 50.91, 50.69, 49.98, 41.09, 39.76, 39.48, 37.98, 37.08, 36.38, 33.10, 32.89, 32.00, 31.14, 19.27, 19.09, 13.11, 13.03; MS (ESMS) m/z 555.4, 557.4, 559.6 (M+H)+, Cl2 isotope pattern.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-isopropyl-propionamide: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.29–7.48 (m, 4H), 7.08–7.20 (m, 3H), 4.67–4.76 (m, 0.6H), 4.49–4.59 (m, 1H), 4.26–4.37 (m, 0.4H), 3.83–3.98 (m, 1H), 3.56–3.67 (m, 0.6H), 3.40–3.49 (m, 0.4H), 2.64–3.28 (m, 8H), 2.48–2.60 (m, 1.5H), 2.25–2.38 (m, 0.5H), 1.29–1.77 (m, 2.5H), 1.07–1.24 (m, 4.5H), 0.87–1.02 (m 6H); MS (ESMS) m/z 551.4, 553.2, 555.6 (M+H)+, Cl2 isotope pattern.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-piperazin-1-yl}-N-isopropyl-3-naphthalen-2-yl-propionamide: MS (ESMS) e/z 545.5 (M+H)+


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: MS (ESMS) e/z 517.5 (M+H)+


2-{4-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methylpropionamide.


The second aspect of Category III comprises compounds having the formula:




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wherein R is a substituted phenyl unit as described herein above and non-limiting examples of R1, R5a, R5b, R7a and R8 are defined herein below in Table IX and in the examples which follow.














TABLE IX





No.
R1
R5a
R5b
R7a
R8







816
methyl
—H
—H
—NH2
naphthylen-2-ylmethyl


817
ethyl
—H
—H
—NH2
naphthylen-2-ylmethyl


818
propyl
—H
—H
—NH2
naphthylen-2-ylmethyl


819
iso-propyl
—H
—H
—NH2
naphthylen-2-ylmethyl


820
cyclopropyl
—H
—H
—NH2
naphthylen-2-ylmethyl


821
cyclopropylmethyl
—H
—H
—NH2
naphthylen-2-ylmethyl


822
allyl
—H
—H
—NH2
naphthylen-2-ylmethyl


823
methyl
—H
—H
—NH2
(2-chlorophenyl)methyl


824
ethyl
—H
—H
—NH2
(2-chlorophenyl)methyl


825
propyl
—H
—H
—NH2
(2-chlorophenyl)methyl


826
iso-propyl
—H
—H
—NH2
(2-chlorophenyl)methyl


827
cyclopropyl
—H
—H
—NH2
(2-chlorophenyl)methyl


828
cyclopropylmethyl
—H
—H
—NH2
(2-chlorophenyl)methyl


829
allyl
—H
—H
—NH2
(2-chlorophenyl)methyl


830
methyl
—H
—H
—NH2
(3-chlorophenyl)methyl


831
ethyl
—H
—H
—NH2
(3-chlorophenyl)methyl


832
propyl
—H
—H
—NH2
(3-chlorophenyl)methyl


833
iso-propyl
—H
—H
—NH2
(3-chlorophenyl)methyl


834
cyclopropyl
—H
—H
—NH2
(3-chlorophenyl)methyl


835
cyclopropylmethyl
—H
—H
—NH2
(3-chlorophenyl)methyl


836
allyl
—H
—H
—NH2
(3-chlorophenyl)methyl


837
methyl
—H
—H
—NH2
(4-chlorophenyl)methyl


838
ethyl
—H
—H
—NH2
(4-chlorophenyl)methyl


839
propyl
—H
—H
—NH2
(4-chlorophenyl)methyl


840
iso-propyl
—H
—H
—NH2
(4-chlorophenyl)methyl


841
cyclopropyl
—H
—H
—NH2
(4-chlorophenyl)methyl


842
cyclopropylmethyl
—H
—H
—NH2
(4-chlorophenyl)methyl


843
allyl
—H
—H
—NH2
(4-chlorophenyl)methyl


844
methyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


845
ethyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


846
propyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


847
iso-propyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


848
cyclopropyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


849
cyclopropylmethyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


850
allyl
—H
—H
—NH2
(2,4-dichlorophenyl)methyl


851
methyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


852
ethyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


853
propyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


854
iso-propyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


855
cyclopropyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


856
cyclopropylmethyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


857
allyl
—CH3
—CH3
—NH2
naphthylen-2-ylmethyl


858
methyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


859
ethyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


860
propyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


861
iso-propyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


862
cyclopropyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


863
cyclopropylmethyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


864
allyl
—CH3
—CH3
—NH2
(2-chlorophenyl)methyl


865
methyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


866
ethyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


867
propyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


868
iso-propyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


869
cyclopropyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


870
cyclopropylmethyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


871
allyl
—CH3
—CH3
—NH2
(3-chlorophenyl)methyl


872
methyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


873
ethyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


874
propyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


875
iso-propyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


876
cyclopropyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


877
cyclopropylmethyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


878
allyl
—CH3
—CH3
—NH2
(4-chlorophenyl)methyl


879
methyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


880
ethyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


881
propyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


882
iso-propyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


883
cyclopropyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


884
cyclopropylmethyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


885
allyl
—CH3
—CH3
—NH2
(2,4-dichlorophenyl)methyl


886
methyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


887
ethyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


888
propyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


889
iso-propyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


890
cyclopropyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


891
cyclopropylmethyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


892
allyl
—CH3
—CH3
—NHCH3
naphthylen-2-ylmethyl


893
methyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


894
ethyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


895
propyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


896
iso-propyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


897
cyclopropyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


898
cyclopropylmethyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


899
allyl
—CH3
—CH3
—NHCH3
(2-chlorophenyl)methyl


900
methyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


901
ethyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


902
propyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


903
iso-propyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


904
cyclopropyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


905
cyclopropylmethyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


906
allyl
—CH3
—CH3
—NHCH3
(3-chlorophenyl)methyl


907
methyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


908
ethyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


909
propyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


910
iso-propyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


911
cyclopropyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


912
cyclopropylmethyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


913
allyl
—CH3
—CH3
—NHCH3
(4-chlorophenyl)methyl


914
methyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


915
ethyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


916
propyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


917
iso-propyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


918
cyclopropyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


919
cyclopropylmethyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


920
allyl
—CH3
—CH3
—NHCH3
(2,4-dichlorophenyl)methyl


921
methyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


922
ethyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


923
propyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


924
iso-propyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


925
cyclopropyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


926
cyclopropylmethyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


927
allyl
—CH3
—CH3
—N(CH3)2
naphthylen-2-ylmethyl


928
methyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


929
ethyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


930
propyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


931
iso-propyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


932
cyclopropyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


933
cyclopropylmethyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


934
allyl
—CH3
—CH3
—N(CH3)2
(2-chlorophenyl)methyl


935
methyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


936
ethyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


937
propyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


938
iso-propyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


939
cyclopropyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


940
cyclopropylmethyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


941
allyl
—CH3
—CH3
—N(CH3)2
(3-chlorophenyl)methyl


942
methyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


943
ethyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


944
propyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


945
iso-propyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


946
cyclopropyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


947
cyclopropylmethyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


948
allyl
—CH3
—CH3
—N(CH3)2
(4-chlorophenyl)methyl


949
methyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


950
ethyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


951
propyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


952
iso-propyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


953
cyclopropyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


954
cyclopropylmethyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl


955
allyl
—CH3
—CH3
—N(CH3)2
(2,4-dichlorophenyl)methyl









The compounds of the second aspect of Category II can be suitably prepared by the procedure outlined herein below in Scheme XIII beginning with analogs such as compound 41.




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EXAMPLE 13
2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazine-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (47)

Preparation of {1-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl carbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (46): 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide hydrochloride, 41, (0.3 g, 0.6 mmol) and tert-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (0.12 g, 0.6 mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (0.22 g, 1.1 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) are dissolved in anhydrous DMF (2.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.2 mL, 1.7 mmol) is added. The reaction mixture is placed in refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. Solvent is removed in vacuo and the product is purified over silica (EtOAc/Hexane, 2/1) to afford 0.7 g of the desired compound. 1H NMR (CDCl3, δ): 7.80–7.58 (m, 4H), 7.42–7.22 (m, 3H), 7.20–7.00 (m, 2H), 6.98–6.50 (m, 2H), 5.40–4.98 (m, 1.5H), 4.70–3.90 (m, 1H), 3.75–3.02 (m, 3.5H), 3.00–2.56 (m, 7H), 2.42–2.35 (m, 1H), 2.18–1.95 (m, 2.5H), 1.50–1.12 (m, 18H), 0.095–0.75 (m, 3H); 13C NMR, δ 174.4, 172.1, 171.9, 170.3, 169.6, 163.7, 162.0, 154.6, 137.3, 133.7, 132.3, 131.4, 130.8, 128.1, 127.8, 127.6, 126.2, 125.6, 115.7, 115.4, 115.2, 80.0, 70.2, 56.7, 55.3, 50.9, 50.0, 49.9, 41.8, 39.5, 38.5, 37.9, 32.7, 32.4, 28.5, 28.3, 26.1, 25.5, 25.3, 23.1, 22.1, 10.6, 10.1.


Preparation of 2-{4-[2-(2-amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazine-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (47): {1-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl carbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester, 46, (0.4 g, 0.6 mmol) is dissolved in 4M hydrogen chloride in dioxane (12 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (12 mL) is added. The organic layers are concentrated in vacuo gives the crude HCl salt of product which is then purified by preparative HPLC to the TFA salt of product (0.28 g, 0.35 mmol, 62% yield). A small amount of product is converted into the free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, 300 MHz): δ 8.25–8.15 (m, 1H), 7.82–7.75 (m, 4H), 7.45–7.15 (m, 6H), 7.00–6.95 (m, 2H), 5.12–4.98 (m, 1H), 4.52 (s, 0.5H), 4.32 (d, J=8.3 Hz, 0.5H), 3.65–3.28 (m, 3H), 3.08–2.50 (m, 10H), 2.35–2.20 (m, 1H), 1.88–1.58 (m, 5H), 1.32 (d, J=3.34Hz, 3H), 1.15 (d, J=18.4 Hz, 4H), 0.8 m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 177.0, 172.3170.7, 170.0, 165.0, 161.5, 137.6, 133.9, 132.5, 131.5, 131.4, 128.4, 128.3, 128.0, 127.8, 127.7, 126.4, 125.8, 115.9, 115.7, 115.5, 70.8, 55.5, 51.3, 50.9, 49.9, 39.8, 38.1, 32.6, 29.3, 26.3, 23.3, 22.5, 10.9, 10.4; HRFAB(positive) m/e 576.3349 calculated for C33H42FN5O3 (M+H)+, Found 576.3339


The following are non-limiting examples of procedures for forming other compounds which comprise the second aspect of Category III.


Preparation of 2-{4-[2-(2-amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide: 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl (0.22 g, 0.4 mmol) and t-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (0.09 g, 0.5 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (0.17 g, 0.9 mmol) and 1-hydroxybenzotriazole (0.07 g, 0.5 mmol) are dissolved in anhydrous DMF (2.5 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.14 mL, 1.3 mmol) is added. This reaction mixture is placed in a refrigerator for overnight. EtOAc (25 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL), the organic layers combined, washed with water (2×50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.22 g (77% yield) of the desired product which is used without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.80–7.64 (m, 4H), 7.45–7.30 (m, 3H), 7.20–7.10 (2H), 6.95–6.85 (m, 2H), 6.95–6.85 (m, 2H), 6.65–632 (m, 1H), 5.50–5.02 (m, 2H), 4.78–4.00 (m, 1H), 3.70–3.10 (m, 3H), 3.02–2.64 (m, 6H), 2.50–2.35 (m, 1H), 2.15–1.76 (m, 1H), 1.55–1.21 (m, 18H), 0.75–0.65 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.5, 174.4, 174.0, 170.0, 169.8, 163.7, 160.4, 155.0, 137.0, 133.6, 132.3, 131.4, 131.3, 131.2, 131.0, 130.8, 128.1, 127.8, 127.6, 126.6, 126.2, 125.6, 125.3, 118.4, 115.8, 115.7, 115.6, 115.5, 115.2, 110.8, 80.0, 70.2, 69.9, 56.9, 56.7, 55.4, 51.5, 51.2, 51.0, 50.1, 49.9, 41.8, 39.6, 37.8, 32.6, 28.5, 28.3, 26.7, 26.0, 25.6, 23.1, 22.2, 10.7, 10.1.


The crude product obtained above (0.22 g, 0.33 mmol) is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. The solution is concentrated in vacuo to afford a residue which is purified by preparative HPLC (w/TFA for salt exchange) to give afford 0.17 g (64% yield) of the desired product. A small amount of product was converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 8.18–8.02 (m, 1H), 7.78–7.58 (m, 4H), 7.40–7.25 (2H), 7.12–7.04 (m, 2H), 6.98–6.80 (2H), 6.46 (s, 0.5H), 6.15 (s, 0.5H), 5.66–5.45 (m, 1H), 5.10–4.82 (m, 1H), 4.49 (br s, 0.5H), 4.28 (d, J=13.0 Hz, 0.5H), 3.60–3.12 (m, 3H), 300–2.58 (m, 5H), 2.51–2.39 (m, 1H), 2.28–2.00 (1H), 1.80 0 1.43 (m, m, 5H), 1.32–1.00 (m, 7H), 0.75–0.63 (m, 3H). HRFAB(positive) m/e 562.3193 calculated for C32H40FN5O3 (M+H)+, Found 562.3216.


Preparation of 2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methyl-propionamide trifluoroacetate: Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methylpropionamide trifluoroacetate (0.3 g, 0.43 mmol) and t-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (88 mg, 0.43 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (124 mg, 0.65 mmol) and 1-hydroxybenzotriazole (117 mg, 0.86 mmol) are dissolved in anhydrous DMF (2.5 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.25 mL, 2.3 mmol) is added. This reaction mixture is placed in a refrigerator for overnight. EtOAc (25 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL), the organic layers combined, washed with water (2×50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.3 g of the desired product which is used without further purification.


The crude product obtained above is dissolved in TFA/DCM/H2O (1/2/0.1, 10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. The solution is concentrated in vacuo to afford a residue which is purified by preparative HPLC (w/TFA for salt exchange) to give afford 0.167 g (59% yield) of the desired product. 1H NMR (CDCl3, 300 MHz) δ 7.45–7.41 (m, 2H0, 7.32–7.27 (m, 2H), 7.17–7.00 (m, 3H), 5.16 (t, J=8.1 Hz, 1H), 4.43 (br s, 0.5H), 4.28 (d, J=13.5 Hz, 0.5H), 3.95 (d, J=14.1 Hz, 0.5H), 3.63 (m, 0.5H), 3.42–3.21 (m, 8H), 3.22–2.81 (m, 6H), 2.84–2.66 (m, 3H), 2.52–2.43 (m, 2H), 2.20–2.13 (m, 1H), 1.82–1.66 (m, 2H), 1.60–1.42 (m, 6H), 0.80 0 0.72 (m, 3H). HRFAB(positive) m/e 594.241399 calculated for C29H38Cl2FN5O3 (M+H)+, Found 594.240266.


Preparation of 2-{4-[2-(2-amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-methyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide trifluoroacetate: 2-}4-[2-Amino-3-(4-fluoro-phenyl)-propionyl}-3-methyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide (505 mg, 0.71 mmol) and t-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (144 mg, 0.71 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (200 mg, 1.07 mmol) and 1-hydroxybenzotriazole (193 mg, 1.42 mmol) are dissolved in anhydrous DMF (2.0 mL). This reaction mixture is cool to 0° C. then N-methylmorpholine (0.3 mL, 2.7 mmol) is added. This reaction mixture is placed in a refrigerator for overnight. EtOAc (25 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL), the organic layers combined, washed with water (2×50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.31 g of the desired product which is used without further purification.


The crude product obtained above is dissolved in TFA/DCM/H2O (1/2/0.1, 8 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (8 mL) is added and the solution is concentrated in vacuo to afford a residue which is purified by preparative HPLC (w/TFA for salt exchange) to give afford 0.250 g (59% yield) of the desired product. 1H NMR (CDCl3, 300 MHz) δ 7.32–7.30 (m, 4H), 7.21–7.18 (m, 2H), 7.12–7.06 (m, 2H), 5.10 (t, J=7.8 Hz, 1H), 4.77 (br s, 0.5H), 4.40 (d, J=12.6 Hz, 0.5H), 4.10–3.95 (m, 1H), 3.61–3.42 (m, 2H), 3.35–3.32 (m, 2H), 3.26–3.25 (m, 1.5H), 3.15–2.90 (m, 4.5H), 2.78–2.56 (m, 6H), 2.00–1.95 (m, 0.5H), 1.59 (s, 4H), 1.50 (br s, 3.5H), 1.41 (br s, 1.5H), 1.27–1.23 (m, 1.5H); 13C NMR δ 174.0, 173.0, 172.0, 165.5, 162.2, 162.0, 137.2, 134.1, 132.9, 132.3, 130.0, 117.0, 116.7, 71.1, 58.5, 56.5, 52.3, 50.9, 50.2, 50.0, 46.5, 41.6, 38.8, 38.0, 35.1, 26.3, 24.6, 24.2, 17.0, 15.9. HRFAB(positive) m/e 546.264721 calculated for C28H37ClFN5O3 (M+H)+, Found 546.262559.


