HK1179280A

HK1179280A - Template-fixed peptidomimetics with cxcr7 modulating activity

Info

Publication number: HK1179280A
Application number: HK13106901.0A
Authority: HK
Inventors: F．O．贡贝特; A.莱德雷尔; R．勒韦; D．奥布雷赫特; B．罗马尼奥利; J.齐默曼; K.帕特尔
Original assignee: 波利弗尔股份公司
Priority date: 2010-02-05
Filing date: 2011-02-04
Publication date: 2013-09-27

Description

Template-fixed peptidomimetics with CXCR7 modulatory activity

The present invention provides novel peptidomimetics in which a chain of α -amino acid residues as defined below is linked to a template that provides specific structural constraints for a β -hairpin-like conformation. These template-immobilized beta-hairpin mimetics have selective modulatory activity towards the CXCR7 receptor and are therefore useful in the treatment of a variety of diseases and disorders mediated by or maintained through CXCR7 activity, or in the pharmacotherapy of specific disease conditions supporting primarily different causes. The present invention relates to methods of using these compounds in the treatment of various diseases and disorders, to pharmaceutical compositions and forms comprising these compounds, and to efficient processes for preparing and producing these compounds and their intermediates.

Many medically relevant biological processes are mediated by signal transduction involving chemokines and their receptors, such as tissue-specific recruitment of leukocytes to sites of inflammation. For other ligand/receptor pairs of its superfamily, GPCRs, the entire downstream activity and sometimes organ-specific function of certain receptors, are not yet fully understood. One such recently de-orphaned GPCR is the chemokine receptor CXCR7(RDC1), which binds with high affinity to the inflammatory and homing chemokines CXCL11 (ITAC) and CXCL12 (SDF-1) (k. balabanian, b. langane et al, j. biol. chem.2005, 280, 35760-.

CXCL12 also binds to yet another chemokine receptor CXCR4, and the CXCL12/CXCR4 axis has been shown to play a key role in different inflammatory and cancer diseases. CXCL12 was recently found to bind to both CXCR4 and CXCR7, suggesting that both physiological and pathological functions of CXCL12 may be mediated by two distinct receptors (c.dambly-Chaudi et.

Unlike CXCR4, CXCR7 does not induce typical chemokine responses such as calcium activation. In contrast, recent findings indicate that this receptor has a critical function in generating a local gradient of CXCL12 for CXCR 4-dependent migration by capturing CXCL 12. These observations tend to indicate a major role for CXCR 7as a decoy receptor ("CXCL 12 trap"), with a key function to clear excess CXCL12 by internalization (b. boldajipout, h. mahabalshwaret, al., Cell 2008, 132, 463-73; Cell adh. migr.2008, 2, 69-70). In addition, CXCR7 has been shown to be able to modulate CXCR4 activity by forming heterodimers, and it may activate other intracellular signal transduction pathways (a.levoye, k.balabanian et al, Blood 2009, 113, 6085-93).

As a result of the close functional relationship between the two receptors, CXCR7 may be implicated in the same disease conditions in which CXCR4 has been shown to play a critical role. In particular, CXCR7 is significantly expressed in a variety of tumors and their respective tumor cell lines (e.g., prostate, bladder, breast cancer, multiple myeloma, rhabdomyosarcoma, non-small cell lung cancer); its expression level is often associated with tumor growth and invasiveness. Two major mechanisms have been proposed by which CXCR7 plays a role in tumor development and metastasis: 1) increase cancer cell proliferation and survival, which can be supported by pro-angiogenic effects; 2) CXCR7 promotes adhesion and transendothelial migration of cancer cells that occurs with CXCR 4-mediated migration.

Furthermore, recent studies have shown that CXCR7 may also be implicated in rheumatoid arthritis, other chronic and/or autoimmune inflammatory diseases (g.graham et al, curr.mol.med.2009, 9(2), 86-93) or pulmonary hypertension, as it is upregulated in certain specific tissues such as the lungs under hypoxic conditions (c.m.costello, p.mcloughlin et al, am.j.physiol.lung Cell mol.physiol.2008, 295(2), 272-.