The following are non-limiting examples of compounds which comprise the second aspect of Category III.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-methyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz δ): 7.47–7.42 (m,2H), 7.30 (br s, 2H), 7.18–7.06 (m, 3H), 5.11–5.04 (m, 1H), 4.34–4.30 (m, 0.5H), 3.98–3.93 (m, 1H), 3.36–3.34 (m, 6H), 3.11–2.90 (m, 5.5H), 2.69–2.30 (m, 4H), 1.98–1.84 (0.5H), 1.60 (s, 3H), 1.51–1.48 (m, 3H), 1.36–1.22 (m, 3H), 1.11–1.09(m, 1.5H). HRFAB(positive) m/e 580.225749 calculated for C28H36Cl2FN5O3 (M+H)+, Found 580.225133.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3-chlorophenyl)-N-methyl-propionamide HCl. 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.23 (m, 5H), 7.12 (m, 1H), 6.99 (m, 2H), 5.08 (m, 1H), 4.54–4.29 (m, 1H), 400–3.79 (m, 1H), 3.62–3.41 (m, 6H), 3.02 (m, 4H), 2.54, 2.50 (2 singlets, 3H, CH3NHC(O), rotamers), 2.32 (m, 1H), 1.93 (m, 1H), 1.62 (m, 1H), 1.54, 1.51, 1.42 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.11 (m, 1H), 0.86 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 173.2, 172.8, 172.1, 171.7, 167.6, 164.4, 162.8, 138.1, 135.7, 133.8, 132.6, 132.5, 131.5, 130.8, 129.2, 129.0, 116.8, 116.7, 116.5, 116.4, 74.2, 70.7, 70.3, 70.2, 69.4, 69.2, 68.3, 67.5, 67.1, 64.7, 64.5, 62.8, 62.3, 62.1, 58.5, 58.3, 54.6, 53.8, 53.0, 52.2, 52.0, 50.7, 50.4, 40.0, 38.8, 37.7, 36.5, 34.4, 32.8, 32.2, 26.3, 24.4, 24.3, 24.1, 20.4, 20.2, 18.5, 15.6, 14.6, 14.1; MS m/z (ESI): 574 (M+H, 100), 608 (M+2+H, 30).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide HCl: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.46–7.31 (m, 6H), 7.15 (m, 2H), 5.27 (m, 1H), 4.70–4.45 (m, 1H), 4.14 (m, 1H), 3.87–3.51 (m, 6H), 3.21 (m, 4H), 2.73, 2.70 (2 singlets, 3H, CH3NHC(O), rotamers), 2.42 (m, 1H), 2.07 (m, 1H), 1.73, 1.60 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.25 (m, 2H), 1.05 (m, 3H); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.5, 172.0, 168.8, 165.5, 162.2, 135.8, 135.2, 134.9, 134.1, 132.8, 132.7, 132.6, 130.3, 116.8, 116.5, 74.0, 72.9, 71.0, 62.6, 58.6, 53.3, 52.3, 40.5, 39.1, 37.9, 34.5, 33.1, 32.5, 26.5, 24.6, 24.3, 20.7, 20.4, 14.4; MS m/z (ESI): 574 (M+H, 100), 576 (M+2+H, 37).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2-chlorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.83 (m, 1H), 7.47 (m, 5H), 7.25 (m, 2H), 5.35 (m, 1H), 4.84–4.52 (m, 1H), 4.19–3.90 (m, 1H), 3.76–3.62 (m, 1H), 3.48–2.92 (m, 9H), 2.86, 2.82 (2 singlets, 3H, CH3NHC(O), rotamers), 2.50–2.05 (m, 1H), 1.87 (m, 1H), 1.77, 1.70, 1.64 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.26 (m, 2H), 1.07 (m, 3H); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.0, 172.9, 172.0, 171.8, 171.5, 171.4, 165.4, 162.2, 137.3, 136.8, 135.6, 134.3, 134.1, 133.5, 133.4, 132.9, 132.8, 132.7, 131.0, 130.0, 129.8, 128.4, 128.3, 117.0, 116.7, 116.4, 69.3, 58.5, 55.9, 54.9, 53.7, 52.4, 51.0, 50.4, 42.5, 39.3, 39.2, 38.1, 33.4, 33.2, 33.0, 32.5, 26.3, 24.6, 24.5, 24.3, 20.7, 20.6, 14.6; MS m/z (ESI): 574 (M+H, 100), 576 (M+2+H, 30).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2,4-dichlorophenyl)-N-methyl-propionamide trifluoroacetate. 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.44 (m, 1H), 7.28 (m, 4H), 7.05 (m, 2H), 5.14 (m, 1H), 4.51–4.30 (m, 1H), 3.98–3.66 (m, 1H), 3.48–3.36 (m, 1H), 3.23–2.82 (m, 8H), 2.69 (2 singlets, 3H, CH3NHC(O), rotamers), 2.55 (m, 1H), 2.19–1.78 (m, 1H), 1.64 (m, 1H), 1.57 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.07 (m, 2H), 0.86 (m, 3H); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.3, 173.2, 172.8, 172.5, 172.0, 165.4, 162.2, 136.7, 136.3, 134.7, 134.6, 134.5, 134.3, 134.1, 132.9, 132.8, 132.7, 130.5, 130.4, 69.1, 69.0, 58.5, 56.1, 55.0, 53.9, 52.4, 51.3, 42.8, 39.4, 38.2, 33.1, 32.9, 32.7, 32.6, 26.3, 24.6, 24.5, 24.3, 20.6, 14.6; MS m/z (ESI): 608 (M+H, 100), 610(M+2+H, 30).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-4-(4-chlorophenyl)-N-methyl-butyramide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.13 (m, 6H), 6.87 (m, 2H), 4.96 (m, 1H), 4.43–4.10 (m, 1H), 3.85–3.70 (m, 1H), 3.53–3.10 (m, 4H), 3.01–2.81 (m, 4H), 2.63 (bs, 3H), 2.50 (m, 2H), 2.08 (m, 2H), 1.79–1.70 (m, 2H), 1.43, 1.31 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 0.96–0.74 (m, 5H), 13C NMR (CD3OD, with rotamers) δ 173.5, 172.0, 169.0, 165.4, 162.2, 140.4, 134.0, 133.7, 132.8, 132.7, 131.5, 130.1, 116.8, 116.5, 69.7, 69.3, 58.5, 54.5, 52.9, 52.3, 50.9, 40.4, 37.9, 32.4, 30.5, 30.2, 27.8, 26.7, 24.6, 24.3, 20.4, 14.4; MS m/z (ESI): 588 (M+H, 100), 590 (M+2+H, 37).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-methyl-piperazin-1-yl}-3-(2-fluorophenyl)-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.29–7.09 (m, 8H), 5.11 (m, 1H), 4.70–4.30 (m, 1H), 4.00 (m, 1H), 3.50 (m, 1H), 3.17–3.00 (m, 7H), 2.67 (bs, 5H), 2.38–1.90 (m, 1H), 1.60, 1.52, 1.49 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.33 (m, 1H), 1.06 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 173.0, 172.1, 171.6, 165.5, 164.7, 162.2, 161.5, 134.1, 133.2, 132.9, 130.3, 125.6, 117.0, 116.7, 116.4, 69.8, 58.5, 56.8, 56.4, 52.3, 51.3, 46.9, 42.2, 38.9, 38.6, 38.1, 29.4, 29.1, 26.3, 24.6, 24.3, 17.0, 16.0; MS m/z (ESI): 530 (M+H, 100).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.861 (m, 3H), 1.027 (m, 2H), 1.445, 1.508, 1.627 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.545 (t, 1H), 2.655, 2.696 (2 singlets, 3H, CH3NHC(O), rotamers), 3.082 (m, 5H), 3.440 (t, 1H), 3.674 (m, 1H), 3.959 (d, 1H, J=13.8), 4.282 (d, 1H, J=13.5), 4.905 (m, 1H), 5.131 (m, 1H), 7.069 (m, 4H), 7.271 (m, 4H) 19F NMR (282 MHz, CD3OD with rotamers) δ 43.059, 44.958, 45.830; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.4, 164.8, 162.7, 162.2, 161.5, 134.3, 164.0, 133.2, 132.8, 132.7, 130.3, 129.9, 126.6, 125.5, 117.0, 116.7, 116.4, 91.8, 69.9, 58.8, 56.1, 55.1 54.0, 52.3, 51.3, 43.1, 39.6, 38.2, 33.1, 32.6, 29.3, 26.2, 24.7, 24.5, 24.3, 20.6, 14.6; MS m/e 558 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD.) δ 1.113 (m, 3H), 1.380 (m, 2H), 1.720, 1.743, 1.816 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.680 (t, 1H), 2.854, 2.900 (2 singlets, 3H, CH3NHC(O), rotamers), 3.281 (m, 5H), 3.352 (m, 3H), 3.492 (t, 1H), 3.845 (t, 1H), 4.333 (d, 1H), 4.600 (d, 1H), 4.863 (m, 1H), 7.266 (m, 5H), 7.519 (m, 3H) 19F NMR (282 MHz, CD3OD with rotamers) δ 44.806, 47.319, 47.342; 13C NMR (75 MHz, CD3OD with rotamers) δ 132.9, 132.8, 132.6, 131.4, 131.3, 126.6,117.5,117.2, 117.0, 116.7, 116.6, 116.4, 114.7, 114.5, 114.4, 114.3, 71.1, 71.0, 56.2, 55.0, 53.9, 52.3, 43.1, 39.6, 39.4, 38.1, 35.6, 35.2, 33.1, 32.3, 26.2, 24.6, 24.5, 24.3, 14.6; MS m/e 560 (M+1); MS m/e 560 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-fluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.895 (m, 3H), 1.183 (m, 2H), 1.454, 1.513, 1.585 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.630, 2.669 (2 singlets, 3H, CH3NHC(O), rotamers), 3.0461 (m, 6H), 3.195 (m, 2H), 3.480 (m, 1H), 4.607 (m, 1H), 5.164 (m, 1H), 7.041 (m, 4H), 7.220 (m, 2H), 7.313 (m, 2H), 19F NMR (282 MHz, CD3OD with rotamers) δ 43.995, 44.249, 46.696, 47.232; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.4, 162.2, 135.4, 134.7, 134.2, 132.8, 132.7, 132.5, 132.4, 117.1, 116.7, 116.5, 116.4, 116.2, 113.6, 71.3, 58.5, 54.9, 53.7, 52.4, 42.3, 38.1, 34.9, 34.6, 33.1, 32.6, 26.3, 24.6, 24.5, 24.3, 20.7, 20.6, 14.5; MS m/e 560 (M+1)


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-difluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.887 (m, 3H), 1.108 (m, 2H), 1.350, 1.515, 1.583 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 2.293 (t, 1H), 2.649, 2.691 (2 singlets, 3H, CH3NHC(O), rotamers), 3.051 (m, 5H), 3.166 (m, 3H), 3.325 (m, 2H), 3.715 (m, 1H), 4.029 (d, 1H), 4.327 (d, 1H), 5.161 (m, 1H), 7.035 (m, 3H), 7.170 (m, 2H), 7.298 (m, 2H); 19F NMR (282 MHz, CD3OD with rotamers) δ 44.732; 13C NMR (75 MHz, CD3OD with rotamers) δ 162.5, 162.0, 134.3, 132.8, 132.7, 127.2, 119.6, 119.4, 118.5, 118.3, 117.0, 116.6, 116.4, 71.1, 58.5, 56.0, 55.0, 53.9, 52.3, 51.1, 42.8, 39.3, 38.1, 35.0, 33.2, 32.7, 26.2, 24.6, 24.5, 24.2, 20.6, 14.6; MS m/e 578 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(2,5-difluorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD) δ 0.852 (m, 3H), 1.055 (m, 2H), 1.397 (m, 1H), 1.765 (m, 1H), 1.988 (m, 1H), 2.360 (m, 1H), 2.510 (m, 1H), 2.632, 2.700 (2 singlets, 3H, CH3NHC(O), rotamers), 2.869 (m, 3H), 3.071 (m, 4H), 4.249 (m, 1H), 4.502 (m, 1H), 5.167 (m, 1H), 7.043 (m, 5H), 7.293 (m, 2H); 19F NMR (282 MHz, CD3OD with rotamers) δ 37.110, 41.494, 45.143, 45.873; 13C NMR (75 MHz, CD3OD with rotamers) δ 132.8, 132.7, 119.1, 117.0, 116.7, 116.4, 69.6, 61.4, 56.2, 55.0, 54.1, 52.1, 51.5, 43.3, 39.7, 38.6, 33.2, 32.6, 31.6, 29.1, 26.3, 25.3, 20.6, 14.6; MS m/e 676 (M+1).


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-piperazin-1-yl}-N-isopropyl-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CD3OD) δ 7.73–7.91 (m, 3H), 7.69 (s, 1H), 7.42–7.55 (m, 2H), 7.21–7.42 (m, 3H), 6.94–7.18 (m, 2H), 5.09–5.31 (m, 1H), 4.57–4.78 (m, 1H), 4.32–4.49 (m, 0.5H), 4.04–4.21 (m, 0.5H), 3.76–4.20 (m, 1H), 3.52–3.76 (m, 1H), 3.15–3.42 (m, 5H), 2.88–3.10 (m, 3H), 2.50–2.83 (m, 1H), 2.14–2.30 (m, 0.5H), 1.62–1.85 (m, 1H), 1.53–1.62 (m, 3H), 1.42–1.53 (m, 3H), 1.18–1.41 (m, 1H), 0.98–1.14 (m, 3H), 0.58–0.84 (m, 3.5H), 0.25–0.58 (m, 2.5H), −0.18–0.09 (m, 2H); 13C NMR (75 MHz, MeOD) δ 173.08, 172.77, 172.25, 171.52, 170.25, 169.51, 165.42, 162.76, 162.20, 136.31, 135.36, 134.31, 134.17, 132.81, 132.71, 129.60, 129.02, 128.89, 127.59, 127.15, 117.03, 116.73, 116.68, 116.39, 71.13, 58.50, 56.27, 54.60, 54.03, 52.59, 52.38, 51.53, 50.17, 42.81, 42.39, 39.32, 38.97, 37.99, 36.12, 35.82, 35.16, 24.63, 24.30, 23.00, 22.61, 22.51, 9.27, 9.10, 5.63, 4.79; MS (ESMS) e/z 630.8 (M+H)+.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CDCl3) δ 7.73–7.92 (m, 3H), 7.69 (s, 1H), 7.40–7.58 (m, 2H), 7.18–7.40 (m, 3H), 6.95–7.16 (m, 2H), 5.08–5.30 (m, 1H), 4.62–4.77 (m, 0.5H), 4.32–4.46 (m, 0.5H), 4.04–4.18 (m, 0.5H), 3.81–3.94 (m, 0.5H), 3.64–3.75 (m, 0.5H), 3.48–3.61 (m, 0.5H), 2.85–3.40 (m, 8H), 2.68–2.79 (m, 0.5H), 2.43–2.68 (m, 3H), 1.99–2.11 (m, 0.5H), 1.12–1.78 (m, 8H), 0.48–0.62 (m, 0.5H), 0.21–0.48 (m, 2.5H), −0.21–0.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.11, 172.78, 172.19, 172.02, 171.51, 136.58, 136.07, 135.36, 134.31, 132.79, 129.44, 129.04, 128.91, 127.60, 127.07, 117.06, 116.77, 116.67, 116.39, 71.24, 58.50, 56.40, 54.56, 54.18, 52.55, 52.37, 51.55, 50.17, 49.74, 42.41, 39.38, 39.01, 36.03, 35.84, 35.66, 35.08, 26.33, 24.63, 24.54, 24.30, 24.24, 9.23, 9.07, 5.62, 5.55, 4.70; MS (ESMS) e/z 602.6 (M+H)+.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-(2-fluoroethyl)-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.39–7.48 (m, 2H), 7.25–7.34 (m, 2H), 7.12–7.21 (m, 1H), 6.95–7.12 (m, 2H), 5.08–5.22 (m, 1H), 4.20–4.58 (m, 3H), 3.93–4.02 (m, 0.66H), 3.68–3.78 (m, 0.33H), 3.38–3.60 (m, 3H), 2.71–3.20 (m, 8H), 2.49–2.63 (m, 1H), 1.84–1.94 (m, 0.33H), 1.62–1.72 (m, 0.66H), 1.40–1.59 (m, 7H), 0.94–1.36 (m, 2H), 0.83–0.93 (m, 3H); MS (ESMS) m/z 640.6, 642.6, 644.5 (M+H)+, Cl2 isotope pattern.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methyl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.38–7.4(m, 2H), 7.23–7.45 (m, 2H), 3.97–7.18 (m, 3H), 5.05–5.20 (m, 1H), 4.44–4.55 (m, 0.66H), 4.27 (d, J=13.2 Hz, 0.33H), 3.94 (d, J=13.2 Hz, 0.66H), 3.59–3.70 (m, 0.33H), 2.74–3.28 (m, 8H), 2.71 (s, 1.25H), 2.67 (s, 1.75H), 2.36–2.49 (m, 1H), 2.06–2.20 (m, 0.33H), 1.25–1.73 (m, 8.66H), 0.94–1.22 (m, 2H), 0.86 (t, J=6.9 Hz, 3H); MS (ESMS) m/z 608.4, 610.6, 612.3 (M+H)+, Cl2 isotope pattern.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-isopropyl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.38–7.49 (m, 2H), 7.24–7.36 (m, 2H), 6.98–7.21 (m, 3H), 5.10–5.24 (m, 1H), 4.47–4.58 (m, 0.66H), 4.24–4.35 (m, 0.33H), 3.84–4.15 (m, 1.66H), 3.68–3.78 (m, 0.33H), 2.75–3.32 (m, 7H), 2.43–2.57 (m, 1.60H), 2.20–2.33 (m, 0.4H), 1.85–1.95 (m, 0.40H), 1.64–1.77 (m, 0.60H), 1.41–1.61 (m, 7H), 0.83–1.30 (m, 12H); MS (ESMS) m/z 636.4, 638.7, 640.8 M+H)+, Cl2 isotope pattern.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-(2-fluoroethyl)-propionamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz with rotamers) δ 7.49–7.36 (m, 6H), 7.24 (m, 2H), 5.33 (m, 1H), 4.76–4.38 (m, 3H), 4.22–3.93 (m, 1H), 3.72–3.53 (m, 3H), 3.36–3.08 (m, 6H), 2.90 (m, 2H), 2.58–2.13 (m, 1H), 1.92 (m, 1H), 1.74, 1.69, 1.66, 1.61 (4 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.27 (m, 3H), 1.07 (m, 3H); 13C NMR (CD3OD, 75 MHz with rotamers) δ 173.0, 172.9, 172.0, 171.5, 165.5, 162.2, 138.4, 137.8, 134.3,134.0, 132.8, 132.7, 132.4, 129.9, 117.0, 116.7, 116.4, 84.4, 82.2, 71.0 58.5, 55.8, 55.0, 53.9, 52.4, 51.0, 42.5, 41.3, 41.0, 39.3, 39.1, 38.1, 35.1, 34.7, 33.2, 32.7, 24.6, 24.5, 24.3, 20.7, 20.6, 14.6; MS m/z (ESI): 606 (M+H, 100), 608 (M+2+H, 37); Anal. Calcd for C35H44ClF8N5O7 0.5 TFA: C, 48.52; H, 5.03; N, 7.86. Found: C, 48.43; H, 4.82; N, 7.84.


The third aspect of Category III comprises compounds having the formula:




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wherein R is a substituted phenyl unit as described herein above and non-limiting examples of R1, R7a, R8, and Q are defined herein below in Table XII and in the examples which follow.













TABLE XII





No.
R1
R7a
Q
R8



















956
methyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


957
ethyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


958
propyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


959
iso-propyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


960
cyclopropyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


961
cyclopropylmethyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


962
allyl
—C(O)NHCH3
pyrrolidin-2-yl
naphthylen-2-ylmethyl


963
methyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


964
ethyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


965
propyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


966
iso-propyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


967
cyclopropyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


968
cyclopropylmethyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


969
allyl
—C(O)NHCH3
pyrrolidin-2-yl
(2-chlorophenyl)methyl


970
methyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


971
ethyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


972
propyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


973
iso-propyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


974
cyclopropyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


975
cyclopropylmethyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


976
allyl
—C(O)NHCH3
pyrrolidin-2-yl
(3-chlorophenyl)methyl


977
methyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


978
ethyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


979
propyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


980
iso-propyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


981
cyclopropyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


982
cyclopropylmethyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


983
allyl
—C(O)NHCH3
pyrrolidin-2-yl
(4-chlorophenyl)methyl


984
methyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


985
ethyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


986
propyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


987
iso-propyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


988
cyclopropyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


989
cyclopropylmethyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


990
allyl
—C(O)NHCH3
pyrrolidin-2-yl
(2,4-dichlorophenyl)methyl


991
methyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


992
ethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


993
propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


994
iso-propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


995
cyclopropyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


996
cyclopropylmethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


997
allyl
—C(O)NHCH3
1-aminocycloprop-1-yl
naphthylen-2-ylmethyl


998
methyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


999
ethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1000
propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1001
iso-propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1002
cyclopropyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1003
cyclopropylmethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1004
allyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2-chlorophenyl)methyl


1005
methyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1006
ethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1007
propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1008
iso-propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1009
cyclopropyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1010
cyclopropylmethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1011
allyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(3-chlorophenyl)methyl


1012
methyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1013
ethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1014
propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1015
iso-propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1016
cyclopropyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1017
cyclopropylmethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1018
allyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(4-chlorophenyl)methyl


1019
methyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1020
ethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1021
propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1022
iso-propyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1023
cyclopropyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1024
cyclopropylmethyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1025
allyl
—C(O)NHCH3
1-aminocycloprop-1-yl
(2,4-dichlorophenyl)methyl


1026
methyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1027
ethyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1028
propyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1029
iso-propyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1030
cyclopropyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1031
cyclopropylmethyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1032
allyl
—C(O)NHCH3
azetidin-2-yl
naphthylen-2-ylmethyl


1033
methyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1034
ethyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1035
propyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1036
iso-propyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1037
cyclopropyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1038
cyclopropylmethyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1039
allyl
—C(O)NHCH3
azetidin-2-yl
(2-chlorophenyl)methyl


1040
methyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1041
ethyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1042
propyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1043
iso-propyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1044
cyclopropyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1045
cyclopropylmethyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1046
allyl
—C(O)NHCH3
azetidin-2-yl
(3-chlorophenyl)methyl


1047
methyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1048
ethyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1049
propyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1050
iso-propyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1051
cyclopropyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1052
cyclopropylmethyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1053
allyl
—C(O)NHCH3
azetidin-2-yl
(4-chlorophenyl)methyl


1054
methyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1055
ethyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1056
propyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1057
iso-propyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1058
cyclopropyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1059
cyclopropylmethyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl


1060
allyl
—C(O)NHCH3
azetidin-2-yl
(2,4-dichlorophenyl)methyl









The compounds of the third aspect of Category III can be suitably prepared by the procedure outlined herein below, utilizing final analogs from the first aspect of this Category as starting points, for example, compound 45, as depicted in Scheme XIV herein below.




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EXAMPLE 14
Pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-[2-ethyl-4-(1-methyl-carbamoyl-2-naphthalen-2-yl-ethyl)piperazin-1-yl]-2-oxo-ethyl]-amide trifluoroacetate (49)

Preparation of 2-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)piperazin-1-yl]-(4-chlorobenzyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (48): 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl, 45, (0.5 g, 0.7 mmol) and Boc-L-proline (0.17 g, 0.78 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.4 mmol) and 1-hydroxybenzotriazole (0.16 g, 0.86 mmol) are dissolved in anhydrous DMF (2.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.6 mL, 5.3 mmol) is added. This reaction mixture is placed in a refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. Solvent is removed in vacuo to afford 0.5 g of the desired product.


Preparation of pyrrolidine-2-carboxylic acid {1-(4-chlorobenzyl)-2-[2-ethyl-4-(1-methyl-carbamoyl-2-naphthalen-2-yl-ethyl)piperazin-1-yl]-2-oxo-ethyl]-amide trifluoroacetate (49): 2-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)piperazin-1-yl]-(4-chlorobenzyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, 48, (0.5 g) is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. The organic layers are combined and concentrated in vacuo and the crude product is purified by preparative HPLC to afford the desired product. A small amount of product is converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, 300 MHz δ): 8.22–8.17 (m, 1H), 7.82–7.47 (m, 4H), 7.47–7.35 (m, 3H), 7.29–7.12 (m, 3H), 6.61–6.45 (m, 1H), 5.13 (quartet, J=8.1 Hz, 0.5H), 5.02 (quartet, J=6.9 Hz, 0.5H), 4.45 (br s, 0.5H), 4.34–4.30 (m, 0.5H), 3.75–3.70 (m, 1H), 3.66–3.62 (m, 2H), 3.50 (br s, 1H), 3.40–3.15 (m, 3H), 3.02–2.83 (m, 5H), 2.81–2.75 (m, 4H), 2.50–2.11 (m, 4H), 1.83–1.75 (m, 2H), 1.70–1.44 (4H), 0.79–0.73 (m, 2H); 13C NMR, δ1174.7, 172.1, 170.4, 137.7, 135.2, 133.7, 132.2, 131.3, 131.1, 129.0, 128.7, 128.2, 127.9, 127.7, 126.2, 125.6, 70.8, 60.7, 55.2, 52.1, 51.3, 50.9, 50.3, 50.0, 49.5, 49.2, 47.5, 41.9, 39.9, 38.7, 38.7, 32.4, 31.8, 31.1, 30.9, 26.2, 23.3, 22.4, 14.5, 10.8, 10.0; HRFAB(positive) m/e 604.305443 Calculated for C34H42ClN5O3 (M+H)+, Found 604.308207.


The following are non-limiting examples of procedures for preparing other analogs encompassed with the third aspect of Category III.


Preparation of Pyrrolidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(1-fluorobenzyl)-2-oxo-ethyl]-amide: 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl, 41, (0.3 g, 0.6 mmol) and Boc-L-proline (0.13 g, 0.6 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.13 g, 1.1 mmol) and 1-hydroxybenzotriazole (0.16 g, 0.86 mmol) are dissolved in anhydrous DMF (2.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.2 mL, 1.7 mmol) is added. This reaction mixture is placed in a refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. Solvent is removed in vacuo to afford 0.39 g of the desired product.


The crude product obtained above is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. The organic layers are concentrated in vacuo gives the crude HCl salt of the product which was then purified by preparative HPLC to give the TFA salt of product (0.2 g, 0.23 mmol, 42% yield). A small amount of product was converted into the free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, 300 MHz δ): 7.75–7.55 (m, 4H), 7.40–7.22 (m, 3H), 7.12–7.02 (m,2H), 6.92–6.80 (m, 2H), 6.50–6.28 (m, 1H), 5.10–4.90 (m, 1H), 4.58–4.20 (m, 1H), 3.79–3.20 (m, 4H), 3.10–2.60(m, 9H), 2.50–2.30 (m, 1H), 2.22–1.50 (m, 11H) 0.80–0.68 (m, 3). HRFAB(positive) m/e 588.3350 calculated for C34H42FN5O3 (M+H)+.