The present invention now provides novel chemical entities which are useful as potent, selective and pharmaceutically acceptable ligands for GPC-receptor CXCR 7. In the compounds described below, particular strategies are employed to stabilize the β -hairpin conformation in a backbone-cyclic β -hairpin mimetic that exhibits selective activity for the CXCR7 receptor. The strategy involves grafting a loop sequence of a natural or non-natural biopolymer onto a template, which functions to constrain the peptide loop backbone to a β -hairpin structure.

Template-binding hairpin mimetics have been described in the literature (D.Obrecht, J.A.Robinson, adv.Med.Chem.1999, 4, 1-68; J.A.Robinson, Syn.Lett.2000, 4, 429-441) and the ability to generate β -hairpin peptidomimetics using combinatorial and parallel synthesis methods has also been determined (L.Jiang, K.Moehle, B.Dhanapanal, D.Obrecht, J.A.Robinson, Helv.Chim.acta.2000, 83, 3097-3112). These methods allow the synthesis and screening of large hairpin mimetic libraries, which in turn significantly facilitates structure-activity studies, as well as the discovery of new molecules with potent and in particular selective agonistic or antagonistic activity.

There are a few general studies in the art describing tetrameric peptides linked to a template for use as agonists and/or antagonists of GPCRs (e.g. WO 2008092281). The present invention now provides novel compounds which differ significantly in structure and exhibit high biological activity and unexpected selectivity for a particular novel receptor in the art, which is the CXCR7 receptor.

The invention relates to novel beta-hairpin peptidomimetics of the general formula (I)

Wherein an individual element T or P is linked to the nitrogen (N) of the next element in either direction from the carbonyl (C = O) point of attachment, and wherein

-

T¹Is an alpha-amino acid residue of one of the formulae

While

T²Is an alpha-amino acid residue of one of the formulae

-or

T¹Is an alpha-amino acid residue of one of the formulae

While

T²Is an alpha-amino acid residue of one of the formulae AA11 to AA17, or an alpha-amino acid residue of one of the formulae

P¹，P³And P⁴Independently is

-NR¹CH(R²⁹)CO-；-NR¹CH(R³⁰) CO-; or-NR¹CH(R³¹)CO-；

P²Is an alpha-amino acid residue of one of the formulae

A is O; NR (nitrogen to noise ratio)¹⁷(ii) a S; SO; or SO₂；

X is OH; NH (NH)₂；OR¹⁶；NR¹R¹⁶(ii) a Or NR¹⁷R¹⁸；

Y is NH₂；F；OR¹⁶；NR¹R¹⁶(ii) a Or NR¹⁷R¹⁸；

R¹，R²And R³Independently is

H；CF₃(ii) a A lower alkyl group; lower alkenyl; aryl-lower alkyl; or heteroaryl-lower alkyl;

R⁴，R⁵，R⁶，R⁷and R⁸Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹⁵)_oOR¹⁷；

-(CHR¹⁵)_oSR¹⁷；-(CHR¹⁵)_oNR¹⁷R¹⁸；-(CHR¹⁵)_oOCONR¹⁷R¹⁸；-(CHR¹⁵)_oNR¹CONR¹⁷R¹⁸；

-(CHR¹⁵)_oNR¹COR¹⁷；-(CHR¹⁵)_oCOOR¹⁷；-(CHR¹⁵)_oCONR¹⁷R¹⁸；-(CHR¹⁵)_oPO(OR¹)₂；

-(CHR¹⁵)_oSO₂R¹⁷；-(CHR¹⁵)_oNR¹SO₂R¹⁷；-(CHR¹⁵)_oSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_oR³⁵(ii) a Or

-(CHR¹)_nO(CHR²)_mR³⁵(ii) a Or

R⁴And R²Together can form

=O；-(CHR¹⁵)_p-；-(CH₂)_nO(CH₂)_m-；-(CH₂)_nS(CH₂)_m-; or- (CH)₂)_nNR¹(CH₂)_m-; or

R⁴And R⁵；R⁵And R⁶；R⁶And R⁷；R⁷And R⁸(ii) a Or R⁶And R⁹Together can form:

-(CHR¹⁵)_p-；-(CH₂)_nO(CH₂)_m-；-(CH₂)_nS(CH₂)_m-; or- (CH)₂)_nNR¹(CH₂)_m-; or

R⁴And R⁵Independently is X;