Preparation of 5-oxo-pyrrolidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazine-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide hydrochloride (0.78 g, 0.83 mmol) and L-pyroglutamic acid (0.11 g, 0.83 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.0 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.66 mmol) are dissolved in anhydrous DMF (4 mL). The reaction mixture is cooled to 0° C., then N-mathylmorpholine (0.6 mL, 5.46 mmol) is added. The reaction mixture is stirred for 3–4 hrs. EtOAc (30 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). The organic layers are combined, washed with water (2×50 mL), dried over Na2SO4, then concentrated in vacuo to provide a crude product which is purified by preparative HPLC to afford 0.14 g of the desired product. 1H NMR (CDCl3, 300 MHz δ): 7.83–7.78 (m, 3H), 7.69 (s, 1H), 7.48–7.45 (m, 2H), 7.35–7.28 (m, 3H), 7.10–7.00 (m, 2H), 5.20–5.11 (m, 1H), 4.69 (br s, 0.5H), 4.50 (d, J=13.9 Hz, 0.5H), 4.19–4.17 (m, 1.5H), 3.96–3.85 (m, 1H), 3.74 (t, J=8.4 Hz, 0.5H), 3.58–3.54 (m, 0.5H), 3.44–3.26 (m, 8H), 3.11–2.91 (m, 3H), 2.85–2.74 (m, 0.5H), 2.57–2.51 (m, 3H), 2.36–2.22 (m, 3H), 2.12–2.09 (m, 0.5H), 3.96–1.85–1.76 (m, 1.5H), 1.73–1.61 (m, 1H), 0.87–0.76 (m, 3H); 13C NMR, (CDCl3, 75 MHz) δ1182.0, 176.0, 175.0, 173.0, 172.0, 168.0, 166.0, 163.0, 135.4, 134.5, 134.3, 134.1, 134.0, 133.0, 132.9, 132.8, 129.9, 129.7, 129.6,129.1, 129.0, 128.6, 127.8, 127.5, 127.3, 117.1, 116.8, 116.5, 71.4, 71.0, 58.1, 56.2, 53.6, 53.4, 51.9, 51.5, 51.0, 40.6, 39.8, 38.3, 37.6, 35.45, 30.9, 27.2, 26.5, 24.1, 23.4, 11.0; HRFAB(positive) m/e 602.314258 calculated for C34H40FN5O4 (M+H)+.


Preparation of azetidine-2-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide. 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide, 41, (0.78 g, 0.83 mmol) and Boc-L-azetidine-2-carboxylic acid (0.17 g, 0.83 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.0 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.66 mmol) are dissolved in anhydrous DMF (2 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.6 mL, 5.46 mmol) is added. The reaction mixture is stirred for 4 hrs. EtOAc (30 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford the desired product which is used without further purification.


2-[2-[2-ethyl-4-(1-methyl-carbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-azetidine-1-carboxylic acid tert-butyl ester is dissolved in DCM/TFA/H2O (2/1/0.1) (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. The organic layers are combined, washed with water (2×50 mL), dried over Na2SO4, then concentrated in vacuo to provide a crude product which is purified by preparative HPLC to afford 32 mg of the desired product. (HCS3621-118). 1H NMR (CDCl3, 300 MHz, δ): 7.90–7.84 (m, 3H), 7.75 (s, 1H), 7.54–7.51 (m, 2H), 7.43–7.34 (m, 3H), 7.18–7.08 (m, 2H), 5.30–5.25 (m, 1H), 5.06–5.00 (m, 1.5H), 4.59 (bs s, 0.5H), 4.43 (d, J=14.2 Hz, 0.5H), 4.21–4.11 (m, 1.5H), 4.00–3.91 (m, 1H), 3.80–3.69 (m, 1H), 3.55 (t, J=7.5 Hz, 0.5H), 3.40–3.38 (m, 3H), 3.32–3.20 (m, 4H), 3.17–2.75 (m, 6H), 2.73–2.67 (m, 1.5H), 2.51–2.24 (m, 1.5H), 2.02–1.54 (m, 2.5H), 0.88–0.77 (m, 3H); 13C NMR, (CDCl3, 75 MHz) δ 172.0, 169.0, 165.4 162.3, 136.8, 136.1, 135.4, 134.2, 133.9, 133.0, 132.8, 132.7, 129.5, 129.4, 129.0, 128.9, 127.6, 127.1, 127.0, 117.1, 116.8, 116.5, 71.3, 60.2, 57.1, 54.2, 52.4, 52.0, 51.9, 50.5, 50.0, 49.9, 49.7, 49.1, 45.5, 42.2, 39.7, 38.5, 35.9, 35.7, 26.3, 25.3, 24.0, 23.4, 11.1; HRFAB(positive) m/e 574.319344 calculated for C33H40FN5O3 (M+H)+, Found 574.320780.


Preparation of azetidine-3-carboxylic acid [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide, 41, (0.78 g, 0.83 mmol) and Boc-azetidine-3-carboxylic acid (0.17 g, 0.83 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.0 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.66 mmol) are dissolved in anhydrous DMF (2 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.6 mL, 5.46 mmol) is added. The reaction mixture is stirred for 3–4 hrs. EtOAc (30 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford the desired product which is used without further purification.


3-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-azetidine-1-carboxylic acid tert-butyl ester is dissolved in DCM/TFA/H2O (2/1/0.1) (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added, the solvent removed in vacuo to give a residue which is purified by preparative HPLC to afford 300 mg of the desired product. 1H NMR (CDCl3, 300 MHz, δ): 7.71–7.64 (m, 3H), 7.55–7.54 (m, 1H), 7.40–7.31 (m, 2H), 7.26–7.13 (m,3H), 6.97–6.87 (m, 3), 5.00 (t, J=7.7 Hz, 1H), 4.46 (br s, 0.5H), 4.32 (d, J=13.8 Hz, 0.5H), 4.08–3.86 (m, 6H), 3.68–3.63 (m, 0.5H), 3.60–3.49 (m, 1.5H), 3.47–3.41 (m, 0.5H), 3.25–3.00 (m, 2H), 3.14–3.03 (m, 3H), 2.98–2.65 (m, 5.5H), 2.54–2.35 (m, 3H), 1.77–1.56 (m, 1.5H), 1.55–1.36 (m, 0.5), 0.69–0.58 (m, 3H); 13C NMR, (CDCl3, 75 MHz) δ 175.0, 173.0, 172.0, 166.0, 163.0, 135.4, 134.1, 133.0, 132.9, 132.8, 132.7, 129.7, 129.5, 129.4, 129.0, 128.9, 128.8, 128.7, 127.7, 127.6, 127.3, 127.1, 117.1, 116.8, 116.5, 71.3, 71.2, 56.8, 53.9, 53.4, 52.2, 52.0, 51.9, 50.7, 50.3, 50.1, 50.0, 49.1, 41.6, 39.7, 38.4, 37.0, 35.7, 26.4, 24.0, 23.4, 11.1; HRFAB(positive) m/e 574.317945 calculated for C33H40FN5O3 (M+H)+, Found 574.319344.


The following are non-limiting examples of other analogs which comprise the third aspect of Category III.


N-[2-{4-[2-(4-Chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide trifluoroacetate: 1H NMR (CDCl3, 300 MHz, δ): 8.85 (s, 2H), 8.20–7.00 (m, 10H), 5.40–5.30 (m, 1H), 4.50–4.05 (m, 2H), 3.70–2.88 m, 8H), 2.80–2.65 (m, 4H), 1.90–1.05 (m, 6H); 13C NMR (CDCl3, 300 MHz) δ 175.0, 167.0, 149.1, 148.0, 146.0, 138.0, 134.0, 133.0, 132.4, 130.1, 124.8, 116.9, 71.6, 55.7, 52.8, 51.2, 50.3, 50.0, 49.7, 46.4, 41.0, 39.0, 38.3, 34.9, 26.4, 17.1, 15.9. HRFAB(positive) m/e 566.233421 calculated for C30H33ClFN5O3 (M+H)+, Found 566.231196.


N-[2-{4-[2-(3,4-Dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-ethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide trifluoroacetate: 1H NMR (CD3OD, 300 MHz): δ 8.80 (s, 1H), 7.97 (s, 1H), 7.39–7.30 (m, 5H), 7.10–7.02 (m, 4H), 5.40 (br, s, 1H), 4.60 (br, s, 1H), 4.45–4.38 (m, 0.5H), 4.18–4.10 (m, 0.5H), 3.70 (br, s, 0.5H), 3.60–3.52 (m, 1H), 3.42–2.85 (m, 9H), 2.78–2.60 (m, 3H), 2.40–2.30 (1H), 1.98–1.78 (m, 2H), 1.62–1.52 (m, 1H), 0.78–0.74 (m, 3H); 13C NMR (CD3OD, 75 MHz) δ 175.0, 174.0, 172.0, 166.5, 165.5, 162.2, 148.2, 148.0, 140.2, 139.1, 134.1, 133.7, 133.0, 132.9, 132.7, 132.3, 132.0, 131.8, 130.8, 125.2, 117.1, 116.8, 116.6, 91.0, 70.7, 57.1, 53.8, 53.4, 53.0, 52.6, 52.2, 50.8, 50.3, 50.0, 49.7, 41.8, 39.5, 38.8, 38.3, 34.4, 26.4, 24.0, 23.4, 11.1. HRFAB(positive) m/e 614.210099 calculated for C31H34Cl2FN5O3 (M+H)+, Found 614.210894.


Pyrrolidine-2-carboxylic acid[2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazine-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, 300 MHz): δ 7.65–7.60 (m, 2H), 7.49 (s, 2H), 7.36–7.25 (m, 3H), 5.33–5.30 (m, 1.5H), 4.92 (br s, 0.5H), 4.56–4.42 (m, 1.5H), 4.21–4.18 (m, 1H), 3.66–3.62 (m, 1H), 3.59–3.48 (m, 5H), 3.45–3.17 (m, 7H), 2.85–2.82 (m, 4H), 2.56 (br s, 1.5H), 2.25–2.02 (m, 3.5H), 1.52–1.50 (m, 1.5H), 1.32–1.26 (m, 1H); 13C NMR (CD3OD, 75 MHz): δ 174.0, 170.0 165.5, 162.2, 140.3, 139.8, 133.9, 133.5, 132.9, 131.8, 130.7, 117.0, 116.7, 116.5, 113.3, 70.9, 70.8, 61.4, 56.6, 56.4, 52.0, 51.2, 50.3, 50.0, 49.7, 49.4, 47.7, 46.8, 42.0, 39.2, 38.5, 34.9, 34.7, 31.6, 26.3, 25.3, 17.1, 16.0. HRFAB(positive) m/e 592.225749 calculated for C29H36Cl2FN5O3 (M+H)+, Found 592.224706.


Pyrrolidine-2-carboxylic acid[2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazine-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, δ): 7.32–7.30 (m, 4H), 7.21–7.18 (m, 2H), 7.10–7.03 (m, 2H), 5.18–5.10 (m, 1H), 4.79 (br s, 0.5H), 4.42 (d, J=13.5 Hz, 0.5H), 4.25 (t, J=7.5 Hz, 1H), 4.10–4.00 (m, 1.5H), 3.60–3.57 (m, 1H), 3.50–3.43 (m, 1H), 3.42–3.27 (m, 6H), 3.20–2.89 (m, 4.5H), 2.82–2.75 (m, 0.5H), 2.63 (d, J=9.0 Hz, 4H), 2.46–2.30 (m, 1H), 2.08–1.75 (m, 4H), 1.38 (d, J=5.7 Hz, 1.5H), 1.12 (d, J=5.7 Hz, 1.5H); 13C NMR δ 174.0, 170.0, 165.5, 162.5, 162.2, 137.4, 134.3, 133.9, 132.9, 132.5, 130.0, 119.9, 117.0, 116.8, 116.5, 116.0, 71.0, 61.4, 56.3, 52.0, 50.9, 50.3, 50.0, 49.7, 47.7, 46.5, 41.5, 39.1, 38.4, 38.0, 35.1, 31.6, 26.3, 25.3, 17.0, 16.0. HRFAB(positive) m/e 558.264721 calculated for C29H37ClFN5O3 (M+H)+, Found 558.263046.


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-ethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, δ): 7.45–7.41 (m, 2H), 7.32–7.28 (m, 2H), 7.17–7.01 (m, 3H), 5.22–5.15 (m, 1H), 4.49 (br s, 0.5H), 4.35–4.21 (m, 1.5), 4.02 (d, J=13.2 Hz, 0.5H), 3.67 (br s, 0.5), 3.46–3.25 (m, 5H), 3.20–2.84 (m, 6H), 2.80–2.52 (m, 5H), 2.38–2.26 (m, 1H), 2.05–1.54 (m, 6H0, 0.82–0.73 (m, 3H); 13C NMR δ 173.0, 172.0, 171.0, 170.0, 169.0, 165.4, 162.2, 140.8, 140.1, 133.9, 133.4, 132.9, 131.8, 131.7, 130.7, 117.0, 116.7, 116.4, 70.8, 61.4, 57.3, 54.4, 52.6, 52.1, 52.0, 50.3, 50.0, 49.7, 49.4, 49.1, 47.7, 42.5, 39.6, 39.1, 38.5, 34.7, 34.5, 31.6, 26.3, 25.2, 24.0, 23.4, 11.1. HRFAB(positive) m/e 606.241399 calculated for C30H38Cl2FN5O3 (M+H)+, Found 606.240332.


1-Amino-Cyclopropanecarboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-ethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, δ): 7.55–6.90 (m, 7H), 5.18–4.22 (m, 3.5H), 4.02–3.90 (m, 0.5H), 3.70–2.15 (m, 17H), 1.88–1.12 (m, 6H), 0.80–0.6 (m, 2H). HRFAB(positive) m/e 592.225749 calculated for C29H36Cl2FN5O3 (M+H)+, Found 592.224973.


N-[2-{4-[2-(4-Chlorophenyl)-1-(2-fluoroethylcarbamoyl)-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide HCl: 1H NMR (CD3OD, with rotamers) δ 9.11 (br s, 2H), 8.42 (br s, 2H), 7.46–7.32 (m, 6H), 7.11 (m, 2H), 5.41 (m, 1H), 4.72–4.11 (m, 4H), 3.94–3.17 (m, 12H), 2.40–0.98 (m, 7H); 13C NMR (CD3OD, with rotamers) δ 171.9, 167.9, 165.5 162.3, 145.4, 135.0, 133.8, 132.9, 132.6, 130.4, 130.0, 126.9, 116.9, 116.7, 84.2, 82.0, 71.1, 54.4, 53.3, 52.9, 51.4, 50.7, 41.5, 41.2, 40.4, 38.1, 34.4, 33.2, 32.6, 20.4, 14.4; MS m/z(ESI): 626 (M+H, 100), 628(M+2+H, 37).


N-[2-{4-[2-(2,4-Dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide HCl: 1H NMR (CD3OD, with rotamers) δ 8.85 (d, 2H, J=5.0 Hz), 8.20 (d, 2H, J=5.5 Hz), 7.31 (s, 1H), 7.19–7.11 (m, 4H), 6.86 (m, 2H), 5.15 (m, 1H), 4.45–4.14 (m, 1H), 3.78 (m, 1H), 3.16 (m, 1H), 3.34 (m, 4H), 3.07–2.99 (m, 5H), 2.43, 2.38 (2 singlets, 3H, CH3NHC(O), rotamers), 2.10–0.70 (m, 7H); 13C NMR (CD3OD, with rotamers) δ 171.9, 168.0, 165.5, 165.4, 162.3, 151.1, 145.0, 136.6, 136.0, 134.6, 134.1, 133.8, 132.9, 130.9, 129.1, 127.0, 117.2, 116.9, 116.7, 69.2, 68.7, 54.5, 53.9, 53.0, 51.7, 51.2, 40.3, 39.2, 38.1, 37.2, 33.1, 32.5, 32.2, 26.6, 20.7, 20.4, 14.4; MS m/z (ESI): 628 (M+H, 100), 630 (M+2+H, 70).


Pyrrolidine-2-carboxylic acid [2-{4-[3-(4-chlorophenyl)-1-methylcarbamoyl-propyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.11 (m, 6H), 6.85 (m, 2H), 4.97 (m, 1H), 4.43–4.07 (m, 2H), 3.87–3.68 (m, 1H), 3.49–3.08 (m, 4H), 3.00–2.80 (m, 4H), 2.61 (bs, 3H), 2.47 (m, 2H), 2.17–2.03 (m, 4H), 1.82–1.44 (m, 6H), 1.00–0.72 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 172.0, 170.0, 168.8, 165.5, 140.3, 133.8, 132.8, 131.5, 130.1, 116.8, 116.5, 70.0, 61.4, 54.4, 51.9, 51.1, 47.7, 40.3, 38.2, 32.4, 31.5, 30.4, 26.7, 25.3, 20.4,14.4; MS m/z (ESI): 600 (M+H, 100), 602 (M+2+H, 37).


2-{4-[2-Aminosulfonyl amino-3-(4-fluorophenyl)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) 6.80˜8.00 (m, 11H), 4.62 (m, 1H), 4.41 (m, 1H), 3.91 (m, 1H), 2.90˜3.50 (m, 10H), 2.46 (d, J=2.7 Hz, 3H), 1.58 (m, 2H), 0.80˜1.50 (m, 5H); 13C NMR (CDCl3, 75 MHz), 171.58, 166.73, 138.61, 132.85, 131.34, 131.29, 131.18, 128.98, 128.49, 127.93, 127.83, 126.82, 126.56, 116.09, 115.80, 68.56, 53.79, 52.28, 47.97, 47.54, 38.92, 38.40, 34.09, 30.50, 26.40, 19.10, 13.54; MS (ES-MS) m/z 584 (M+1).


Pyrrolidine-2-carboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(2-fluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-2-oxo-ethyl)-amide: 1H NMR (300 MHz, CD3OD) δ 0.84 (t, 3H), 1.055 (m, 2H), 1.39 (m, 2H), 1.83 (m, 5H), 2.36 (m, 2H), 2.67, 2.70 (2 singlets, 3H, CH3NHC(O), rotamers), 3.02 (m, 8H), 3.95 (m, 1H, J=12.3), 4.22 (m, 1H), 4.49 (m, 1H), 5.17 (m, 1H), 7.07 (m, 4H), 7.27 (m, 4H); 19F NMR (282 MHz, CD3OD with rotamers) δ 42.67, 42.69, 44.86, 45.59; 13C NMR (75 MHz, CD3OD with rotamers) δ 133.2, 132.8, 129.9, 125.5, 117.0, 116.7, 116.4, 69.8, 61.4, 56.1, 55.0, 54.1, 52.0, 51.4, 50.2, 47.7, 43.1, 39.7, 38.6, 32.6, 31.6, 29.3, 29.0, 26.2, 25.3, 20.6, 14.6; MS m/e 572 (M+1).


Pyrrolidine-2-carboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(4-fluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-2-oxo-ethyl)-amide: 1H NMR (300 MHz, CD3OD) δ 0.90 (t, 3H), 1.12 (m, 2H), 1.53 (m, 2H), 1.78 (m, 2H), 1.98 (m, 5H), 2.36 (m, 1H), 2.60, 2.64 (2 singlets, 3H, CH3NHC(O), rotamers), 2.85 (m, 1H), 3.05 (m, 8H), 3.33 (m, 8H), 3.55 (m, 1H), 4.24 (m, 1H), 4.74 (m, 1H), 5.19 (m, 1H), 7.05 (m, 4H), 7.22 (m, 2H), 7.31(m, 2H); 19F NMR (282 MHz, CD3OD with rotamers) δ 44.92, 45.29, 45.38, 46.17; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.5, 162.9, 162.2, 134.9, 133.9, 132.8, 132.6, 132.5, 117.1, 116.7, 116.6, 116.5, 116.3, 71.3, 61.4, 55.5, 54.7, 52.0, 50.3, 41.8, 38.4, 34.8, 34.6, 33.2, 32.5, 31.6, 26.4, 25.3, 20.7, 20.5, 14.5; MS m/e 570 (M+1).


Pyrrolidine-2-carboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(3,4-difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-2-oxo-ethyl)-amide: 1H NMR (300 MHz, CD3OD) δ 0.929 (m, 3H), 1.179 (m, 2H), 1.53 (m, 2H), 1.776 (m, 2H), 1.97 (m, 5H), 2.34 (m, 2H), 2.63, 2.67 (2 singlets, 3H, CH3NHC(O), rotamers), 2.79 (m, 1H), 3.04 (m, 8H), 3.33 (m, 8H), 3.689 (m, 1H), 4.69 (m, 1H), 5.19 (m, 1H), 7.04 (m, 1H), 7.18 (m, 3H), 7.31 (m, 3H); 19F NMR (282 MHz, CD3OD with rotamers) δ 19.44, 19.98, 22.28, 22.61, 45.27, 46.08; 13C NMR (75 MHz, CD3OD with rotamers) δ 171.6, 171.3, 169.4, 169.2, 164.4, 162.8, 162.3, 162.1, 133.7, 132.7, 132.6, 132.5, 132.5, 127.0, 119.4, 119.3, 119.3, 118.4, 118.2, 118.1, 116.7, 116.6, 116.4,116.3, 70.7, 70.6, 61.1, 54.6, 51.8, 50.5, 49.9, 49.6, 49.4, 38.2, 34.5, 32.4, 31.3, 26.1, 25.0, 25.0, 20.3, 14.3; MS m/e 589 (M+1).