R⁹，R¹⁰，R¹¹and R¹²Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹⁵)_rOR¹⁷；

-(CHR¹⁵)_rSR¹⁷；-(CHR¹⁵)_rNR¹⁷R¹⁸；-(CHR¹⁵)_rOCONR¹⁷R¹⁸；-(CHR¹⁵)_rNR¹CONR¹⁷R¹⁸；

-(CHR¹⁵)_rNR¹COR¹⁷；-(CHR¹⁵)_oCOOR¹⁷；-(CHR¹⁵)_oCONR¹⁷R¹⁸；-(CHR¹⁵)_rPO(OR¹)₂；

-(CHR¹⁵)_rSO₂R¹⁷；-(CHR¹⁵)_rNR¹SO₂R¹⁷；-(CHR¹⁵)_rSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_oR³⁵(ii) a Or

-(CHR¹)_rO(CHR¹)_oR³⁵(ii) a Or

R¹¹And R¹²Together can form

= O; or = NR¹；

R¹³And R¹⁴Independently is

H；F；Cl；Br；CF₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹⁵)_oOR¹⁷；

-(CHR¹)_rO(CHR¹)_oR³⁵；

R¹⁵Is H; f; CF (compact flash)₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group;

cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; an aryl group; a heteroaryl group;

aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；-(CHR¹)_oSR¹⁷；

-(CHR¹)_oNR¹⁷R¹⁸；-(CHR¹)_oNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CHR¹)_oCOOR¹⁷；

-(CHR¹)_oCONR¹⁷R¹⁸；-(CHR¹)_oSO₂R¹⁷(ii) a Or- (CHR)¹)_oSO₂NR¹⁷R¹⁸；

R¹⁶Is CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group;

aryl-lower alkyl; heteroaryl-lower alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl;

aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl;

-(CHR¹)_sOR¹⁷；-(CHR¹)_sSR¹⁷；-(CHR¹)_sNR¹⁷R¹⁸；-(CHR¹)_oCOR¹⁷；

-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR¹⁷R¹⁸(ii) a Or- (CHR)¹)_oSO₂R¹⁷；

R¹⁷，R¹⁸，R¹⁹And R²⁰Independently is

H; a lower alkyl group; lower alkenyl; lower alkoxy; a cycloalkyl group; a heterocycloalkyl group;

aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl; or

Structural element-NR¹⁷R¹⁸and-NR¹⁹R²⁰Can independently form:

a heterocycloalkyl group; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl;

or a radical of one of the formulae

Z, Z 'and Z' are independently

-CR³⁹(ii) a Or N;

R²¹，R²²，R²³and R²⁴Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；

-(CHR¹)_oSR¹⁷；-(CHR¹)_oNR²R¹⁷；-(CHR¹)_oOCONR²R¹⁷；-(CHR¹)_oNR²CONR³R¹⁷；

-(CHR¹)_oNR²COR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR²R¹⁷；-(CHR¹)_oPO(OR²)₂；

-(CHR¹)_oSO₂R¹⁷；-(CHR¹)_oNR²SO₂R¹⁷；-(CHR¹)_oSO₂NR²R¹⁷；-(CR¹R²)_oR³⁸(ii) a Or

-(CHR¹)_nO(CHR²)_mR³⁸；

R²⁵And R²⁶Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_rOR¹⁷；-(CHR¹)_rSR¹⁷；

-(CHR¹)_rNR²R¹⁷；-(CHR¹)_rOCONR²R¹⁷；-(CHR¹)_rNR²CONR³R¹⁷；-(CHR¹)_rNR²COR¹⁷；

-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR²R¹⁷；-(CHR¹)_rPO(OR²)₂；-(CHR¹)_rSO₂R¹⁷；

-(CHR¹)_rNR²SO₂R¹⁷；-(CHR¹)_rSO₂NR²R¹⁷；-(CR¹R²)_oR³⁸(ii) a Or

-(CHR¹)_rO(CHR²)_oR³⁸；

R²⁷Is H; f; cl; br; CF (compact flash)₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；

-(CHR¹)_rO(CHR²)_oR³⁸；

R²⁹Is H; an alkyl group; an alkenyl group; cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl;

-(CHR⁴)_oOR¹⁷；-(CHR⁴)_oSR¹⁷(ii) a Or- (CHR)⁴)_rNR¹⁷R¹⁸；

R³⁰Is- (CR)¹R⁴)_nR³⁵；-(CH₂)_nO(CH₂)_mR³⁵；-(CH₂)_nS(CH₂)_mR³⁵(ii) a Or- (CH)₂)_nNR¹(CH₂)_mR³⁵；