N-[2-{4-[2-(3,4-Difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-isonicotinamide: 1H NMR (300 MHz, CD3OD) δ 0.90 (t, 3H), 1.140 (m, 2H), 1.52 (m, 2H), 1.79 (m, 1H), 1.96 (m, 1H), 2.61, 2.67 (2 singlets, 3H, CH3NHC(O), rotamers), 3.03 (m, 3H), 3.22 (m, 5H), 3.33 (m, 3H), 3.78 (m, 1H), 4.77 (m, 1H), 5.33 (m, 1H), 7.12 (m, 5H), 7.35 (m, 2H), 8.16 (d, 2H, J=5.7, 2-pyr-H), 8.93 (d, 2H, J=4.2, 3 pyr-H); 19F NMR (282 MHz, CD3OD with rotamers) δ 22.322, 22.354, 22.787, 45.402, 46.214; 13C NMR (75 MHz, CD3OD with rotamers) δ 165.5, 150.1, 149.9, 145.6, 145.4, 134.2, 132.9, 132.8, 132.7, 127.2, 124.2, 119.7, 119.4, 119.3, 118.7, 118.3, 118.2, 117.1, 116.8, 116.5, 114.6, 71.4, 71.1, 56.1, 54.4, 53.8, 52.7, 52.6, 51.1, 50.8, 42.7, 39.5, 38.4, 34.6, 33.3, 32.7, 26.3, 20.7, 20.6, 14.6; MS m/e 596 (M+1).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(2,5-difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, CD3OD) δ 0.847 (m, 3H), 1.264 (m, 2H), 1.427 (m, 5H), 1.450 (m, 5H), 1.853 (m, 3H), 2.037 (m, 1H), 2.696, 2.732 (2 singlets, 3H, CH3NHC(O), rotamers), 2.944 (m, 3H), 3.466 (m, 3H), 3.750 (m, 1H), 4.210 (m, 2H), 5.280 (m, 1H), 7.049 (m, 5H), 7.294 (m, 2H); 19F NMR (282 MHz, CD3OD with rotamers) δ 37.012, 41.402, 44.910, 45.792; 13C NMR (75 MHz, CD3OD with rotamers) δ 132.8, 117.0, 116.7, 116.4, 69.6, 58.5, 55.2, 52.3, 50.2, 38.2, 32.6, 26.2, 24.7, 24.3, 20.6, 14.6; MS m/e 688 (M+1).


4-Amino-cyclohexanecarboxylic acid [2-{4-[2-(3,4-difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, CD3OD) δ 0.890 (m, 3H), 1.094 (m, 2H), 1.470 (m, 2H), 1.680 (m, 4H), 1.813 (m, 4H), 2.489 (m, 2H), 2.659, 2.776 (2 singlets, 3H, CH3NHC(O), rotamers), 2.894 (m, 2H), 3.012 (m, 3H), 3.989 (m, 1H), 4.295 (m, 1H), 4.531 (m, 1H), 5.112 (m, 1H), 7.024 (m, 3H), 7.159 (m, 2H), 7.294 (m, 3H); 19F NMR (282 MHz, CD3OD with rotamers) δ 18.657, 19.025, 21.450, 21.721, 44.742, 45.624; 13C NMR (75 MHz, CD3OD with rotamers) δ 132.7, 127.1, 119.6, 119.3, 118.3, 116.9, 116.6, 116.3, 71.2, 56.0, 55.0, 54.1, 51.6, 51.1, 42.8, 40.8, 39.9, 385, 35.0, 33.2, 32.7, 28.6, 26.3, 26.0, 20.6, 14.6; HRMS m/e for C33H44F3N5O3 (M+1) calc.: 616.347451, found: 616.349725.


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.39–7.48 (m, 2H), 7.24–7.36 (m, 2H), 6.99–7.20 (m, 3H), 5.08–5.26 (m, 1H), 4.48–4.60 (m, 0.66H), 4.18–4.38 (m, 1.33H), 3.95–4.07 (m, 0.66H), 3.64–3.74 (m, 0.33H), 3.21–3.32 (m, 1H), 2.76–3.19 (m, 6H), 2.71 (s, 1.4H), 2.66 (s, 1.6H), 1.59–2.10 (m, 3.7H), 1.35–1.54 (m, 1H), 0.99–1.28 (m, 2H), 0.83–0.93 (m, 3H); 13C NMR (75 MHz, MeOD, Rotamers) δ 171.93, 171.62, 170.64, 169.72, 169.44, 165.46, 163.16, 162.68, 162.21, 161.71, 133.96, 133.61, 133.45, 132.90, 132.73, 132.24, 131.93, 131.80, 130.74, 117.04, 116.76, 116.47, 70.70, 70.63, 61.35, 55.66, 54.86, 53.98, 52.06, 51.98, 50.57, 49.99, 49.35, 47.73, 41.99, 39.65, 38.80, 38.47, 34.60, 34.47, 33.18, 32.55, 31.64, 26.38, 25.28, 20.67, 20.57, 14.55; MS (ESMS) m/z620.4, 622.4, 624.6 (M+H)+, Cl2 isotope pattern.


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-isopropylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.39–7.50 (m, 2H), 7.24–7.36 (m, 2H)m, 7.00–7.21 (m, 3H), 5.11–5.28 (m, 1H), 4.48–4.59 (m, 0.6H), 4.17–4.36 (m, 1.4H), 3.84–4.05 (m, 1.6H), 3.70–3.81 (m, 0.4H), 2.76–3.26 (m, 8H), 2.46–2.63 (m, 1.4H), 2.22–2.41 (m, 1.6H), 1.62–2.28 (m, 4H), 1.42–1.57 (m, 1H), 0.83–1.37 (m, 12H); MS (ESMS) m/z 648.5, 650.6, 652.1 (M+H, +, Cl2 isotope pattern


Pyrrolidine-2-carboxylic acid [2-{4-[2-(3-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide dihydrochloride. 1H NMR (CD3OD, with rotamers) δ 7.10–6.80 (m, 8H), 4.98 (m, 1H), 4.42–3.97 (m, 3H), 3.73–3.30 (m, 7H), 2.88 (m, 4H), 2.40, 2.36 (2 singlets, 3H, CH3NHC(O), rotamers), 2.19 (m, 1H), 1.80–1.45 (m, 6H), 0.98–0.68 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 171.8, 169.5, 167.5, 165.4, 162.2, 138.3, 135.9, 133.9, 132.9, 132.8, 131.8, 131.0, 129.5, 129.2, 117.1, 116.8, 116.5, 114.1, 74.5, 71.1, 70.6, 69.5, 62.6, 61.4, 54.7, 54.0, 53.5, 51.8, 51.2, 47.8, 40.2, 38.2, 34.7, 32.5, 31.6, 26.6, 25.3, 20.7, 20.4, 14.4; MS m/z (ESI): 586 (M+H, 100), 588 (M+2+H, 37).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide dihydrochloride. 1H NMR (CD3OD, with rotamers) δ 7.18 (m, 6H), 6.92 (m, 2H), 5.04 (m, 1H), 4.48–3.82 (m, 3H), 3.56–3.16 (m, 8H), 3.01 (m, 4H), 2.46, 2.42 (2 singlets, 3H, CH3NHC(O), rotamers), 2.23 (m, 1H), 1.89–1.61 (m, 4H), 1.30–1.00 (m, 3H), 0.77 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 171.8, 170.0, 168.0, 165.5, 162.2, 135.0, 134.9, 134.0, 132.9, 132.8, 132.7, 130.3, 117.1, 116.8, 116.5, 97.8, 97.5, 74.5, 71.1, 70.6, 69.5, 62.6, 61.4, 54.7, 52.1, 51.9, 51.1, 50.6, 47.8, 40.3, 38.3, 34.4, 32.5, 31.6, 26.6, 25.4, 20.7, 20.4, 14.4; MS m/z (ESI): 586 (M+H, 100), 588 (M+2+H, 30).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(2-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.29 (m, 1H), 7.05 (m, 5H), 7.85 (m, 2H), 4.95 (m, 1H), 4.33–4.19 (m, 1H), 4.00 (m, 1H), 3.83–3.50 (m, 1H), 3.32–3.14 (m, 1H), 3.06–2.65 (m, 10H), 2.48 (m, 1H), 2.44, 2.41 (2 singlets, 3H, CH3NHC(O), rotamers), 2.11 (m,1H), 1.79–1.44 (m, 4H), 1.21 (m, 1H), 0.90 (m, 2H), 0.65 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 173.0, 172.5, 172.4, 172.0, 168.6, 168.5, 165.4, 162.3, 137.5, 137.0, 135.6, 134.0, 133.5, 133.4, 133.0, 132.8, 132.7, 131.0, 129.9, 129.8, 128.4, 128.3, 117.0, 116.7, 116.4, 69.4, 69.3, 61.4, 56.0, 54.8, 53.8, 52.1, 51.1, 47.7, 42.8, 39.7, 38.5, 33.5, 33.3, 33.1, 32.5, 31.6, 26.3, 25.3, 20.6, 14.6,; MS m/z (ESI): 586 (M+H, 100), 588 (M+2+H, 30).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(2,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.45 (m, 1H), 7.28 (m, 4H), 7.06 (dd, 2H, J=17.6, 8.8 Hz), 5.16 (m, 1H), 4.14–4.23 (m, 2H), 4.04–3.69 (m, 1H), 3.54–3.36 (m, 1H), 3.28–2.69 (m, 9H), 2.69, 2.65 (2 singlets, 3H, CH3NHC(O), rotamers), 2.35 (m, 2H), 1.98 (m, 4H), 1.63–1.41 (m, 2H), 1.07 (m, 2H), 0.86 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 172.5, 172.0, 171.9, 169.1, 169.0, 165.5, 162.3, 136.7, 136.4, 136.1, 134.8, 134.6, 134.5, 134.0, 133.9, 133.0, 132.9, 132.7, 130.5, 130.4, 128.6, 128.5, 117.0, 116.7, 116.4, 69.2, 69.0, 61.4, 56.1, 54.9, 54.0, 52.1, 51.2, 47.7, 42.8, 39.7, 39.3, 38.6, 33.2, 32.9, 32.7, 32.6, 31.6, 26.3, 25.3, 20.6, 14.6; MS m/z (ESI): 620 (M+H, 100), 622 (M+2+H, 70).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(4-chlorophenyl)-1-(2-fluoroethylcarbamoyl)-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.12–7.03 (m, 6H), 6.88 (m, 2H), 5.00 (m, 1H), 4.41–4.01 (m, 4H), 3.90–3.60 (m, 1H), 3.34–2.57 (m, 12H), 2.47–2.13 (m, 2H), 1.84–1.53 (m, 4H), 1.32 (m, 1H), 1.00 (m, 3H), 0.71 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 172.0, 171.7, 171.5, 169.0, 165.5, 162.2, 138.5, 137.9, 134.0, 133.8, 132.8, 132.7, 132.4, 129.9, 129.8, 117.0, 116.7, 116.4, 84.5, 82.3, 71.1, 61.4, 55.9, 54.9, 54.0, 52.1, 51.0, 47.7, 42.7, 41.3, 41.0, 39.6, 39.2, 38.5, 35.1, 34.7, 33.3, 32.7, 31.6, 25.3, 20.7, 20.6, 14.6; MS m/z (ESI): 618 (M+H, 100), 620 (M+2+H, 37).


Pyrrolidine-2-carboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(2-fluorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazin-1-yl}-2-oxo-ethyl)-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.27–7.03 (m, 8H), 5.13 (m, 1H), 4.69–4.30 (m, 1H), 4.24 (m, 1H), 3.99 (m, 1H), 3.49 (m, 2H), 3.16–3.00 (m, 8H), 2.65 (m, 5H), 2.38 (m, 1H), 2.00 (m, 4H), 1.30 (m, 1H), 1.05 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 171.9, 171.5, 169.6, 165.5, 164.7, 162.3, 161.5, 133.9, 133.3, 132.9, 130.2, 125.7, 117.0, 116.7, 116.4, 113.2, 69.9, 61.4, 56.7, 56.4, 52.0, 51.3, 47.8, 46.9, 42.2, 39.2, 38.5, 31.6, 29.3, 29.2, 26.3, 25.3, 17.1, 16.0; MS m/z (ESI): 542 (M+H, 100).


Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-[2-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.60–7.89 (m, 3H), 7.69 (s, 1H), 7.42–7.53 (m, 2H), 7.25–7.38 (m, 3H), 7.01–7.16 (m, 2H), 5.06–5.22 (m, 1H), 4.76–4.90 (m, 0.4H), 4.40–4.55 (m, 0.6H), 4.04–4.33 (m, 2H), 3.61–3.89 (m, 1H), 2.66–3.33 (m, 7H), 2.51–2.63 (m, 3H), 2.28–2.46 (m, 1H), 1.70–2.02 (m, 3H), 1.32–1.49 (m, 1.4H), 1.09–1.25 (m, 1.6H); 13C NMR (75 MHz, MeOD, Rotamers) δ 172.40, 171.96, 170.75, 170.50, 169.73, 165.49, 162.79, 162.25, 135.37, 134.37, 133.90, 133.86, 132.90, 129.63, 129.50, 129.05, 128.94, 128.73, 127.66, 127.26, 117.01, 116.78, 116.53, 71.30, 61.35, 56.20, 52.01, 50.26, 50.51, 50.14, 47.75, 46.33, 41.18, 39.13, 38.36, 37, 69, 35.82, 31.60, 26.38, 25.31, 17.03, 15.93; MS (ESMS) m/z 574.4 (M+H)+.


Pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-[4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-amide. 1H NMR (CDCl3, 300 MHz) 7.42˜7.89 (m, 6H), 7.19˜7.34 (m, 3H), 6.96˜7.10 (m, 2H), 4.00˜4.90 (m, 6H), 3.30˜3.90 (m, 8H), 2.80˜3.20 (m, 3H), 2.50˜2.75 (m, 3H), 2.36 (m, 1H), 1.60˜2.10 (m, 5H), 1.25 (m, 2H), 0.95 (m, 3H); MS (ES-MS) m/z 602 (M+1).


A fourth aspect of Category III melanocortin receptor ligands relate to compounds wherein R5a and R5b are taken together to form a carbocyclic or heterocyclic ring having from 3 to 10 atoms, said compounds having the general scaffold with the formula:




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wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R5a/R5b ring, R7a, R8 and Q are defined herein below in Table XIII.














TABLE XIII





No.
R1
R5a/R5b ring
Q
R7a
R8







1061
—CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1062
—CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1063
—CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1064
—CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1065
—CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1066
—CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1067
—CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1068
—CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1069
—CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1070
—CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1071
—CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1072
—CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1073
—CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1074
—CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1075
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1076
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1077
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1078
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1079
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1080
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1081
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1082
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1083
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1084
—CH2CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1085
—CH2CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1086
—CH2CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1087
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1088
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1089
—CH2(C3H5)
cyclopropyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1090
—CH2(C3H5)
cyclobutyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1091
—CH2(C3H5)
cyclopentyl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1092
—CH2(C3H5)
azetidin-2-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1093
—CH2(C3H5)
azetidin-3-yl
—NH2
—C(O)NHCH3
naphthylen-2-ylmethyl


1094
—CH2(C3H5)
cyclopropyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1095
—CH2(C3H5)
cyclobutyl
—NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1096
—CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1097
—CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1098
—CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1099
—CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1100
—CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1101
—CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1102
—CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1103
—CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1104
—CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1105
—CH2CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1106
—CH2CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1107
—CH2CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1108
—CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1109
—CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1110
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1111
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1112
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1113
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1114
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1115
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1116
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1117
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1118
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1119
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1120
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
naphthylen-2-ylmethyl


1121
—CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1122
—CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1123
—CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1124
—CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1125
—CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1126
—CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1127
—CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1128
—CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1129
—CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1130
—CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1131
—CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1132
—CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1133
—CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1134
—CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1135
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1136
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1137
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1138
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1139
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1140
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1141
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1142
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1143
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1144
—CH2CH2CH3
cyclopentyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1145
—CH2CH2CH3
azetidin-2-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1146
—CH2CH2CH3
azetidin-3-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1147
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1148
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1149
—CH2(C3H5)
cyclopropyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1150
—CH2(C3H5)
cyclobutyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1151
—CH2(C3H5)
cyclopentyl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1152
—CH2(C3H5)
azetidin-2-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1153
—CH2(C3H5)
azetidin-3-yl
—NH2
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1154
—CH2(C3H5)
cyclopropyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1155
—CH2(C3H5)
cyclobutyl
—NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1156
—CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1157
—CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1158
—CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1159
—CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1160
—CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1161
—CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1162
—CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1163
—CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1164
—CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1165
—CH2CH3
cyclopentyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1166
—CH2CH3
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1167
—CH2CH3
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1168
—CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1169
—CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1170
—CH2CH═CH2
cyclopropyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1171
—CH2CH═CH2
cyclobutyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1172
—CH2CH═CH2
cyclopentyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1173
—CH2CH═CH2
azetidin-2-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1174
—CH2CH═CH2
azetidin-3-yl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1175
—CH2CH═CH2
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1176
—CH2CH═CH2
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1177
—CH2CH2CH3
cyclopropyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1178
—CH2CH2CH3
cyclobutyl
—NH2
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1179
—CH2CH2CH3
cyclopropyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl


1180
—CH2CH2CH3
cyclobutyl
—NHCH3
—C(O)N(CH3)2
(3,4-dichlorophenyl)methyl









The compounds of the fourth aspect of Category III can be suitably prepared by the procedure outlined herein below, utilizing final analogs from the first aspect of this Category as starting points, for example, compound 41, as depicted in Scheme XVII herein below.




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EXAMPLE 15
1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-ethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide (50)

Preparation of 1-amino-cyclopropanecarboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-ethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide (50): Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-(3,4-dichlorophenyl)-N-methylpropionamide, 41, (0.3 g, 0.43 mmol) and 1-amino-cyclopropanecarboxylic acid (87 mg, 0.43 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (124 mg, 0.65 mmol) and 1-hydroxybenzotriazole (117 mg, 0.86 mmol) are dissolved in anhydrous DMF (2.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.25 mL, 2.3 mmol) is added. The reaction mixture is placed in refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. Solvent is removed in vacuo and the product dissolved in a mixture of trifluoroacetic acid, dichloromethane, and water (1:2:0.1) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added and the solvents are removed in vacuo and the resulting residue purified over prep HPLC to afford 232 mg (71% yield) of the desired compound. 1H NMR (CD3OD, 330 MHz): δ 7.55–6.90 (m, 7H), 5.18–4.22 (m, 3.5H), 4.02–3.90 (m, 0.5H), 3.70–2.15 (m, 17H), 1.88–1.12 (m, 6H), 0.80–0.6 (m, 2H). HRFAB(positive) m/e 592.225749 calculated for C29H36Cl2FN5O3 (M+H)+, Found 592.224973.


The following are non-limiting examples of compounds which comprise the fourth aspect of Category III.


1-Amino-cylopropanecarboxylic acid {2-{4-{2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, 300 MHz) ) δ 7.46–7.40-(m, 2H), 7.26–7.05 (m, 5H), 5.11–5.07 (m, 1H), 4.31 (d J=12.8 Hz, 0.5H), 4.01–3.92 (m, 1H), 3.44–3.38 (m, 0.5H), 3.35–3.33 (m, 4H), 3.11–2.95 (m, 8H), 2.68–2.66 (m, 5H), 2.33–2.29 (m, 1H), 1.80–1.32 (m, 6H). HRFAB(positive) m/e 578.210099 calculated for C28H34Cl2FN5O3 (M+H)+, Found 578.207967.


1-Amino-cylopropanecarboxylic acid {2-{4-{2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate: 1H NMR (CD3OD, 300 MHz)) δ 7.33–7.23 (m, 4H), 7.21–7.18 (m, 2H), 7.10–7.05 (m, 2H), 5.08 (t, J=7.8 Hz, 1H), 4.77 (br s, 0.5H), 4.40 (d, J=12.6 Hz, 0.5H), 4.05–4.00 (m, 1H), 3.68–3.60 (m, 0.5H), 3.50–3.40 (m, 0.5H), 3.34–3.24 (m, 3H), 3.20–2.80 (m, 8H), 2.66–2.60 (m, 4H), 1.98–1.90 (m, 0.5H), 1.69–1.60 (m, 1H), 1.55–1.40 (m, 5H), 1.13–1.00 (m, 1.5H); 13C NMR (CD3OD, 75 MHz) ) δ 174.0, 173.0, 172.0, 171.0, 165.5, 162.5, 162.2, 162.0, 137.4, 134.0, 132.8, 132.4, 130.0, 116.8, 71.1, 56.3, 52.3, 50.9, 50.3, 50.0, 49.7, 46.4, 41.4, 38.7, 38.0, 36.7, 35.0, 26.4, 17.0, 15.9, 13.9. HRFAB(positive) m/e 544.249071 calculated for C28H35ClFN5O3 (M+H)+, Found 544.248512.


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-(2-fluoroethylcarbamoyl)-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz)) δ 7.50–7.38 (m, 6H), 7.25 (m, 2H), 5.33 (m, 1H), 4.76–4.49 (m, 3H), 4.23–3.90 (m, 1H), 3.73–3.54 (m, 2H), 3.40–3.01 (m, 8H), 2.83 (m, 1H), 2.52–2.04 (m, 1H), 1.90–1.06 (m, 11H); 13C NMR (CD3OD, 75 MHz) ) δ 172.2, 171.8, 171.5, 170.9, 165.5, 162.2, 138.5, 137.8, 134.2, 134.0, 133.8, 132.7, 132.6, 132.4, 129.9, 117.1, 116.7, 116.5, 84.5, 82.2, 71.0, 55.9, 54.9, 53.7, 52.3, 51.0, 42.5, 41.3, 41.0, 39.2, 38.0, 36.7, 35.1, 34.7, 33.2, 32.7, 20.8, 20.6, 14.6, 13.9, 13.8; MS m/z (ESI): 604 (M+H, 100), 606 (M+2+H, 37).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-(2-fluoroethylcarbamoyl)-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz, with rotamers) δ 7.50–7.40 (m, 6H), 7.27 (dd, 2H, J=18.9, 10.1 Hz), 5.36 (m, 1H), 4.76–4.49 (m, 3H), 4.22–3.94 (m, 1H), 3.70–3.57 (m, 2H), 3.35–3.04 (m, 8H), 2.90 (s, 3H), 2.83 (m, 1H), 2.48–2.07 (m, 1H), 1.94–1.05 (m, 11H); 13C NMR (CD3OD, 75 MHz, with rotamers) δ 172.4, 172.0, 171.6, 169.6, 165.5, 162.4, 138.6, 138.0, 134.3, 132.8, 132.4, 129.9, 117.0, 116.7, 116.4, 113.7, 84.5, 82.3, 71.1, 55.9, 55.0, 53.8, 52.3, 51.1, 44.0, 42.6, 41.3, 41.0, 39.3, 39.1, 38.0, 35.1, 34.7, 33.3, 32.7, 20.6, 14.6, 13.8; MS m/z (ESI): 618 (M+H, 100), 620(M+2+H, 37).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz, with rotamers) δ 7.39–7.09 (m, 8H), 5.22 (m, 1H), 4.66–4.38 (m, 1H), 4.14–3.75 (m, 1H), 3.56–2.89 (m, 10H), 2.75, 2.72 (2 singlets, 3H, CH3NHC(O), rotamers), 2.37–0.95 (m, 11H); 13C NMR (CD3OD, 75 MHz, with rotamers) δ 172.5, 172.2, 171.8, 170.9, 170.5, 165.3, 162.2, 138.6, 137.8, 134.1, 132.7, 132.3, 129.9, 129.8, 117.1, 116.7, 116.5, 71.2, 55.9, 54.9, 53.7, 52.3, 50.9, 42.4, 39.2, 38.0, 36.7, 35.1, 34.8, 33.1, 32.6, 26.3, 20.7, 20.6, 14.6, 13.9, 13.8; MS m/z (ESI): 572 (M+H, 100), 574 (M+2+H, 37).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz, with rotamers) δ 7.46–7.16 (m, 8H), 5.30 (m, 1H), 4.77–4.47 (m, 1H), 4.24–3.87 (m, 1H), 3.74 (m, 1H), 3.43–3.04 (m, 8H), 286,2 2.85 (2 singlets, 3H, CH3NHC(O), rotamers), 2.81, 2.77 (2 singlets, 3H, CH3NHC(CH2—CH2)C(O), rotamers), 2.58–2.00 (Im, 1H), 1.83–1.02 (m, 11H); 13C NMR (CD3OD, 75 MHz, with rotamers) δ 172.1, 171.7, 171.2, 169.8, 165.5, 162.2, 138.4, 137.5, 134.2, 133.8, 132.8, 132.7, 132.4, 130.0, 129.8, 117.1, 116.8, 116.5, 71.1, 55.8, 54.9, 53.6, 52.3, 50.7, 44.1, 42.2, 39.1, 37.9, 35.0, 34.8, 33.3. 33.2, 32.6, 26.3, 20.7, 20.6, 14.5, 13.8, 13.6; MS m/z (ESI): 586 (M+H, 100), 588 (M+2+H, 37).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(2,4-dichlorophenyl-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz, with rotamers) 6 7.45 (m, 1H), 7.26 (m, 4H), 7.06 (m, 2H), 5.12 (m, 1H), 4.57–4.35 (m, 1H), 4.05–3.63 (m, 2H), 3.41–2.87 (m, 6H), 6H), 2.68, 2.64 (2 singlets, 3H, CH3NHC(O), rotamers), 2.28–1.74 (m, 1H), 1.65–0.77 (m, 11H); 13C NMR (CD3OD, 75 MHz, with rotamers) δ 172.2, 171.9, 171.0, 170.6, 165.4, 162.5, 162.2, 136.5, 136.3, 135.4, 135.0, 134.5, 134.1, 132.9, 132.8, 132.6, 130.6, 130.5, 128.7, 128.5, 119.9, 117.1, 116.8, 116.5, 69.0, 68.9, 55.9, 54.7, 52.3, 50.8, 42.2, 39.2, 38.0, 36.7, 33.0, 32.7, 32.5, 26.4, 20.7, 20.6, 14.6, 14.0, 13.8; MS m/z (ESI): 606 (M+H, 100), 608 (M+2+H, 70).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(2,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide trifluoroacetate. 1H NMR (CD3OD, 300 MHz, with rotamers) δ 7.55 (m, 1H), 7.39 (m, 4H), 7.19 (m, 3H), 5.25 (m, 1H), 4.59–4.36 (m, 1H), 4.06–3.75 (m, 1H), 3.57–2.98 (m, 9H), 2.98, 2.85, 2.77 (3 singlets, 6H, CH3NHC(O) and CH3NHC(CH2—CH2)C(O), rotamers), 2.65 (m, 1H), 2.24–0.94 (m, 11H); 13C NMR (CD3OD, 75 MHz, with rotamers) δ 172.8, 172.6, 172.0, 171.6, 169.6, 136.8, 136.3, 134.5, 134.1, 132.8 130.4, 128.5, 117.3, 116.7, 116.4, 69.2, 69.1, 63.6, 56.3, 55.0, 52.4, 52.2, 51.6, 44.1, 43.2, 39.7, 39.2, 38.0, 36.0, 33.2, 33.0, 32.8, 32.6, 26.3, 20.6, 14.7, 13.8, 13.6; MS m/z (ESI): 620 (M+H, 100), 622 (M+2+H, 70).


1-Amino-cyclopropanecarboxylic acid (1-(4-fluorobenzyl)-2-{4-[2-(2-fluorophenyl)-1-methylcarbamoyl-ethyl]-2-methyl-piperazin-1-yl}-2-oxo-ethyl)-amide trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.27–7.03 (m, 8H), 5.07 (t, 1H, J=7.7 Hz), 4.68–4.33 (m, 1H), 3.99 (m, 1H), 3.52 (m, 1H), 3.19–2.97 (m, 7H), 2.74–2.63 (m, 5H), 2.37–1.82 (m, 1H), 1.66 (m, 1H), 1.49–1.29 (m, 4H), 1.01 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 172.2, 171.8, 170.9, 165.5, 164.7, 162.2, 161.4, 134.1, 133.3, 132.8, 130.3, 125.7, 117.0, 116.8, 116.4, 65.8, 56.6, 56.4, 52.3, 51.2, 46.8, 42.0, 38.8, 38.5, 38.0, 36.7, 29.3, 26.3, 17.0, 15.9, 13.9; MS m/z (ESI): 528 (M+H, 100).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(3,4-difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, CD3OD) δ 0.880 (m, 3H), 1.177 (m, 2H), 1.393 (m, 2H), 1.444 (m, 2H), 1.493 (m, 2H), 1.651 (m, 1H), 2.631, 2.669 (2 singlets, 3H, CH3NHC(O), rotamers), 3.182 (m, 3H), 3.206 (m, 3H), 3.753 (m, 1H), 4.692 (m, 1H), 5.129 (m, 1H), 7.040 (m, 3H), 7.145 (m, 2H), 7.288 (m, 2H), 19F NMR (282 MHz, CD3OD with rotamers) δ 19.561, 20.168, 22.322, 22.663, 45.202, 46.12; 13C NMR (75 MHz, CD3OD with rotamers) δ 163.3, 162.8, 162.2, 137.8, 137.1, 134.2, 134.1, 132.9, 132.7, 132.6, 127.2, 119.6, 119.4, 118.5, 118.4, 118.3, 118.2, 117.1, 116.7, 116.4, 71.114, 71.0, 56.1, 54.9, 52.3, 51.2, 50.3, 50.1, 42.9, 38.0, 36.7, 34.9, 33.1, 32.7, 26.3, 20.7, 20.6, 14.6, 13.9, 13.8; MS m/e 674 (M+1).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(3,4-difluorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (300 MHz, CD3OD) δ 0.902 (m, 3H), 1.091 (m, 2H), 1.481 (m, 4H), 1.655 (m, 2H), 1.753 (m, 1H), □2.273 (m, 1H), 2.653, 2.713 (2 singlets, 3H, CH3NHC(O), rotamers), 2.707 (m, 5H), 3.046 (m, 4H), 3.166 (m, 1H), 4.580 (m, 1H), 5.160 (m, 1H), 7.045 (m, 3H), 7.142 (m, 2H), 7.278 (m, 2H), 19F NMR (282 MHz, CD3OD with rotamers) δ 18.901, 19.388, 21.878, 22.176, 45.099, 45.884; 13C NMR (75 MHz, CD3OD with rotamers) δ 134.3, 132.8, 132.7, 127.1, 119.6, 119.4, 118.2, 117.0, 116.7, 116.4, 71.1, 56.1, 55.0, 53.8, 52.3, 51.3, 50.2, 44.0, 43.0, 39.2, 38.0, 35.0, 34.6, 33.2, 32.7, 26.2, 20.6, 14.6, 13.7; MS m/e 588 (M+1).


The fifth aspect of Category III comprises compounds having the formula:




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wherein R is a substituted phenyl unit as described herein above and non-limiting examples of R1, R7a, R8, and Q are defined herein below in Table XIV and in the examples which follow.













TABLE XIV





No.
R1
Q
R7a
R8







1181
—CH3
—CH2OCH3
—C(O)NH2
naphthylen-2-ylmethyl


1182
—CH3
—CH2OCH3
—C(O)NH2
(2-chlorophenyl)methyl


1183
—CH3
—CH2OCH3
—C(O)NH2
(3-chlorophenyl)methyl


1184
—CH3
—CH2OCH3
—C(O)NH2
(4-chlorophenyl)methyl


1185
—CH3
—CH2OCH3
—C(O)NH2
(2,4-dichlorophenyl)methyl


1186
—CH3
—CH2OCH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


1187
—CH3
—CH2OCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1188
—CH3
—CH2OCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1189
—CH3
—CH2OCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1190
—CH3
—CH2OCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1191
—CH3
—CH2OCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1192
—CH3
—CH2OCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1193
—CH2CH3
—CH2OCH3
—C(O)NH2
naphthylen-2-ylmethyl


1194
—CH2CH3
—CH2OCH3
—C(O)NH2
(2-chlorophenyl)methyl


1195
—CH2CH3
—CH2OCH3
—C(O)NH2
(3-chlorophenyl)methyl


1196
—CH2CH3
—CH2OCH3
—C(O)NH2
(4-chlorophenyl)methyl


1197
—CH2CH3
—CH2OCH3
—C(O)NH2
(2,4-dichlorophenyl)methyl


1198
—CH2CH3
—CH2OCH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


1199
—CH2CH3
—CH2OCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1200
—CH2CH3
—CH2OCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1201
—CH2CH3
—CH2OCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1202
—CH2CH3
—CH2OCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1203
—CH2CH3
—CH2OCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1204
—CH2CH3
—CH2OCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1205
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
naphthylen-2-ylmethyl


1206
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
(2-chlorophenyl)methyl


1207
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
(3-chlorophenyl)methyl


1208
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
(4-chlorophenyl)methyl


1209
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
(2,4-dichlorophenyl)methyl


1210
—CH2CH2CH3
—CH2OCH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


1211
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1212
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1213
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1214
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1215
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1216
—CH2CH2CH3
—CH2OCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1217
—CH3
—OCH3
—C(O)NH2
naphthylen-2-ylmethyl


1218
—CH3
—OCH3
—C(O)NH2
(2-chlorophenyl)methyl


1219
—CH3
—OCH3
—C(O)NH2
(3-chlorophenyl)methyl


1220
—CH3
—OCH3
—C(O)NH2
(4-chlorophenyl)methyl


1221
—CH3
—OCH3
—C(O)NH2
(2,4-dichlorophenyl)methyl


1222
—CH3
—OCH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


1223
—CH3
—OCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1224
—CH3
—OCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1225
—CH3
—OCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1226
—CH3
—OCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1227
—CH3
—OCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1228
—CH3
—OCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1229
—CH2CH3
—OCH3
—C(O)NH2
naphthylen-2-ylmethyl


1230
—CH2CH3
—OCH3
—C(O)NH2
(2-chlorophenyl)methyl


1231
—CH2CH3
—OCH3
—C(O)NH2
(3-chlorophenyl)methyl


1232
—CH2CH3
—OCH3
—C(O)NH2
(4-chlorophenyl)methyl


1233
—CH2CH3
—OCH3
—C(O)NH2
(2,4-dichlorophenyl)methyl


1234
—CH2CH3
—OCH3
—C(O)NH2
(3,4-dichlorophenyl)methyl


1235
—CH2CH3
—OCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1236
—CH2CH3
—OCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1237
—CH2CH3
—OCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1238
—CH2CH3
—OCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1239
—CH2CH3
—OCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1240
—CH2CH3
—OCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1241
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1242
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1243
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1244
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1245
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1246
—CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1247
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1248
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1249
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1250
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1251
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1252
—CH2CH3
—CH(CH3)NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1253
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1254
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1255
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1256
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1257
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1258
—CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1259
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
naphthylen-2-ylmethyl


1260
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(2-chlorophenyl)methyl


1261
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(3-chlorophenyl)methyl


1262
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(4-chlorophenyl)methyl


1263
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1264
—CH2CH3
—C(CH3)2NHCH3
—C(O)NHCH3
(3,4-dichlorophenyl)methyl









The following are non-limiting examples of compounds which comprise the fifth aspect of Category III.


Preparation of 2-{3-ethyl-4-[3-(4-fluorophenyl)-2-(2-methoxy-acetylamino)-propionyl]piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl (0.3 g, 0.6 mmol) and methoxy acetic acid (0.05 mL, 0.6 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (0.22 g, 1.1 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) are dissolved in anhydrous DMF (2.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.2 mL, 1.7 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, the organic layer is separated, and the aqueous layer is extracted with EtOAc (3×30 mL). The organic extracts are combined, washed with water (2×50 mL), dried over Na2SO4 and concentrated in vacuo and the crude product is purified by preparative HPLC to afford 0.18 g (44% yield) of the trifluoroacetate salt of the desired product. 1H NMR (CD3OD, δ): 7.88–7.68 (m, 4H), 7.49–7.00 (m, 7H), 5.25–5.12 (m, 1H), 4.98–4.92 (m, 4H), 4.70 (br s, 0.5H), 4.52 (d, J=13.0 Hz, 0.5H), 4.18 (d, J=10.4 Hz, 0.5H), 3.96 (dd, J=13.0, 6.5 Hz, 0.5H), 3.86 (s, 2H), 3.75 (t, J=3.9 Hz, 0.5H), 3.61 (d, J=13.0 Hz, 0.5H), 3.52–3.18 (m, 7H), 3.18–2.92 (m, 3H), 2.85–2.78 (m, 0.5H), 2.60–2.45 (m, 2H), 2.12–2.05 ( m, 0.5H), 1.98–1.70 (m, 2H), 0.85–0.78 (m, 3H); 13C NMR, δ 173.0, 172.0, 170.0, 168.0, 166.0, 163.0, 162.0, 135.5, 134.4, 134.1, 133.0, 132.8, 132.7, 129.9, 129.7, 129.6, 129.1, 129.0, 128.6, 127.8, 127.5, 127.3, 117.0, 116.8, 116.5, 72.7, 71.4, 71.0, 60.0, 56.0, 53.4, 51.5, 51.4, 51.1, 51.0, 40.5, 39.9, 38.4, 35.4, 35.3, 26.5, 24.1, 23.4, 11.0, 10.8. HRFAB(positive) m/e 563.3034 calculated for C32H39FN4O4 (M+H)+, Found 563.3051.


Preparation of [2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester trifluoroacetate: To a cold solution of 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide HCl, 41, (0.3 g, 0.6 mmol) in anhydrous DCM (5 mL) is added methyl chloroformate (0.1 mL, 1.3 mmol) and DIEA (0.2 mL, 1.1 mmol). The reaction mixture is allowed to stir for 2 hours at this temperature. EtOAc (15 mL) and water (15 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×20 mL). All organic layers are combined and washed with water (2×20 mL), and dried over Na2SO4. Solvent is removed in vacuo and the product is purified by preparative HPLC to give TFA salt (0.14 g, 0.21 mmol, 35% yield). A small amount of product was converted into the free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 7.83–7.75 (m, 3H), 7.67 (s, 1H), 7.46–7.28 (m, 3H), 7.17–7.13 (m, 2H), 7.00–6.94 (m, 2H), 6.60–6.40 (m, 0.5H), 5.66–5.63 (m, 0.5H), 4.95–4.78 (m, 1H), 4.30 (br s, 0.5H), 4.32–4.28 (m, 0.5H), 3.68 (s, 2H), 3.61 (s, 1H), 3.50–3.28 (m, 3H), 3.00–2.76 (m, 8H), 2.55–2.40 (m, 2H), 2.19 (td, J=10.4, 2.6 Hz, 1H), 1.90–1.75 (m, 1H), 1.65–1.22 (m, 2H), 0.83 (quartet, J=7.2 Hz, 3H); 13C NMR; δ 171.9, 170.3, 169.8, 163.8, 160.5, 156.4, 137.3, 133.7, 132.3, 132.1, 132.0, 131.4, 131.3, 131.2, 128.3, 127.9, 127.8, 127.7, 126.3, 125.7, 115.9, 115.7, 115.4, 70.7, 70.5, 55.4, 52.5, 51.9, 51.7, 51.6, 51.1, 51.0, 50.2, 49.7, 41.8, 40.0, 39.2, 37.9, 32.3, 26.2, 26.0, 23.3, 22.2, 10.8, 10.4. HRFAB (positive) m/e 549.2877 calculated for C31H37FN4O4 (M+H)+, Found 549.2868.


3-(3,4-Dichlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-(2-methyl-2-methylamino-propionyl amino)-propionyl}-3-methyl-piperazin-1-yl}-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, δ): 7.20–7.16 (m, 2H), 7.04 (br s, 2H), 6.91-(m, 3H), 4.85 (br s, 1H), 4.04 (d J=13.2 Hz, 0.5H), 3.76–3.55 (m, 1H), 3.12–3.07 (m, 7H), 2.81–2.58 (m, 6H), 2.44–2.30 (m, 6H), 1.58–1.55 (m, 0.5H), 1.33–1.22 (m, 6H), 1.08–0.95 (m, 2H), 0.85–0.83 (m, 1H). HRFAB(positive) m/e 594.241399 calculated for C29H38Cl2FN5O3 (M+H)+, Found 594.238873.


3-(3,4-Dichlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-(2-methylamino-propionylamino)-propionyl]-3-methyl-piperazin-1-yl}-N-methyl-propionamide: 1H NMR (CD3OD): δ 7.59–7.54 9 m, 2H), 7.44 (bs, 2H), 7.30–7.19 (m, 3H), 5.28–5.19 (m, 1H), 4.44 (d, J=12.4 Hz, 0.5H), 4.14–3.95 (m, 2H), 3.61–3.60 (m, 0.5H), 3.48–3.46 (m, 3H), 3.32–2.92 (m, 7H), 2.82–2.78 (m, 4H), 2.72–2.67 (m, 5H), 1.97–1.87 (m, 0.5H), 1.64 (d, J=7.0 Hz, 3H), 1.47–1.34 (m, 1.5H), 1.24–1.22 (m, 1H); 13C NMR (CD3OD): δ 173.0, 172.0, 170.0, 165.5, 162.3, 140.3, 139.8, 133.9, 133.5, 132.9, 131.8, 130.8, 116.8, 70.8, 58.6, 56.4, 51.8, 51.2, 50.3, 50.0, 49.6, 46.8, 42.0, 39.2, 38.5, 34.6, 32.2, 26.3, 17.2, 16.7, 16.0. HRFAB(positive) m/e 580.225749calculated for C28H36Cl2FN5O3 (M+H)+, Found 580.223868.


3-(3,4-Dichlorophenyl)-2-{4-[2-(2-dimethylamino-acetylamino)-3-(4-fluorophenyl)-propionyl]-3-methyl-piperazin-1-yl}-N-methyl-propionamide. 1H NMR (CD3OD): δ 7.68–7.60 (m, 2H), 7.55–7.45 (m, 2H), 7.38–7.18 (m, 3H), 5.39–5.30 (m, 1H), 4.98–4.91 (m, 0.5H), 4.58–4.49 (m, 0.5H), 4.20–4.10 (m, 3H), 3.72–3.48 (m, 5H), 3.32–3.08 (m, 10H), 2.92–2.85 (m, 5H), 2.58–2.48 (m, 0.5H), 2.05–1.92 (m, 0.5H), 1.54–1.48 (m, 1.5H), 1.3–1.20 (m, 1.5H); 13C NMR δ 174.0, 172.0, 165.5, 162.7, 140.3, 139.9, 133.8, 133.5, 132.8, 131.8, 130.7, 117.1, 116.8, 116.5, 70.9, 70.7, 59.4, 56.6, 56.4, 52.0, 51.2, 50.2, 50.0, 49.6, 49.4, 49.1, 46.844.8, 42.0, 39.3, 38.5, 34.9, 34.7, 26.3, 17.1, 16.0. HRFAB(positive) m/e 580.225749 calculated for C28H36Cl2FN5O3 (M+H)+, Found 580.223768.


2-{4-[3-(4-Fluorophenyl)-2-methylamino-propionyl]-2-oxo-3-propyl-piperazin-1-yl}-3-naphthalen-2-yl-N-(2,2,2-trifluoroethyl)-propionamide: 1H NMR (300 MHz, MeOD, Rotamers) δ 8.78–8.84 (m, 0.4H), 7.78–7.91 (m, 3H), 7.72 (s, 0.2H), 7.65 (s, 0.8H), 7.38–7.59 (m, 3H), 7.13–7.30 (m, 2H), 6.94–7.11 (m, 2H), 5.58–5.72 (m, 1H), 4.52–4.66 (m, 1.6H), 3.82–4.36 (m, 2H), 3.40–3.66 (m, 2H), 3.14–3.32 (m, 3.4H), 2.78–3.03 (m, 1.4H), 2.65–2.74 (m, 0.6H), 2.61 (s, 0.6H), 2.58 (s, 2.4H), 0.64–1.16 (m, 2H), 0.18–0.58 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 172.83, 170.14, 168.35, 167.42, 165.92, 162.82, 162.66, 162.35, 135.67, 135.28, 134.39, 133.1, 133.05, 132.58, 132.46, 130.91, 130.39, 129.76, 129.16, 129.09, 128.90, 128.49, 128.07, 127.86, 127.35, 117.83, 117.54, 117.36, 117.08, 60.63, 60.70, 59.42, 58.46, 58.14, 57.32, 43.90, 43.13, 42.85, 42.36, 41.90, 41.44, 40.98, 40.96, 39.63, 37.38, 36.84, 35.92, 35.75, 32.58, 20.03, 19.88, 14.09; MS (ESMS) m/z 601.3 (M+H)+.