R³¹Is an alkyl group; an alkenyl group; - (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²R¹⁶；-(CR¹R¹⁵)_qNR¹⁷R³²；

-(CR¹R¹⁵)_qNR¹⁷COR¹⁸；-(CH₂)_qC(=NR¹⁵)NR¹⁷R¹⁸；-(CH₂)_qC(=NOR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_qC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；

-(CR¹R¹⁵)_qN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qOR¹⁷；-(CR¹R¹⁵)_qOR³²；

-(CR¹R¹⁵)_qSR¹⁷；-(CR¹R¹⁵)_qSO₂R¹⁷；-(CR¹R¹⁵)_qNR¹⁷SO₂R¹⁸；-(CR¹R¹⁵)_qSO₂NR²R¹⁶；

-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR¹⁹SO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qPO(OR²)₂；

-(CH²)_nO(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nO(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；

-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；

-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nS(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；

-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；

-(CR¹R¹⁵)_qCOOR¹⁷；-(CR¹R¹⁵)_qCONR¹⁷R¹⁸(ii) a Or- (CR)¹R¹⁵)_qCOR³³；

R³²is-COR²⁹；-COR³⁰；-CO(CR¹R¹⁵)_oR¹⁷；-CO(CR¹R¹⁵)_oOR¹⁷；-CO(CR¹R¹⁵)_oNR¹⁷R¹⁸；

-CO(CR¹R¹⁵)_oNR²R¹⁶；-CO(CR¹R²⁹)NR¹⁷R¹⁸；-CO(CR¹R³⁰)NR¹⁷R¹⁸；

-CO(CR¹R³⁴)NR¹⁷R¹⁸；-CO(CHR¹)_oCONR¹⁷R¹⁸；-CO(CHR¹)_oCONR¹⁷SO₂R¹⁸；

-CO(CR¹R¹⁵)_oNR¹⁷SO₂R¹⁸；-CONR¹(CHR¹⁷)_nNR²(CHR¹⁵)_mR¹⁶；

-CO(CHR¹⁷)_nO(CHR¹⁵)_mR¹⁶；-CONR¹(CHR¹⁷)_nO(CHR¹⁵)_mR¹⁶；-SO₂R²⁹；

-SO₂R³⁰；-SO₂(CR¹R¹⁵)_oR¹⁷(ii) a or-SO₂(CR¹R¹⁵)_oNR¹⁷R¹⁸；

R³³is-NR¹C(R²)(R²⁹)COOR¹⁷；-NR¹C(R²)(R²⁹)CONR¹⁷R¹⁸；-NR¹C(R²)(R³⁰)COOR¹⁷；

-NR¹C(R²)(R³⁰)CONR¹⁷R¹⁸；-NR¹C(R²)(R³⁴)COOR¹⁷(ii) a or-NR¹C(R²)(R³⁴)CONR¹⁷R¹⁸；

R³⁴Is- (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CH₂)_qC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_qC(=NOR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_qC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qNR²C(=NR¹⁹)NR¹⁷R¹⁸；

-(CR¹R¹⁵)_qN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qOR¹⁷；-(CR¹R¹⁵)_qSR¹⁷；-(CR¹R¹⁵)_qSO₂R¹⁷；

-(CR¹R¹⁵)_qNR¹⁷SO₂R¹⁸；-(CR¹R¹⁵)_qSO₂NR¹R¹⁶；-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；

-(CR¹R¹⁵)_qNR²SO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qPO(OR¹)₂；-(CH₂)_nO(CH₂)_mNR¹⁷R¹⁸；

-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nO(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nO(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；

-(CH₂)_nS(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nS(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nS(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qCOOR¹⁷(ii) a Or- (CR)¹R¹⁵)_qCONR¹⁷R¹⁸；

R³⁵Is an aryl radical of one of the formulae

Or a heteroaryl group of one of the formulae

R³⁶And R³⁷Independently is

H；F；Cl；Br；CF₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH)₂)_oR³⁸；-(CH₂)_oOR¹⁷；