[2-{4-[2-(3,4-Dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester: 1H NMR (300 MHz, MeOD, Rotamers) δ 7.40–7.50 (m, 2H), 7.23–7.34 (m, 2H), 7.12–7.21 (m,1H), 6.99–7.21 (m, 2H), 4.78–4.88 (m, 1H), 4.57–4.68 (m, 0.6H), 4.28–4.37 (m, 0.4H), 4.00–4.10 (m, 0.4H), 3.64 (s, 3H), 3.44–3.54 (m, 0.4H), 2.62–3.32 (m,12H), 2.12–2.28 (m, 0.4H), 1.26–1.77 (m, 2.5H), 0.94–1.26 (m, 1.5H), 0.88 (dd, J=13.2, 6.6 Hz, 3H); MS (ESMS) m/z 581.4, 583.2, 585.6 (M+H)+, Cl2 isotope pattern.


[2-{4-[2-(2-Chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.20 (m, 1H), 7.07 (m, 5H), 6.85 (m, 2H), 4.62 (m, 1H), 4.47–4.16 (m, 1H), 3.89–3.49 (m, 1H), 3.42 (s, 3H), 3.25–2.64 (m, 9H), 2.45, 2.40 (2 singlets, 3H, CH3NHC(O), rotamers), 2.10–1.60 (m, 1H), 1.42–1.23 (m, 2H), 0.90–0.66 (m, 5H); 13C NMR (CD3OD, with rotamers) δ 172.7, 172.5, 172.0, 170.3, 165.4, 162.2, 159.3, 137.0, 135.6, 134.2, 133.5, 132.8, 132.7, 131.1, 130.9, 130.4, 129.9, 128.6, 128.4, 117.0, 116.4, 69.7, 69.3, 55.6, 54.0, 53.7, 53.4, 53.1, 51.5, 41.4, 40.2, 38.8, 33.2, 32.5, 26.4, 20.6, 20.5, 14.6; MS m/z (ESI): 547 (M+H, 100), 549 (M+2+H, 35).


[2-{4-[2-(4-Chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester trifluoroacetate. 1H NMR (CD3OD, with rotamers) δ 7.45 (m, 4H), 7.20 (m, 2H), 7.05 (m, 2H), 4.84 (m,1H), 4.72–4.03 (m, 1H), 4.16–3.76 (m, 1H), 3.70 (s, 3H), 3.43 (m, 1H), 3.24–2.97 (m, 8H), 2.66, 2.61 (2 singlets, 3H, CH3NHC(O), rotamers), 2.50–1.89 (m, 1H), 1.75–0.99 (m, 4H), 0.90 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 172.6, 172.3, 170.9, 169.3, 164.4, 162.8, 161.6, 161.4, 159.1, 158.7, 137.3, 135.9, 134.4, 134.1, 134.0, 132.7, 132.5, 132.2, 132.1, 130.0, 129.7, 118.4, 116.7, 116.5, 116.4, 116.3, 71.3, 70.8, 55.0, 53.9, 53.4, 53.2, 53.1, 52.9, 51.2, 49.9, 40.7, 39.8, 38.4, 38.0, 34.3, 33.0, 32.3, 26.2, 26.1, 20.4, 20.2, 14.3, 14.2; MS m/z (ESI): 547 (M+H, 100), 549 (M+2+H, 35).


[2-{4-[2-(3-Chlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.27 (m, 5H), 7.18 (m, 1H), 7.05 (m, 2H), 4.84 (m, 1H), 4.68–4.39 (m, 1H), 4.13–3.70 (m, 1H), 3.63 (s, 3H), 3.38–2.89 (m, 9H), 2.66, 2.61 (2 singlets, 3H, CH3NHC(O), rotamers), 2.37–1.81 (m, 1H), 1.69 (m, 1H), 1.47 (m, 1H), 1.11 (m, 2H), 0.90 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 173.0, 172.8, 172.0, 170.4, 165.4, 162.2, 159.3, 141.7, 140.3, 135.8, 135.6, 134.3, 132.9, 132.8, 132.7, 131.5, 131.3, 130.9, 129.3, 128.7, 128.2, 117.0, 116.7, 116.4, 71.5, 71.0, 55.5, 54.2, 53.8, 53.3, 53.1, 51.3, 41.3, 40.1, 38.7, 34.9, 33.2, 32.5, 26.4, 20.6, 20.5, 14.5; MS m/z (ESI): 547 (M+H, 100), 549 (M+2+H, 35).


3-(4-Chlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-(2-hydroxy-2-methyl-propionylamino)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.18–7.09 (m, 6H), 6.94 (m, 2H), 4.97 (m, 1H), 4.59–4.29 (m, 1H), 3.99–3.66 (m, 1H), 3.53–3.28 (m, 1H), 3.15–2.75 (m, 8H), 2.54, 2.49 (2 singlets, 3H, CH3NHC(O), rotamers), 2.30–1.72 (m, 1H), 1.55–1.42 (m, 2H), 1.22, 1.16 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.01 (m, 2H), 0.80 (t, 3H, J=7.2 Hz); 13C NMR (CD3OD, with rotamers) δ 179.3, 178.9, 171.9, 171.8, 171.3, 169.8, 164.4, 162.8, 161.4, 161.2, 137.6, 136.3, 134.3, 133.8, 133.7, 132.8, 132.7, 132.6, 132.2, 132.1, 129.9, 129.7, 118.4, 116.7, 116.6, 116.4, 116.3, 73.8, 71.3, 70.9, 55.2, 54.2, 53.9, 51.2, 51.0, 50.8, 50.0, 40.9, 40.2, 38.6, 38.3, 34.6, 34.4, 33.2, 32.4, 28.0, 27.9, 27.8, 26.2, 26.1, 20.3, 20.2, 14.4, 14.3; MS m/z(ESI): 575 (M+H, 100), 577 (M+2+H, 30).


3-(3-Chlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-(2-hydroxy-2-methyl-propionylamino)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.17 (m, 5H), 7.07–6.89 (m, 3H), 4.98 (m, 1H), 4.59–4.30 (m, 1H), 4.00–3.66 (m, 1H), 3.54–3.27 (m, 1H), 3.13–2.75 (m, 8H), 2.54, 2.49 (2 singlets, 3H, CH3NHC(O), rotamers), 2.31–1.71 (m, 1H), 1.61–1.39 (m, 2H), 1.22, 1.16 (2 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.02 (m, 2H), 0.80 (m 3H); 13C NMR (CD3OD, with rotamers) δ 179.5, 179.1, 172.2, 172.0, 171.5, 170.0, 165.5, 162.2, 161.6, 161.1, 141.5, 140.1, 135.8, 135.6, 133.9, 132.9, 132.8, 131.5, 131.3, 129.3, 129.2, 128.7, 117.1, 116.7, 116.4, 74.0, 71.5, 71.0, 55.5, 54.5, 54.2, 51.5, 51.2, 51.1, 41.2, 40.5, 38.8, 38.5, 35.0, 34.9, 33.4, 32.6, 28.2, 28.1, 26.4, 20.5, 20.4, 14.5; MS m/z(ESI): 575 (M+H, 100), 577 (M+2+H, 30).


3-(2,4-Dichlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-(2-hydroxy-2-methyl-propionylamino)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-propionamide trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.46 (d, 1H, J=8.8 Hz), 7.24 (m, 4H), 7.04 (dd, 2H, J=18.2, 8.9 Hz), 5.05 (m, 1H), 4.59–4.30 (m, 1H), 3.93–3.66 (m, 1H), 3.54–3.35 (m, 1H), 3.18–2.94 (m, 6H), 2.77 (m, 2H), 2.67, 2.62 (2 singlets, 3H, CH3NHC(O), rotamers), 2.15–1.69 (m, 1H), 1.58–1.41 (m, 2H), 1.31, 1.28, 1.25 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers), 1.10 (m, 2H), 0.86 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 179.0, 178.8, 172.2, 172.0, 171.5, 165.5, 162.2, 136.5, 136.4, 135.5, 135.0, 134.6, 134.0, 133.0, 130.6, 130.5, 128.7, 128.5, 117.0, 116.7, 116.4, 74.1, 69.4, 69.0, 56.0, 54.7, 54.2, 51.4, 51.0, 50.9, 42.0, 40.5, 39.1, 39.0, 33.5, 32.8, 32.7, 32.6, 28.3, 28.1, 26.4, 20.6, 20.4, 14.6; MS m/z (ESI): 609 (M+H, 100), 611 (M+2+H, 70).


{1-(4-Fluorobenzyl)-2-[4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-2-propyl-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δ 7.00˜7.90 (m, 11H), 4.84 (m, 1H), 3.80˜4.20 (m, 1H), 3.99˜3.90 (m, 14H), 2.66 (m, 3H), 1.50˜1.80 (m, 2H), 1.00˜1.40 (m, 2H), 0.93 (m, 3H); MS (ES-MS) m/z 563 (M+1).


2-{4-[3-(4-Fluorophenyl)-2-(2-hydroxy-2-methyl-propionylamino)-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) δ 6.93˜7.90 (m, 11H), 5.00˜5.18 (m, 1H), 3.20˜3.70 (m, 4H), 2.70˜3.01 (m, 9H), 1.00˜1.70 (m, 10H), 0.88 (m, 3H); MS (ES-MS) m/z 591 (M+1).


2-{4-[3-(4-Chlorophenyl)-2-methylamino-propionyl]-3-propyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, 300 MHz) δ 7.000˜7.83 (m, 11H), 3.20˜3.70 (m, 4H), 2.40˜3.10 (m, 10H), 2.05˜2.35 (m, 5H), 1.00˜1.83 (m, 4H), 0.91 (m, 3H); MS (ES-MS) m/z 535 (M+1).


[2-{4-[2-(2,4-Dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-propyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid methyl ester trifluoroacetate: 1H NMR (CD3OD, with rotamers) δ 7.47 (d, 1H, J=8.7 Hz), 7.26 (m, 4H), 7.04 (dd, 2H, J=16.4, 8.1 Hz), 4.81 (m, 1H), 4.61–4.33 (m, 1H), 4.04–3.56 (m, 1H), 3.62 (s, 3H), 3.38 (m, 1H), 3.20–2.77 (m, 8H), 2.68, 2.64 (2 singlets, 3H, CH3NHC(O), rotamers), 2.19–1.72 (m, 1H), 1.57–1.39 (m, 2H), 1.03 (m, 2H), 0.86 (m, 3H); 13C NMR (CD3OD, with rotamers) δ 173.3, 173.0, 171.0, 165.4, 162.2, 159.3, 158.9, 136.4, 135.2, 134.6, 134.3, 133.0, 132.8, 132.7, 130.6, 130.5, 128.7, 128.5, 116.9, 116.7, 116.4, 69.4, 69.1, 55.8, 54.2, 53.9, 53.4, 53.1, 51.2, 50.6, 41.8, 40.2, 39.1, 38.8, 33.2, 32.7, 32.5, 26.4, 20.5, 14.6; MS m/z (ESI): 581 (M+H, 100), 583 (M+2+H, 70)


2-{4-[3-(4-Fluorophenyl)-2-(2-methylamino-acetylamino)-propionyl]-3-methyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide: 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.75–7.89 (m, 3H), 7.69 (s, 1H), 7.22–7.54 (m, 5H), 6.99–7.15 (m, 2H), 5.03–5.22 (m, 1H), 4.34–4.49 (m, 0.6H), 3.42–4.12 (m, 6H), 2.48–3.30 (m, 9H), 1.85–2.00 (m, 1H), 1.02–1.43 (m, 3H); MS (ESMS) m/z 548.4 (M+H)+.


The compounds which comprise Category III are also compounds wherein R7a is hydrogen, as described herein above, and as provided by example in the description of Category II analogs according to the present invention.


The Category IV melanocortin receptor ligands according to the present invention comprises the 2-hydrocarbyl-pyrrolidines having the general scaffold with the formula:




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the first aspect of which comprises pyrrolidine analogs having the formula:




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wherein R, R1, and R8 are defined herein above. The compounds which comprise the first aspect of Category IV can be prepared by the procedure outline herein below in Scheme XVI. Starting material 51 can be obtained from N-Boc-3-(R)-hydroxypyrrolidine as set forth therein below.


Preparation of N-Boc-3-R-hydroxypyrrolidine: Di-tert-butyl dicarbonate (14.0 g, 63.1 mmol) is added to a stirred solution of 3-R-hydroxypyrrolidine (5.0 g, 57.4 mol) and triethylamine (16 mL, 114.8 mmol) dissolved in dichloromethane (58 ml) at 0° C. The resulting solution is allowed to warm to room temperature and stirred for 4 hours. The solution is then diluted with dichloromethane (50 mL), washed twice with 1 N HCl and twice with aq. NaHCO3 solution. The organic layer is then dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (9.9 g, 92%) as a white solid which is sufficiently pure for use without further purification.


Preparation of N-Boc-2-S-allyl-4-R-hydroxypyrrolidine: A solution of N-Boc-3-R-hydroxypyrrolidine (3.0 g, 16.0 mmol), and TMEDA (6.4 mL, 40.1 mmol) is dissolved in THF (50 mL) and cooled to −78° C. To this reaction mixture is added a solution of 1.3 M sec-butyl lithium (50 mL) in cyclohexanes with stirring. The resulting orange-colored mixture is allowed to warm to −40° C. and stirred for 2.75 hours. The mixture is again cooled to −78° C. and allyl bromide (3.1 mL, 35.3 mmol) is added. This mixture is slowly warmed to room temperature with stirring over 4.5 hours. The reaction is quenched with aq. NH4Cl solution and extracted with ethyl acetate (150 mL). The organic layer is then dried over Na2SO4, filtered and concentrated in vacuo. The oily residue is purified over silica gel (CH2Cl2/acetone, 3:1) to afford the desired product (2.0 g, 56%) as a clear oil.


Preparation of N-Boc-2-(S)-allyl-4-(R)-(benzyloxy)pyrrolidine: Sodium hydride (408 mg, 11.5 mmol) is added in portions to a stirred solution of N-Boc-2-S-allyl-4-R-hydroxypyrrolidine (2.0 g, 8.8 mmol) in DMF at 0° C. and the reaction mixture is stirred for 20 min. Benzylbromide (2.3 g, 13.2 mmol) in DMF(5 mL) is then added and the resulting solution is stirred for 5 hours at room temperature. The reaction is quenched with aq. NH4Cl solution and extracted twice with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil residue is purified over silica gel (hexanes/EtOAc, 6:1) to afford the desired product as a clear oil.




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EXAMPLE 16
1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid [2-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluor-benzyl)-2-oxo-ethyl]-amide (56)

Preparation of 2-allyl-4-benzyloxy-pyrrolidine (52): 2-Allyl-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester, 51, (0.76 g, 2.4 mmol) is dissolved in methylene chloride (33 mL), and trifluoroacetic acid (25 mL) is added. The reaction mixture is stirred for 1 hour and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.


Preparation of [2-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (53): To a solution of 2-allyl-4-benzyloxy-pyrrolidine, 52, (0.52 g. 2.4 mmol) in DMF (15 mL) are added Boc-D-(4-fluorophenyl)alanine (0.74 g, 2.6 mmol), 1-hydroxybenzotriazole hydrate (0.73 g, 4.8 mmol), and N-methylmorpholine (1.5 g, 14.4 mmol), EDC (0.55 g, 2.9 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1 hr and then warmed to room temp and stirred an additional 1.5 hr. The reaction is quenched with saturated NH4Cl solution and the mixture is extracted 3 times with EtOAc (70 mL). The organic layers are combined, washed with saturated NaCl solution, dried over Na2SO4, and the solvent is removed in vacuo. The crude product is purified over silica (88/12 hexane/ethyl acetate) to afford 0.67 g (58% yield) of the desired compound as a white solid. 1H NMR (300 MHz, MeOD, Rotamers) δ 7.20–7.50 (m, 6.6H), 6.52–7.10 (m, 2.4H), 5.58–5.85 (m, 1H), 4.85–5.20 (m, 2H), 4.30–4.61 (m, 3H), 3.11–4.25 (m, 5H), 2.85–3.05 (m, 2H), 2.47–2.80 (m, 1H), 1.83–2.27 (m, 2H), 1.33–1.48 (m, 9H); MS (ESMS) m/z 483.1 (M+H)+.


Preparation of 1-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-2-amino-3-(4-fluorophenyl)-propan-1-one (54): [2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 53, (0.67 g, 1.4 mmol) is dissolved in methylene chloride (21 mL), and trifluoroacetic acid (9 mL) is added. The reaction mixture is stirred for 1 hourr and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.


Preparation of 3-[2-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (55): To solution of 1-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-2-amino-3-(4-fluorophenyl)-propan-1-one, 54, (1.4 mmol) is dissolved in DMF (10 mL) are added N-Boc-tetrahydroisoquinoline-3-carboxylic acid (0.47 g, 1.5 mmol), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol), N-methylmorpholine (0.84 g, 8.3 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.32 g, 1.7 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then warmed to room temperature and stirred an additional 1.5 hour. The reaction is quenched with saturated NH4Cl solution and then extracted 3 times with EtOAc (70 mL). The organic layers are combined, washed with saturated NaCl solution, dried over Na2SO4, and the solvent is removed in vacuo. The crude product is purified over silica to afford 0.69 g (77% yield) of the desired product as a white solid. 1H NMR (300 MHz, MeOD, Rotamers) δ 6.90–7.41 (m, 13H), 5.55–5.81 (m, 1H), 4.32–5.12 (m, 8H), 3.94–4.18 (m, 2H), 2.75–3.89 (m, 6H), 2.39–2.64 (m, 1H), 1.78–2.29 (m, 2H), 1.20–1.64 (m, 10H); MS (ESMS) m/z 642.2 (M+H)+.


Preparation of 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [2-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluor-benzyl)-2-oxo-ethyl]-amide (56): 3-[2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 55, (200 mg) is dissolved into CH2Cl2 (3 mL) and trifluoroacetic acid (1 mL) is added. The reaction mixture is stirred for 5 hours and concentrated. The residue is purified by reverse phase HPLC to afford 50 mg of the desired product. 1H NMR (CDCl3, 300 MHz) δ 6.80˜7.50 (m, 13H), 5.75 (m, 1H), 5.06 (m, 2H), 4.30˜4.70 (m, 6H), 4.06 (m, 2H), 3.75 (m, 1H), 2.90˜3.30 (m, 6H), 2.69 (m, 1H), 2.23 (m, 1H), 1.80˜2.00 (m, 2H); MS (ES-MS) m/z 542 (M+1).


Category V melanocortin receptor ligands according to the present invention comprise the 2-oxo-3-hydrocarbyl-piperazines having the general scaffold with the formula:




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wherein R1 comprises a substituted alkyl unit. The first aspect of Category V comprises the 2-oxo-3-hydrocarbyl-piperazines having the formula:




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wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R7a and R8 are provided herein below in Table XV.












TABLE XV





No.
R1
R7a
R8


















1265
methoxymethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1266
methoxyethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1267
methoxypropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1268
ethoxymethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1269
ethoxyethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1270
ethoxypropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1271
propoxymethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1272
propoxyethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1273
propoxypropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1274
iso-propoxymethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1275
iso-propoxyethyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1276
iso-propoxypropyl
—C(O)NHCH3
naphthylen-2-ylmethyl


1277
methoxymethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1278
methoxyethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1279
methoxypropyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1280
ethoxymethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1281
ethoxyethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1282
ethoxypropyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1283
propoxymethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1284
propoxyethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1285
propoxypropyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1286
iso-propoxymethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1287
iso-propoxyethyl
—C(O)NHCH3
(4-chlorophenyl)methyl


1288
iso-propoxypropyl
—C(O)NHCH3
(4-chlorophenyl)methyl


129
methoxymethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1290
methoxyethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1291
methoxypropyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1292
ethoxymethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1293
ethoxyethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1294
ethoxypropyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1295
propoxymethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1296
propoxyethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1297
propoxypropyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1298
iso-propoxymethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1299
iso-propoxyethyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1300
iso-propoxypropyl
—C(O)NHCH3
(2,4-dichlorophenyl)methyl


1301
methoxymethyl
—C(O)NH2
naphthylen-2-ylmethyl


1302
methoxyethyl
—C(O)NH2
naphthylen-2-ylmethyl


1303
methoxypropyl
—C(O)NH2
naphthylen-2-ylmethyl


1304
ethoxymethyl
—C(O)NH2
naphthylen-2-ylmethyl


1305
ethoxyethyl
—C(O)NH2
naphthylen-2-ylmethyl


1306
ethoxypropyl
—C(O)NH2
naphthylen-2-ylmethyl


1307
propoxymethyl
—C(O)NH2
naphthylen-2-ylmethyl


1308
propoxyethyl
—C(O)NH2
naphthylen-2-ylmethyl


1309
propoxypropyl
—C(O)NH2
naphthylen-2-ylmethyl


1310
iso-propoxymethyl
—C(O)NH2
naphthylen-2-ylmethyl


1311
iso-propoxyethyl
—C(O)NH2
naphthylen-2-ylmethyl


1312
iso-propoxypropyl
—C(O)NH2
naphthylen-2-ylmethyl


1313
methoxymethyl
—C(O)NH2
(4-chlorophenyl)methyl


1314
methoxyethyl
—C(O)NH2
(4-chlorophenyl)methyl


1315
methoxypropyl
—C(O)NH2
(4-chlorophenyl)methyl


1316
ethoxymethyl
—C(O)NH2
(4-chlorophenyl)methyl


1317
ethoxyethyl
—C(O)NH2
(4-chlorophenyl)methyl


1318
ethoxypropyl
—C(O)NH2
(4-chlorophenyl)methyl


1319
propoxymethyl
—C(O)NH2
(4-chlorophenyl)methyl


1320
propoxyethyl
—C(O)NH2
(4-chlorophenyl)methyl


1321
propoxypropyl
—C(O)NH2
(4-chlorophenyl)methyl


1322
iso-propoxymethyl
—C(O)NH2
(4-chlorophenyl)methyl


1323
iso-propoxyethyl
—C(O)NH2
(4-chlorophenyl)methyl


1324
iso-propoxypropyl
—C(O)NH2
(4-chlorophenyl)methyl


1325
methoxymethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1326
methoxyethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1327
methoxypropyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1328
ethoxymethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1329
ethoxyethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1330
ethoxypropyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1331
propoxymethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1332
propoxyethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1333
propoxypropyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1334
iso-propoxymethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1335
iso-propoxyethyl
—C(O)NH2
(2,4-dichlorophenyl)methyl


1336
iso-propoxypropyl
—C(O)NH2
(2,4-dichlorophenyl)methyl









The compounds of the first aspect of Category V can be suitably prepared by the procedure outlined herein below in Scheme XVII.




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EXAMPLE 17
2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (66)

Preparation of 2-(2-tert-butoxycarbonylamino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester (57): Naphthylen-2-ylacetic acid methyl ester HCl (3.3 g, 12.5 mmol), 3-methoxy-2-N-Boc-aminopropionic acid (2.7 g, 12.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.4 g, 25.0 mmol) and 1-hydroxybenzotriazole (2.8 g, 15.0 mmol) are dissolved in anhydrous DMF (10 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (4.1 mL, 37.5 mmol) is added. This reaction mixture is placed in the refrigerator overnight. EtOAc (75 mL) and water (500 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×75 mL). The organic layers are combined and washed with water (100 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford 5.2 g (97% yield) of the desired product. 1H NMR (3000 MHz, CDCl3, δ): 7.84–7.72 (m, 3H), 7.60 (s, 1H), 7.50–7.40 (m, 2H), 7.28–7.20 (m, 1H), 5.40 (br s, 1H), 4.94 (quartet, 9.0 Hz, 1H), 4.24 (br s, 1H), 3.80(m, 1H), 3.72 (s, 3H), 3.42 (m, 1H), 3.30 (m, 1H), 3.24 (s, 3H), 1.41 (s, 9H); 13C NMR, δ 171.8, 170.4, 155.3, 133.7, 133.6, 132.7, 128.4, 127.9, 127.7, 126.4, 126.0, 80.3, 72.2, 59.1, 54.0, 53.6, 52.6, 38.1, 28.5.


Preparation of 2-(2-amino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester HCl (58): 2-(2-tert-butoxycarbonylamino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester, 57, (5.2 g, 12.1 mmol) is dissolved in 4M hydrogen chloride in dioxane (40 mL) and stirred at room temperature for 1 hour. 1,2-Dichloroethane (40 mL) is added. The solution is concentrated in vacuo to afford 4.43 g (quantitative yield) of the desired product.


Preparation of 2-[3-methoxy-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester (59): 2-(2-Amino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester, 58, (4.43 g, 12.1 mmol) and 2-nitrobenzene sulfonyl chloride (2.8 g, 12.7 mmol) are dissolved in any THF (20 mL). The mixture is cooled to 0° C. and triethyl amine (5 mL) is added to the reaction mixture which is then allowed to stir overnight at room temperature. Water (100 mL) is added and the reaction mixture pH adjusted to 3 with 1M KHSO4. The solution is extracted with EtOAc (3×100 mL) and the organic layers are combined and dried over Na2SO4. The solvent is removed in vacuo to afford 6.4 g (quantitative yield) of the desired product. 1H NMR (300 MHz, CDCl3, δ): 8.02 (m, 1H), 7.8 (m, 4H), 7.60 (m, 3H), 7.48 (m, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.58 (d, J=6.25 Hz, 1H), 4.57 (quartet, J=6.25 Hz, 1H), 4.02 (quartet, J=6.25 Hz, 1H), 3.70 (s, 3H), 3.47 (m, 2H), 3.44 (m, 2H), 3.49 (s, 3H); 13C NMR, δ 171.5, 168.7, 147.9, 134.2, 133.6, 133.5, 133.2, 132.7, 131.0, 128.4, 128.3, 127.9, 127.5, 126.5, 126.1, 125.9, 72.3, 59.1, 56.6, 53.8, 52.7, 38.0.


Preparation of 2-[3-methoxymethyl-4(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester (60): 1,2-Dibromoethane (11 mL, 125 mmol) and K2CO3 (15.5 g, 112.3 mmol) are added to a 2-[3-methoxy-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 59, (6.4 g, 12.4 mmol) solution in anhydrous DMF (30 mL). The reaction mixture is stirred at 60° C. overnight. The reaction mixture is cooled to room temperature and the pH is adjusted to 3 with 1M KHSO4. The solution is extracted with EtOAc (3×100 mL) and the organic layers are combined and dried over Na2SO4. The solvent is removed in vacuo to afford 5.6 g (85% yield) of the desired product. 1H NMR (300 MHz, CDCl3, δ): 7.89 (m, 1H), 7.70 (m, 3H), 7.57 (m, 3H), 7.47 (m, 1H), 7.41 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 5.39 (m, 1H), 4.37 (s, 3H), 3.62 (m, 4H), 3.46 (m, 2H), 3.35 (m, 1H), 3.20 (m, 2H), 3.13 (s, 3H); 13C NMR, δ 170.4, 165.7, 156.5, 147.9, 134.2, 134.1, 133.6, 133.4, 132.6, 132.4, 130.8, 128.4, 127.8, 127.7, 127.2, 126.4, 126.0, 124.6, 74.1, 65.0, 58.9, 58.1, 52.7, 44.3, 41.8, 34.3.


Preparation of 2-[3-methoxymethyl-4-(2-nitro-benzenesulfonyl)-piperazine-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester (61): To a solution of 2-[3-methoxymethyl-4(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 60, (5.6 g, 10.4 mmol) in anhydrous THF (10 mL) is added 1.0M borane-tetrahydrofuran complex (31.2 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and allowed to stir for twenty minutes. Additional methanol (6 mL) is and the reaction mixture is allowed to warm to the room temperature. The solvent is removed in vacuo and the product purified over silica (EtOAc/Hexane, 1:1) to afford 3.5 g (64% yield) of the desired product. 1H NMR (CDCl3, δ): 8.05 (m, 1H), 7.75 (m,3H), 7.62 (m, 4H), 7.50 (m, 2H), 7.30 (dd, J=8.4, 2.1 Hz, 1H), 3.94 (t, J=6.3 Hz, 1H), 3.66 (s, 3H), 3.58 (t, J=6.8 Hz, 1H), 3.30–2.95 (m, 7H), 2.82 (s, 3H), 2.79 (m, 2H), 2.40 (dt, J=12.7, 4.3 Hz, 1H); 13C NMR, δ 171.8, 148.0, 136.0, 134.1, 133.7, 132.4, 132.0, 131.5, 128.1, 127.9, 127.7, 126.3, 125.8, 124.5, 69.5, 68.7, 58.7, 53.8, 52.8, 51.6, 46.6, 42.8, 35.4.


Preparation of 2-(3-methoxymethyl-piperazine-1yl)-3-naphthalen2-yl-propionic acid methyl ester (62): To a solution of 2-[3-methoxymethyl-4-(2-nitro-benzenesulfonyl)-piperazine-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 61, (3.5 g, 6.67 mmol) in anhydrous DMF (40 mL) is added potassium carbonate (5.5 g, 40.0 mmol) and 4-mercaptophenol (2.5 g, 20.0 mmol). The reaction mixture is stirred for six hours at room temperature, then cooled in a ice bath and pH is adjusted to 3 with 1M HCl. The reaction mixture is extracted with Et2O (4×100 mL). All organic layers are combined and extracted with 1M HCl (100 mL). All aqueous layers are combined and cooled in a ice bath and the pH is adjusted to 10 with K2CO3. The aqueous layer is extracted with EtOAc (4×125 mL) and dried over Na2SO4. The solvent is removed in vacuo to afford 2.2 g (97% yield) of the desired product. 1H NMR (CDCl3, δ): 7.85–7.78 (m, 3H), 7.65 (s, 1H), 7.54–7.40 (m, 2H), 7.35 (dd, J=7.2, 2.4Hz, 1H), 3.59 (s, 3H), 3.56 (dd, J=6.0, 2.5 Hz, 1H), 3.40–3.10 (m, 5H), 3.38 (s, 3H), 3.05–2.78 (m, 5H), 2.59 (dt, J=7.2, 2.5 Hz, 1H), 2.20 (t, J=10.8 Hz, 1H); 13C NMR, δ 171.8, 135.9, 133.7, 132.5, 128.2, 127.9, 127.8, 126.2, 125.7, 74.8, 69.9, 59.4, 55.2, 52.3, 51.4, 50.8, 45.6, 35.8.


Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester (63): 2-(3-Methoxymethyl-piperazine-1yl)-3-naphthalen2-yl-propionic acid methyl ester, 62, (2.2 g, 6.4 mmol) and N-Boc-(4-flouro)phenylalanine (1.9 g, 6.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.9 g, 12.9 mmol) are dissolved in anhydrous DMF (20 mL). This reaction mixture is cooled to 0° C. then N-methylmorpholine (0.75 mL, 6.8 mmol) is added. This reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (300 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×150 mL). All organic layers are combined and washed with water (100 mL), and dried over Na2SO4. The solution is concentrated in vacuo and the residue purified over silica (EtOAc/Hexane, 1:1) to afford 3.6 g (92% yield) of the desired product. 1H NMR (CDCl3, δ): 7.72–7.58 (m, 3H), 7.44 (s, 1H), 7.40–7.22 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 7.10–6.98 (m, 2H), 6.82 (t, J=8.2 Hz, 2H), 5.88–5.64 (m, 1H), 4.82–4.50 (m, 1.5H), 4.18 (d, J=12.3 Hz, 0.5H), 3.58–3.44 (m, 3H), 3.42–3.30 (m, 1.5H), 3.08–3.72 (m, 10H), 2.68–2.45 (m, 2H), 2.40–2.18 (m, 1H), 1.70 (d, J=12.3 Hz, 0.5H), 1.35–1.25 (m, 1H), 1.30 (s, 9H); 13C NMR, δ 171.8, 171.4, 170.4, 163.9, 160.2, 153.0, 152.8, 136.0, 133.6, 132.6, 132.3, 131.4, 127.9, 127.7, 127.5, 126.2, 125.6, 115.5, 115.2, 115.1, 115.0, 79.5, 79.2, 69.6, 68.9, 68.3, 68.1, 60.3, 58.6, 58.3, 53.7, 52.0, 51.2, 48.8, 46.5, 45.6, 42.3, 40.0, 38.7, 35.3, 28.4.


Preparation of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid (64): LiOH (0.71 g, 29.7 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 63, (3.6 g, 5.9 mmol) in THF/H2O (2/1, 60 mL). The reaction mixture is stirred for overnight. The reaction mixture is cooled in ice bath and pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The solution is concentrated in vacuo to afford 3.7 g 100% yield) of the desired product.


Preparation of {1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2oxo-ethyl}-carbamic acid tert-butyl ester (65): To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid, 64, (2.7 g, 4.3 mmol) and PyBOP (2.9 g, 5.6 mmol) in anhydrous dichloromethane (15 mL) is added 2M methyl amine solution in THF (4.4 mL, 8.8 mmol) and triethyl amine (1.5 mL, 10.7 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (200 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×100 mL). All organic layers are combined and washed with brine (100 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford 2.6 g (100% yield) of the desired product. 1H NMR (CDCl3, δ): 7.62–7.50 (m, 3H), 7.45 (s, 1H), 7.35–7.12 (m, 3H), 7.05–6.92 (m, 2H), 6.82–6.70 (m, 2H), 5.45 (dd, J=20.5, 8.2 Hz, 0.5H), 4.75–4.45 (m, 1H), 4.05 (d, J=12.3 Hz, 0.5H), 3.5–3.20 (m, 1H), 3.20–3.08 (m, 1H), 3.08–2.98 (m, 1H), 2.92 (s, 8H), 2.84–2.64 (m, 2H), 2.55 (br s, 2H), 2.40–1.85 (m, 1H), 1.6 (s, 7H), 1.22 (d, J=6.6 Hz, 7H); 13C NMR, δ 171.6, 171.4, 171.2, 170.2, 163.5, 160.3, 154.9, 137.3,137.2, 132.6, 132.3, 132.1, 131.2, 127.6, 127.5, 126.0, 125.4, 115.4, 115.1, 114.9, 79.5, 79.3, 70.2, 69.6, 69.3, 58.9, 58.8, 53.3, 51.2, 49.8, 49.6, 48.7, 48.3, 46.3, 42.9, 39.8, 38.9, 38.6, 33.6, 28.3, 26.5, 26.4, 25.8, 25.7.


Preparation of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide HCl (66): {1-(4-Fluoro-benzyl)2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2oxo-ethyl}-carbamic acid tert-butyl ester, 65, is dissolved in 4M HCl in dioxane (60 mL). The reaction mixture is stirred for 90 minutes then 1,2-dichloroethane (60 mL) is added. The solution is concentrated in vacuo to afford 3.6 g (98% yield) of the desired product.


The following are non-limiting examples of analogs which comprise the first aspect of Category V of the present invention.


2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide: 1H NMR (CD3OD, with rotamers) δ 7.33–7.09 (m, 8H), 4.77–4.20 (m, 2H), 3.58–3.38 (m, 3H), 3.30 (s, 3H), 3.25–2.70 (m, 9H), 2.67, 2.64 (2 singlets, 3H, CH3NHC(O), rotamers), 2.20–1.65 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 173.0, 172.5, 170.3, 169.0, 165.9, 162.6, 162.2, 161.7, 138.8, 138.0, 134.0, 133.7, 133.3, 133.2, 132.3, 131.8, 131.5, 129.9, 129.8, 117.5, 117.3, 117.2, 117.1, 71.9, 71.0, 59.9, 59.7, 55.3, 52.6, 52.4, 43.6, 40.1, 38.6, 37.9, 35.3, 26.3; MS m/z (ESI): 491 (M+H, 100), 493 (M+2+H, 37).

  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2-chlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(3-chlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2,4-dichlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2-chlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(3-chlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2,4-dichlorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-N-methyl-3-naphthalen-2-yl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2-fluorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(3-fluorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2-fluorophenyl)-N-methyl-propionamide;
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(2,4-difluorophenyl)-N-methyl-propionamide; and
  • 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-N-methyl-3-naphthalen-2-yl-propionamide.


The second aspect of Category V relates to compounds having the formula:




embedded image



the first iteration of which relates to W units having the formula —NHC(O)Q wherein R is a substituted or unsubstituted aryl unit as described herein above and non-limiting examples of R1, R7a, R8 and Q are provided herein below in Table XVI.













TABLE XVI





No.
R1
Q
R7a
R8



















300
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


301
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


302
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


303
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


1337
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


1338
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


1339
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
naphthylen-2-ylmethyl


1340
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1341
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1342
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1343
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1344
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1345
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1346
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1347
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1348
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1349
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1350
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1351
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1352
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1353
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NH2
(4-chlorophenyl)methyl


1354
methoxymethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1555
ethoxymethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1356
propoxymethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1357
methoxyethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1358
ethoxyethyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1359
methoxypropyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1360
ethoxypropyl
THQ-3-yl
—C(O)NH2
naphthylen-2-ylmethyl


1361
methoxymethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1362
ethoxymethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1363
propoxymethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1364
methoxyethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1365
ethoxyethyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1366
methoxypropyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1367
ethoxypropyl
THQ-3-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1368
methoxymethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1369
ethoxymethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1370
propoxymethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1371
methoxyethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1372
ethoxyethyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1373
methoxypropyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1374
ethoxypropyl
THQ-3-yl
—C(O)NH2
(4-chlorophenyl)methyl


1375
methoxymethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1376
ethoxymethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1377
propoxymethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1378
methoxyethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1379
ethoxyethyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1380
methoxypropyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1381
ethoxypropyl
pyrrolidin-2-yl
—C(O)NH2
naphthylen-2-ylmethyl


1382
methoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1383
ethoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1384
propoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1385
methoxyethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1386
ethoxyethyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1387
methoxypropyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1388
ethoxypropyl
pyrrolidin-2-yl
—C(O)NH2
(3,4-dichlorophenyl)methyl


1389
methoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1390
ethoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1391
propoxymethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1392
methoxyethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1393
ethoxyethyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1394
methoxypropyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1395
ethoxypropyl
pyrrolidin-2-yl
—C(O)NH2
(4-chlorophenyl)methyl


1396
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1397
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1398
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1399
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1400
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1401
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1402
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1403
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1404
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1405
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1406
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1407
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1408
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1409
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1410
methoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1411
ethoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1412
propoxymethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1413
methoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1414
ethoxyethyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1415
methoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1416
ethoxypropyl
2-aminopyrrolidin-5-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1417
methoxymethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1418
ethoxymethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1419
propoxymethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1420
methoxyethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1421
ethoxyethyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1422
methoxypropyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1423
ethoxypropyl
THQ-3-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1424
methoxymethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1425
ethoxymethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1426
propoxymethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1427
methoxyethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1428
ethoxyethyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1429
methoxypropyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1430
ethoxypropyl
THQ-3-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1431
methoxymethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1432
ethoxymethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophepyl)methyl


1433
propoxymethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1434
methoxyethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1435
ethoxyethyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1436
methoxypropyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1437
ethoxypropyl
THQ-3-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1438
methoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1439
ethoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1440
propoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1441
methoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1442
ethoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1443
methoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1444
ethoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
naphthylen-2-ylmethyl


1445
methoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1446
ethoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1447
propoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1448
methoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1449
ethoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1450
methoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1451
ethoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
(3,4-dichlorophenyl)methyl


1452
methoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1453
ethoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1454
propoxymethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1455
methoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1456
ethoxyethyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1457
methoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl


1458
ethoxypropyl
pyrrolidin-2-yl
—C(O)NHCH3
(4-chlorophenyl)methyl









The compounds of the second aspect of Category V can be suitably prepared by the procedure outlined herein below in Scheme XVIII beginning with compounds which comprises the first aspect of this Category, for example, compound 66.




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EXAMPLE 18
Pyrrolidine-2-carboxylic acid {1-(4-fluoro-benzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (68)

Preparation of 2-{1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (67): 2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide HCl, 66, (0.36 g, 0.55 mmol) and BOC-L-Proline (0.13 g, 0.6 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.2 g, 1.1 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) are dissolved in anhydrous DMF (1.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.5 mL, 4.1 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. The solvent is removed in vacuo to afford 0.39 g of the desired product.


Preparation of pyrrolidine-2-carboxylic acid {1-(4-fluorobenzyl)-2-[2-methoxy-methyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (68): Crude 2-{1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 67, is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. Removal of solvents in vacuo gives the crude hydrogen chloride salt of product which is then purified by preparative HPLC to afford 0.22 g (54% yield) of the desired product as the trifluoroacetate salt. A small amount of product is converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 7.80–7.60 (m, 4H), 7.45–7.25 (m, 3H), 7.18–7.00 (m, 2H), 7.00–6.85 (m, 2H), 6.32–6.28 (m, 0.5H), 5.08–4.92 (m, 1H), 4.78–4.69 (,0.5H), 4.10 (d, J=13.0 Hz, 0.5H), 3.70–3.58 (m, 1H), 3.58–3.15 (m, 8H), 2.98–2.46 (m, 11H), 2.28–2.15 (m, 0.5H), 2.15–1.50 (m, 8H). HRFAB(positive) m/e 604.2399 calculated for C34H42FN5O4 (M+H)+, Found 604.3292.


The following are non-limiting examples of other compounds according to the various aspects of Category V.


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-methoxymethyl-piperazine-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, δ): 7.47–7.41 (m, 2H), 7.28–7.25 (m, 2H), 7.16–7.12 (m, 1H), 7.08–7.02 (m, 2H), 5.11 (t, J=15.0 Hz, 1H), 4.63 (brs, 0.5H), 4.25 (d, J=13.5 Hz, 0.5H), 3.95 (d, J=12.9 Hz, 0.5H0, 3.74–3.66 (m, 0.5H), 3.58 (t, J=6.3 Hz, 0.5H), 3.47–3.40 (m, 0.5H), 3.38–3.30 (m, 1H), 3.32 (s, 3H), 3.26–3.17 (m, 4H), 3.02–2.89 (m, 6.5H), 2.80–2.68 (m, 4H), 2.53–2.46 (m, 1H), 2.12 (t, J=11.1 Hz, 0.5H), 1.70–1.51 (m, 2H), 1.46–1.31 (m, 3H). HRFAB(positive) m/e 608.220664 calculated for C29H36Cl2FN5O4 (M+H)+, Found 608.218817.


Pyrrolidine-2-carboxylic acid[2-{4-[2-(3,4-dichlorophenyl)-1-methylcarbamoyl-ethyl]-2-methoxymethyl-piperazin-1-yl}-1-(4-fluorobenzyl)-2-oxo-ethyl]amide: 1H NMR (CD3OD, δ): 7.46–7.42 (m,2H), 7.32–7.26 (m, 2H), 7.17–7.14 (m, 1H), 7.09–7.04 (m, 2H), 5.17 (t, J=8.1 Hz, 1H), 4.65 (br s, 0.5H), 4.27–4.23 (m, 2H), 4.0 (m, 0.5H), 3.80 (bs, 0.5H), 3.57 (t, J=9.3 Hz, 0.5H), 3.45–3.20 (m, 10H), 3.09–2.89 (m, 6H), 2.78–2.68 (m, 3H), 2.52–2.28 (m, 2H), 2.20–1.72 (m, 4H); HRFAB(positive) m/e 622.236314 calculated for C30H38Cl2FN5O4 (M+H)+, Found 622.234445


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-methoxy-methylpiperazin-1-yl}-N-methyl-3-naphthalen-2yl-propionamide: 1H NMR (CDCl3, δ): 8.08 (t, J=6.7 Hz, 1H), 7.74–7.64 (m, 3H), 7.40–7.25 (m, 3H), 7.10–7.04 (m, 2H), 6.95–6.88 (m, 2H), 4.98 (quartet, J=6.7 Hz, 1H), 4.84 (quartet, J=6.7 Hz, 1H), 4.68–4.58 (m, 1H), 4.18–4.12 (m, 1H), 3.65–3.55 (m, 1H), 3.46–3.30 (m, 4H), 3.28–3.20 (m, 3H), 2.95–2.70 (m, 5H), 2.78–2.60 (m, 5H), 2.58–2.45 (m, 2H), 2.20–2.02 (m, 2H), 1.65 (dd, J=10.6, 3.99 Hz, 1H), 1.25–1.22 (m, 4H); HRFAB(positive) m/e 592.3299 calculated for C33H42FN5O4 (M+H)+, Found 592.3354.