-O(CH₂)_oR³⁸；-(CH₂)_oSR¹⁷；-(CH₂)_oNR¹⁷R¹⁸；-(CH₂)_oOCONR¹⁷R¹⁸；

-(CH₂)_oNR¹CONR¹⁷R¹⁸；-(CH₂)_oNR¹COR¹⁷；-(CH₂)_oCOOR¹⁷；-(CH₂)_oCONR¹⁷R¹⁸；

-(CH₂)_oPO(OR¹)₂；-(CH₂)_oSO₂R¹⁶(ii) a Or- (CH)₂)_oCOR¹⁷；

R³⁸Is an aryl radical of the formula

R³⁹，R⁴⁰And R⁴¹Independently is

H；F；Cl；Br；OH；NH₂；NO₂；CN；CF₃；OCHF₂；OCF₃；-NR¹R¹⁷；-(CH₂)_oCOOR¹⁷；

-(CH₂)_oCONR¹R¹⁷(ii) a A lower alkyl group; lower alkoxy; or lower alkenyl;

R⁴²is H; a lower alkyl group; or aryl-lower alkyl;

n and m are independently integers from 0 to 5, provided that n + m.ltoreq.6;

o is 0 to 4; p is 2 to 6; q is 1 to 6; r is 1 to 3; s is 0 to 4

And pharmaceutically acceptable salts thereof.

Each individual radical "R" having the same number x^x"(x =1-42) is independently selected in a particular formula, and thus these groups are the same or different.

As used herein, the term "alkyl", alone or in combination (i.e., as part of another group, such as "arylalkyl") refers to a saturated straight-chain or branched hydrocarbon residue having up to 12, preferably up to 8, carbon atoms and which may be optionally substituted. In a preferred embodiment of the invention, "alkyl" is "lower alkyl" which refers to alkyl groups having up to 6 carbon atoms.

The term "alkenyl", alone or in combination, refers to a straight-chain or branched hydrocarbon residue having up to 12, preferably up to 8, carbon atoms and containing at least one, or depending on the chain length, up to four, ethylenic double bonds. The alkenyl moiety is optionally substituted and can exist as an E or Z configuration, which are all part of this invention.

The term "cycloalkyl", alone or in combination, refers to a saturated or partially unsaturated alicyclic moiety having from 3 to 10 carbon atoms and which may be optionally substituted. Examples of such moieties include, but are not limited to, cyclohexyl, norbornyl (norbonyl), decahydronaphthyl (decalinyl), and the like.

The term "heterocycloalkyl", alone or in combination, describes a saturated or partially unsaturated monocyclic or bicyclic moiety having from 3 to 9 ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen, or sulfur. The term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1, 7-diazaspiro [4.4] nonane, and the like. The heterocycloalkyl ring may be optionally substituted.

The term "aryl", alone or in combination, refers to an aromatic carbocyclic hydrocarbon residue containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted with up to 3 substituents, such as Br, Cl, F, CF₃，OCF₃，OCHF₂，N(CH₃)₂，NO₂Lower alkyl, lower alkenyl, phenyl or phenoxy.

The term "heteroaryl", alone or in combination, refers to an aromatic heterocyclic residue containing one or two five-membered and/or six-membered rings, at least one of which contains up to 4 heteroatoms selected from O, S and N, such that the heteroaryl residue or tautomeric form thereof may be attached via any suitable atom. The heteroaryl ring is optionally substituted, for example as indicated above for "aryl".

The term "arylalkyl", as used herein, refers to an alkyl group, as defined above, substituted with an aryl group, as defined above. Examples of arylalkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and the like. Similarly, the term "aryl-lower alkyl" refers to the moieties described above but wherein the alkyl is a "lower alkyl" group.

The term "heteroarylalkyl", as used herein, refers to an alkyl group, as defined hereinbefore, substituted with a heteroaryl group, as defined hereinbefore. Similarly the term "heteroaryl-lower alkyl" refers to the moieties described above but wherein the alkyl is a "lower alkyl" group.

The term "aryl-cycloalkyl", as used herein, refers to a cycloalkyl group, as defined hereinbefore, substituted by, or fused with, an aryl group, as defined hereinbefore. Examples of aryl-cycloalkyl moieties include, but are not limited to, phenylcyclopentyl, 2, 3-dihydro-1H-indenyl, 1, 2, 3, 4-tetrahydronaphthyl, and the like.

The term "aryl-heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as defined above, substituted with or fused to an aryl group, as defined above. Examples of aryl-heterocycloalkyl moieties include, but are not limited to, indolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, and the like.

The term "heteroaryl-cycloalkyl", as used herein, refers to a cycloalkyl group, as defined hereinbefore, substituted with or fused to a heteroaryl group, as defined hereinbefore. Examples of heteroaryl-cycloalkyl moieties include, but are not limited to, 5, 6, 7, 8-tetrahydroquinolinyl and the like.

The term "heteroaryl-heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as defined above, substituted with or fused to a heteroaryl group, as defined above. Examples of heteroaryl-heterocycloalkyl moieties include, but are not limited to, 4- (thiazol-2-yl) piperazinyl, 5, 6, 7, 8-tetrahydro-1, 6-naphthyridinyl, and the like.

The terms "cycloalkyl-aryl", "heterocycloalkyl-aryl", "cycloalkyl-heteroaryl", and "heterocycloalkyl-heteroaryl", as used herein, are defined similarly to the terms "aryl-cycloalkyl", "aryl-heterocycloalkyl", "heteroaryl-cycloalkyl", and "heteroaryl-heterocycloalkyl", as previously defined, but are linked in the opposite direction, e.g., the term refers to 2- (piperazin-1-yl) thiazolyl instead of 4- (thiazol-2-yl) piperazinyl, with the same remaining rationale.

The terms "alkoxy" and "aryloxy", alone or in combination, refer to-O-alkyl and-O-aryl, respectively, wherein alkyl or aryl is as defined above.

The term "optionally substituted" is intended to mean a group, such as but not limited toThe alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxy, and aryloxy groups may be substituted with one or more substituents independently selected from, but not limited to, for example, amino (-NH), or a pharmaceutically acceptable salt thereof₂) Dimethylamino, nitro (-NO)₂) Halogen (F, Cl, Br, I), CF₃Cyano (-CN), hydroxy, methoxy, oxo (= O), carboxy, phenyl, phenyloxy, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, and the like.

The term "lower" refers to residues and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" refers to a saturated straight or branched hydrocarbon residue having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

The peptidomimetics of the invention can also be diastereomers (e.g. epimers) of the compounds of formula (I) which are based on chiral centers whose absolute stereochemistry is not explicitly defined above. These stereoisomers can be prepared by adapting a process described below in which either the epimer or the enantiomer of the chiral starting material is used. Where stereochemistry is not indicated above, each individual epimer as well as mixtures of the two are part of the present invention.

Yet another embodiment of the invention may also include compounds that are equivalent to compounds of formula (I) except that one or more atoms are replaced with an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g., enriched in²H(D)、³H、¹¹C、¹⁴C、¹²⁷I, etc. These isotopic analogs, and pharmaceutical salts and formulations thereof, are considered to be useful agents in therapy and/or diagnosis, for example, but not limited to, fine-tuning the half-life time in vivo can result in optimized dosing regimens.

Particular embodiments of the present invention relate to derivatives of formula (I),

wherein especially

aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_sOR¹⁷；-(CHR¹)_sSR¹⁷；

-(CHR¹)_sNR¹⁷R¹⁸；-(CHR¹)_oCOR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR¹⁷R¹⁸(ii) a Or

-(CHR¹)_oSO₂R¹⁷；

R¹⁷，R¹⁸，R¹⁹And R²⁰Independently is

aryl-lower alkyl; or heteroaryl-lower alkyl; or

Structural element-NR¹⁷R¹⁸and-NR¹⁹R²⁰Can independently form:

or a group of one of the above formulae C1 to C8;

R³¹is an alkyl group; an alkenyl group; - (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²R¹⁶；-(CR¹R¹⁵)_qNR¹⁷COR¹⁸；

-(CH₂)_qC(=NR¹⁵)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qOR¹⁷；

-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；

-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；

-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qCONR¹⁷R¹⁸(ii) a Or- (CR)¹R¹⁵)_qCOR³³；

s is 2-4

Wherein all other elements of formula (I) are as described above.