{1-(4-Fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid methyl ester: 1H NMR (CDCl3, δ): 7.75–7.6 (m, 3H), 7.58 (s, 1H), 7.50–7.42 (m, 2H), 7.42–7.38 (m, 1H), 7.08–7.00 (m, 2H), 6.90–6.82 (m, 2H), 5.55 (t, J=8.2 Hz, 0.5H), 4.82–4.68 (m, 1H), 4.62–4.55 (m, 0.5H), 4.15 (d, J=13.0 Hz, 0.5H), 3.58 (s, 2H), 3.52 (m, 2H), 3.43–3.28 (m, 3H), 3.28–3.20 (m, 3H), 3.15 (2H), 2.98–2.72 (m, 4H), 2.72–2.58 (m, 4H), 2.58–2.42 (m, 1H), 2.32–2.20 (m, 0.5H), 2.12–2.00 (m, 0.5H), 1.60 (dd, J=13.0, 2.6 Hz, 0.5H); HRFAB(positive) m/e 565.2826 calculated for C31H37FN4O5 (M+H)+, Found 565.2806; Elemental Analysis: calculated for C31H37FN4O5. (1.23 TFA) (MW. 704.57): C, 57.01%; H, 5.47%; N, 7.95%; Found: C, 57.03%; H, 5.33%; N, 7.97%.


2-{4-[3-(4-Fluorophenyl)-2-(2-hydroxy-2-methyl-propionylamino)-propionyl]-3-methoxy methyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide. 1H NMR (CDCl3, δ): 8.08–7.95 (m, 3H), 7.88 (d, J=9.4 Hz, 1H), 7.70–7.60 (m, 2H), 7.52 (d, J=9.4 Hz, 1H), 7.48–7.38 (m, 2H), 7.21 (t, J=4.7 Hz, 2H_), 5.28–5.18 (m, 1H), 5.15–4.98 (m, 2H), 5.02 (s, 3H), 4.55 (d, J=9.4 Hz, 0.5H), 4.28 (d, J=9.4 Hz, 0.5H), 4.15–4.05 (m, 1H), 3.92–3.05 (m, 12.5H), 2.85–2.62 (m, 3H), 2.20 (d, J=7.0 Hz, 0.5H), 2.02–1.95 (m, 1H), 1.52–1.40 (m, 5H); HRFAB(positive) m/e 593.3139 calculated for C33H41FN4O5 (M+H)+, Found 593.3157; Elemental Analysis: calculated for C33H41FN4O5. (1.28 TFA) (MW. 738.51): C, 57.83%; H, 5.77%; N, 7.59%; Found: C, 57.83%; H, 5.70%; N, 7.77%.


{1-(4-Fluoro-benzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-maphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid ethyl ester. 1H NMR (CDCl3, δ): 7.72–7.64 (m, 3H), 7.5 (s, 1H), 7.36–7.30 (m, 2H), 7.30–7.26 (m, 1H), 7.06–7.02 (m, 2H), 6.90–6.72 (dt, J=9.8, 2.6 Hz, 2H), 6.33(s, 0.5H), 5.50–5.45 (m, 1H), 5.25 (s, 3H), 4.82–4.60 (m, 1.5H), 4.20–3.98 (m, 2H), 3.58–3.49 (m, 1H), 3.48–3.35 (m, 6H), 3.30–3.18 (m, 4H), 2.96–2.84 (m, 3H), 2.75–2.62 (m, 3.5H), 2.58–2.44 (m, 1H), 2.28–2.20 (m, 0.5H), 2.12–1.98 (m, 0.5H), 1.59 (d, J=9.8 Hz, 0.5H); HRFAB(positive) m/e 579.2982 calculated for C32H39FN4O5 (M+H)+, Found 579.2980; Elemental Analysis: calculated for C32H39FN4O5. (0.95 TFA) (MW. 686.61): C, 59.29%; H, 5.86%; N, 8.16%; Found: C, 59.29%; H, 5.98%; N, 8.14%.


2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-3-(4-chlorophenyl)-N-methyl-propionamide: 1H NMR (CD3OD, with rotamers) δ 7.55–7.42 (m, 6H), 7.29 (m, 2H), 5.34 (t, 1H, J=7.6 Hz), 5.00–4.60 (m, 1H), 4.35–4.13 (m, 1H), 3.93–3.82 (m, 1H), 3.65 (m, 2H), 3.52, 3.50 (2 singlets, 3H, CH3OCH2, rotamers), 3.45–3.05 (m, 8H), 2.89, 2.85 (2 singlets, 3H, CH3NHC(O), rotamers), 2.68–2.16 (m, 1H), 1.79, 1.74, 1.69 (3 singlets, 6H, NH2C(CH3)2C(O), rotamers); 13C NMR (CD3OD, with rotamers) δ 173.2, 173.0, 172.5, 171.9, 171.3, 165.5, 162.4, 162.2, 161.9, 137.8, 137.0, 134.3, 134.1, 134.0, 133.0, 132.9, 132.8, 132.4, 130.1, 129.9, 119.9, 117.0, 116.8, 116.5, 72.7, 72.1, 70.0, 59.8, 59.7, 58.5, 54.4, 52.6, 52.4, 52.0, 50.8, 43.4, 39.8, 39.2, 38.0, 35.1, 35.0, 26.4, 24.6, 24.3; MS m/z (ESI): 576 (M+H, 100), 578 (M+2+H, 37).


Pyrrolidine-2-carboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methoxymethyl-piperazin-1-yl}-1-(4-fluoro-benzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, with rotamers) δ 7.55–7.43 (m, 6H), 7.29 (m, 2H), 5.39 (t, 1H, J=7.7 Hz), 5.06–4.58 (m, 1H), 4.48 (t, 1H, J=7.2 Hz), 4.40–4.22 (m, 1H), 3.94–3.82 (m, 2H), 3.67 (m, 2H), 3.54, 3.51 (2 singlets, 3H, CH3OCH2, rotamers), 3.49 (m, 2H), 3.24 (m, 6H), 2.90, 2.86 (2 singlets, 3H, CH3NHC(O), rotamers), 2.73–2.56 (m, 2H), 2.27–2.01 (m, 4H); 13C NMR (CD3OD, with rotamers) δ 172.5, 171.8, 171.7, 169.4, 169.1, 164.4, 162.8, 162.0, 137.9, 137.0, 134.0, 133.7, 132.7, 132.6, 132.2, 132.1, 129.8, 129.6, 116.7, 116.5, 116.4, 116.3, 72.3, 71.7, 70.7, 61.1, 59.6, 59.5, 54.4, 52.1, 52.0, 51.9, 51.8, 50.5, 50.0, 47.5, 43.3, 39.6, 39.3, 38.2, 34.8, 31.4, 31.3, 26.2, 26.1 25.1, 25.0; MS m/z (ESI): 588 (M+H, 100), 590 (M+2+H, 37).


1-Amino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methoxymethyl-piperazin-1-yl}-1-(4-fluoro-benzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, with rotamers) δ 7.41–7.26 (m, 6H), 7.17 (m, 2H), 5.18 (t, 1H, J=7.8 Hz), 4.83–4.38 (m, 1H), 4.18–3.93 (m, 1H), 3.72 (m, 1H), 3.45 (m, 2H), 3.36, 3.35 (2 singlets, 3H, CH3OCH2, rotamers), 3.24–2.89 (m, 8H), 2.75, 2.72 (2 singlets, 3H, CH3NHC(O), rotamers), 2.45–1.95 (m, 1H), 1.74–1.43 (m, 4H); 13C NMR (CD3OD, with rotamers) δ 173.0, 172.4, 172.2, 171.6, 171.0, 170.5, 165.5, 162.4, 162.2, 138.3, 137.4, 134.2, 132.9, 132.8, 132.7, 132.4, 130.0, 129.9, 117.1, 116.8, 116.5, 72.4, 71.7, 71.0, 59.8, 59.7, 54.7, 52.5, 52.4, 52.0, 50.6, 43.6, 40.1, 39.1, 37.9, 36.7, 35.1, 26.4, 13.9, 13.8; MS m/z (ESI): 574 (M+H, 100), 576 (M+2+H, 37).


1-Methylamino-cyclopropanecarboxylic acid [2-{4-[2-(4-chlorophenyl)-1-methylcarbamoyl-ethyl]-2-methoxymethyl-piperazin-1-yl}-1-(4-fluoro-benzyl)-2-oxo-ethyl]-amide: 1H NMR (CD3OD, with rotamers) δ 7.46–7.31 (m, 6H), 7.19 (dd, 2H, J=15.6, 7.0 Hz), 5.26 (m, 1H), 4.86–4.42 (m, 1H), 4.18–3.98 (m, 1H), 3.73 (m, 2H), 3.41, 3.40 (2 singlets, 3H, CH3OCH2, rotamers), 3.21–3.07 (m, 8H), 2.87 (m, 1H), 2.84, 2.83 (2 singlets, 3H, CH3NHC(O), rotamers), 2.80, 2.78 (2 singlets, 3H, CH3NHC(CH2—CH2)C(O), rotamers), 2.43–1.97 (m, 1H), 1.80–1.61 (m, 4H); 13C NMR (CD3OD, with rotamers) δ 172.9, 172.3, 172.1, 171.4, 169.8, 165.5, 162.2, 138.3, 137.4, 134.2, 133.0, 132.9, 132.7, 132.4, 130.0, 129.9, 117.0, 116.8, 116.5, 113.6, 72.5, 71.8, 71.0, 59.7, 54.7, 52.4, 52.0, 50.7, 44.1, 43.6, 40.1, 39.1, 37.9, 35.1, 33.2, 26.4, 13.7; MS m/z (ESI): 588 (M+H, 100), 590 (M+2+H, 37).


3-(4-Chlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-methylamino-propionyl]-3-methoxymethyl-piperazin-1-yl}-N-methyl-propionamide: 1H NMR (CD3OD, with rotamers) δ 7.32–7.08 (m, 8H), 4.65 (m, 1H), 4.27 (m, 1H), 3.57 (m, 2H), 3.26 (s, 3H), 3.25–2.84 (m, 8H), 2.69, 2.68 (2 singlets, 3H, CH3NHC(O), rotamers), 2.64 (s, 3H), 2.44 (m, 1H), 2.09 (m, 1H), 1.31 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 173.0, 169.0, 165.9, 162.7, 139.0, 138.1, 133.6, 133.5, 133.4, 132.3, 131.4, 129.9, 129.7, 117.6, 117.3, 117.1, 71.8, 71.6, 70.9, 60.4, 59.6, 59.4, 55.5, 52.4, 50.7, 43.6, 40.0, 38.3, 37.1, 35.3, 33.1, 32.7, 26.3; MS m/z (ESI): 505 (M+H, 100), 507 (M+2+H, 37.


3-(4-Chlorophenyl)-N-(2-fluoro-ethyl)-2-{4-[3-(4-fluorophenyl)-2-methylamino-propionyl]-3-methoxymethyl-piperazin-1-yl}-propionamide: 1H NMR (CD3OD, with rotamers) δ 7.40–7.17 (m, 8H), 4.75 (m, 1H), 4.56–4.29 (m, 2H), 3.70–3.26 (m, 8H), 3.38, 3.35 (2 singlets, 3H, CH3OCH2, rotamers), 3.07–2.92 (m, 4H), 2.77, 2.72 (2 singlets, 3H, CH3NHC(4-F-Bn)C(O), rotamers), 2.57 (m, 1H), 2.22 (m, 1H), 1.48 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 172.8, 168.8, 139.0, 133.6, 133.4, 133.3, 132.3, 131.3, 129.8117.6, 117.3, 84.6, 82.4, 71.7, 70.9, 60.5, 59.4, 55.5, 51.8, 43.7, 41.2, 41.0, 40.1, 38.2, 34.7, 33.1; MS m/z (ESI): 537 (M+H, 100), 539 (M+2+H, 37).


3-(4-Chlorophenyl)-2-{4-[3-(4-fluorophenyl)-2-methylamino-propionyl]-3-methoxy-methyl-piperazin-1-yl}-N-(2,2,2-trifluoroethyl)-propionamide: 1H NMR (CD3OD, with rotamers) δ 7.42–7.03 (m, 8H), 4.75 (m, 1H), 4.19 (m, 1H), 4.83 (m, 2H), 3.54 (m, 2H), 3.35–3.16 (m, 2H), 3.22, 3.21 (2 singlets, 3H, CH3OCH2, rotamers), 3.10 (m, 1H), 3.93–2.76 (m, 5H), 2.61, 2.58 (2 singlets, 3H, CH3NHC(4-F-Bn)C(O), rotamers), 2.38 (m, 1H), 2.11 (m, 1H), 1.30 (m, 1H); 13C NMR (CD3OD, with rotamers) δ 173.5, 168.8, 165.9, 162.7, 138.9, 138.7, 133.6, 133.5, 133.4, 132.3, 131.4, 129.8, 128.0, 124.3, 117.6, 117.3, 117.0, 113.3, 71.6, 71.0, 70.8, 60.4, 59.5, 59.4, 55.4, 52.6, 51.4, 51.2, 43.9, 41.5, 41.0, 40.1, 38.2, 35.1, 34.1, 33.1; MS m/z (ESI): 573 (M+H, 100), 575 (M+2+H, 37).


FORMULATIONS

The present invention also relates to compositions or formulations which comprise the melanocortin receptor ligands according to the present invention. In general, the compositions of the present invention comprise:

    • a) an effective amount of one or more melanocortin receptor ligands according to the present invention; and
    • b) one or more pharmaceutically acceptable excipients.


The compositions of this invention are typically provided in unit dosage form. For the purposes of the present invention the term “unit dosage form” is defined herein as comprising an effective amount of one or more melanocortin receptor ligands. The compositions of the present invention contain in one embodiment from about 1 mg to about 750 mg of one or more melanocortin receptor ligands, while in other embodiments the compositions comprise from about 3 mg to about 500 mg, or from about 5 mg to about 300 mg respectively.


For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”


The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.


Non-limiting examples of substances which can serve as pharmaceutically-acceptable excipients or components thereof are sugars, inter alia, lactose, glucose and sucrose, sorbitol, mannitol; starches, inter alia, corn starch and potato starch; cellulose and its derivatives, inter alia, sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; vegetable oils, propylene glycol, glycerin, and polyethylene glycol; agar; alginic acid; wetting agents and lubricants, inter alia, sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and buffers.


Standard pharmaceutical formulation techniques are disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition and Peptide and Protein Drug Delivery, Marcel Dekker, NY, 1991. Dosage forms useful for making the compositions of the present invention or which are compatible with the methods of use as described herein below are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976); Standard-Release Injectable Products, ed. J. Senior and M. Radomsk, Interpharm Press; Denver, Colo. (2000)


The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.


Related to this aspect are the various precursor or “pro-drug” forms of the analogs of the present invention. It may be desirable to formulate the compounds of the present invention as a chemical species which itself is not a melanocortin receptor ligand as described herein, but instead are forms of the present analogs which when delivered to the body of a human or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach, blood serum, said chemical reaction releasing the parent analog. Or alternatively, said “pro-drug” form may cross the blood/brain barrier before undergoing a change which releases the melanocortin receptor ligand in its active form. The term “pro-drug” relates to these species which are converted in vivo to the active pharmaceutical.


METHOD OF USE

The present invention also relates to a method for controlling one or more melanocortin receptor, MC-3 or MC-4, mediated or melanocortin receptor modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the melanocortin receptor ligands according to the present invention.


Because the melanocortin receptor ligands of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time. Non-limiting examples of diseases which are affected by an antagonist or agonist which stimulates the MC-3 or MC-4 receptor, obesity and other body weight disorders, inter alia, anorexia and cachexia. Utilizing the melanocortin receptor ligands of the present invention will therefore affect a variety of diseases, disease states, conditions, or syndromes resulting from body weight disorders, inter alia, insulin resistance, glucose intolerance, Type-2 diabetes mellitus, coronary artery disease, elevated blood pressure, hypertension, dyslipidaemia, cancer (e.g., endometrial, cervical, ovarian, breast, prostate, gallbladder, colon), menstrual irregularities, hirsutism, infertility, gallbladder disease, restrictive lung disease, sleep apnea, gout, osteoarthritis, and thromboembolic disease.


MC-3 and MC-4 receptor ligands are also effective in treating disorders relating to behavior, memory (including learning), cardiovascular function, inflammation, sepsis, cardiogenic and hypovolemic shock, sexual dysfunction, penile erection, muscle atrophy, nerve growth and repair, intrauterine fetal growth, and the like.


Although the melanocortin receptor ligands of the present invention are discrete chemical entities, the method of delivery or the method of use may be coupled with other suitable drug delivery systems. For example, a drug delivery technique useful for the compounds of the present invention is the conjugation of the compound to an active molecule capable of being transported through a biological barrier (see e.g. Zlokovic, B. V., Pharmaceutical Research, Vol. 12, pp. 1395–1406 (1995)). A specific example constitutes the coupling of the compound of the invention to fragments of insulin to achieve transport across the blood brain barrier (Fukuta, M., et al. Pharmaceutical Res., Vol. 11, pp. 1681–1688 (1994)). For general reviews of technologies for drug delivery suitable for the compounds of the invention see Zlokovic, B. V., Pharmaceutical Res., Vol. 12, pp. 1395–1406 (1995) and Pardridge, W M, Pharmacol. Toxicol., Vol. 71, pp. 3–10 (1992).


PROCEDURES

Functional activity (in vitro pre-screening) can be evaluated using various methods known in the art. For example, measurement of the second messenger, cAMP, as described in citation (iv) above, evaluation by Cytosensor Microphysiometer techniques (Boyfield et al. 1996), or by using the compounds of the invention alone, or in combination with natural or synthetic MSH-peptides.


The compounds of the present invention will interact preferentially (i.e., selectively) to MC-4 and/or MC-3, relative to the other melanocortin receptors. Selectivity is particularly important when the compounds are administered to humans or other animals, to minimize the number of side effects associated with their administration. MC-3/MC-4 selectivity of a compound is defined herein as the ratio of the EC50 of the compound for an MC-1 receptor (“EC50-MC-1”) over the EC50 of the compound for the MC-3 (EC50-MC-3)/MC-4 (EC50-MC-4) receptor, the EC50 values being measured as described above. The formulas are as follows:

MC-3 selectivity=[EC50-MC-1]/[EC50-MC-3]
MC-4 selectivity=[EC50-MC-1]/[EC50-MC-4]


For the purposes of the present invention a receptor ligand (analog) is defined herein as being “selective for the MC-3 receptor” when the above-mentioned ratio “MC-3-selectivity” is at least about 10. In other treatments, methods, or compositions this value is at least about 100, while for yet other embodiments of the present invention the selectivity is at least about 500. A compound is defined herein as being “selective for the MC-4 receptor” when the above-mentioned ratio “MC-4-selectivity” is at least about 10. In other treatments, methods, or compositions this value is at least about 100, while for yet other embodiments of the present invention the selectivity is at least about 500.


All documents cited in the Detailed Description of the Invention are, are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.


While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims
  • 1. A compound having the formula:
  • 2. A compound having the formula:
  • 3. A compound selected from the group consisting of:
  • 4. A compound selected from the group consisting of:
  • 5. A compound selected from the group consisting of:
CROSS REFERENCE TO RELATED APPLICATION

This application claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/420,578, filed Oct. 23, 2002.

US Referenced Citations (16)
Number Name Date Kind
4251438 Moon Feb 1981 A
5492916 Morriello et al. Feb 1996 A
5494919 Morriello et al. Feb 1996 A
5536716 Chen et al. Jul 1996 A
5556853 Tsubotani et al. Sep 1996 A
5721250 Morriello et al. Feb 1998 A
5721251 Chen et al. Feb 1998 A
5783582 Guo et al. Jul 1998 A
5804578 Chakravarty et al. Sep 1998 A
5877182 Nargund et al. Mar 1999 A
5880125 Nargund Mar 1999 A
5936089 Carpino et al. Aug 1999 A
5965565 Chen et al. Oct 1999 A
6294534 Nargund et al. Sep 2001 B1
6350760 Bakshi et al. Feb 2002 B1
20030220324 Fotsch et al. Nov 2003 A1
Foreign Referenced Citations (39)
Number Date Country
WO 9413696 Jun 1994 WO
WO 9419367 Sep 1994 WO
WO 9602530 Feb 1996 WO
WO 9613265 May 1996 WO
WO 9631478 Oct 1996 WO
WO 9638471 Dec 1996 WO
WO 9805292 Feb 1998 WO
WO 9810653 Mar 1998 WO
WO 9852929 Nov 1998 WO
WO 9955679 Nov 1999 WO
WO 9958501 Nov 1999 WO
WO 9964002 Dec 1999 WO
WO 0066558 Nov 2000 WO
WO 0074679 Dec 2000 WO
WO 0105331 Jan 2001 WO
1 122242 Aug 2001 WO
WO 0170337 Sep 2001 WO
WO 0170708 Sep 2001 WO
WO 0191752 Dec 2001 WO
WO 0200654 Jan 2002 WO
WO 0215909 Feb 2002 WO
WO 0248124 Jun 2002 WO
WO 02059095 Aug 2002 WO
WO 02059107 Aug 2002 WO
WO 02059108 Aug 2002 WO
WO 02059117 Aug 2002 WO
WO 02064576 Aug 2002 WO
WO 02068387 Sep 2002 WO
WO 02068388 Sep 2002 WO
WO 02070511 Sep 2002 WO
WO 02076947 Oct 2002 WO
WO 02079194 Oct 2002 WO
WO 02085925 Oct 2002 WO
WO 03009850 Feb 2003 WO
WO 03013571 Feb 2003 WO
WO 03022835 Mar 2003 WO
WO 03031410 Apr 2003 WO
WO 03035627 May 2003 WO
WO 03061660 Jul 2003 WO
Related Publications (1)
Number Date Country
20050010031 A1 Jan 2005 US
Provisional Applications (1)
Number Date Country
60420578 Oct 2002 US