In a further particular embodiment of the invention, the elements of the general formula (I) are defined as follows

T¹Is that^DPro；^DPip；^DTic；^DTiq；^DOic；^DAzt；^DPro((3R)OH)；^DPro((3S)OH)；^DPro((3R)NH₂)；^DPro((3S)NH₂)；^DPro((4R)OH)；^DPro((4S)OH)；^DPro((4R)NH₂)；^DPro((4S)NH₂)；^DPro ((4S) NHBz); or^DMor；

T²Is Thr; alloThr; ser; hSer; pro ((3R) OH); pro ((3S) OH); hyp (Bn); (4S) -Hyp (Bn); pro ((3R) NH)₂)；Pro((3S)NH₂)；Pro((4R)NH₂)；Pro((4S)NH₂) (ii) a Pro ((4S) F); pro ((4S) NHBz); or Mor; or

At T¹Is that^DPro((3R)OH)；^DPro((3S)OH)；^DPro((3R)NH₂)；^DPro((3S)NH₂)；^DPro((4R)NH₂)；^DPro((4S)NH₂)；^DPro ((4S) NHBz); or^DIn the case of the Mor,

then T²Can also be

Pro; pip; tic; tiq; oic; or Azt;

P¹，P³and P⁴Independently is

Ala; arg; asn; asp; cit; cys; glu; gln; gly; his; ile; leu; lys; met; orn; phe; pro; ser; thr; trp; tyr; val; abu; agb, respectively; agp; ala (tBu); ala (cPr); ala (2 furyl); ala (3 furyl); ala (Ppz); ala (1 Pyraz); ala (2 Quin); ala (3 Quin); ala (4 Quin); ala (tet); azt; bbta; bip; cha; chg; dab; dab (ac); dab (cPr); dab (ipr); dab (4 Me)₂NPhSO₂)；Dab(MeOEtNCO)；Dab(MePpzCO)；Dab(MeSO₂)；Dab(morphCO)；Dab(1Nal)；Dab(2Nal)；Dap；Dap(CONH₂)；Dap(MeOEt)；Dap((MeOEt)₂)；Deg；Gly(tBu)；hArg；hCha；hCys；hHis；hLys；hPhe；hSer；hSer(Me)；hTrp；hTyr；His(Me)；His(Bn)；Hyp(Bn)；(4S)-Hyp(Bn)；Hyp(4BrBn)；Hyp(3CNBn)；Hyp(4CNBn)；Hyp(CONHPh) (ii) a Hyp (Ph); lys (ac); lys (bz); lys (cpr); lys (ipr); lys (Me); lys (Nic); lys ((5R) OH); lys (4 oxa); met (O)₂)；1Nal；2Nal；Nle；Nle(6OBn)；OctG；Oic；Orn(cPr)；Orn(iPr)；2Pal；3Pal；4Pal；Phe(2Cl)；Phe(3Cl)；Phe(4Cl)；Phe(3，4Cl₂)；Phe(2F)；Phe(3F)；Phe(4F)；Phe(4CN)；Phe(4CF₃)；Phe(4COOMe)；Phg；Pip；Pro((4R)Bn)；Pro((4S)F)；Pro((4S)cHex)；Pro(5，5Me₂)；Ser(Bn)；Ser(Me)；Thi；alloThr；Thr(Bn)；Thz；Thz(5，5Me₂) (ii) a Tic; tic (7 OH); trp (7 aza); trp (5 Br); trp (6 Br); trp (6 CF)₃)；Trp(5Cl)；Trp(6Cl)；Trp(5，6Cl)；Trp(5OH)；Tyr(Bn)；Tyr(Me)；Tyr(4MeOCOBn)；Tyr(Ph)；Tyr(4OHPh)；Tza；Gln(Alk1)；Gln(Alk2)；Gln(Alk3)；Gln(Alk4)；Gln(Alk5)；Gln(Alk6)；Gln(Alk7)；Gln(Alk8)；Gln(Alk9)；Gln(Alk10)；Gln(Alk11)；Gln(Alk12)；Gln(Alk13)；Gln(Alk14)；Gln(Alk15)；Gln(Alk16)；Gln(Alk17)；Gln(Alk18)；Gln(Alk19)；Gln(Alk20)；Gln(Alk21)；Gln(Alk22)；Gln(Alk23)；Gln(Alk24)；Gln(Alk25)；Gln(Alk26)；Gln(Alk27)；Gln(Alk28)；Gln(Alk29)；Gln(Alk30)；Gln(Alk31)；Gln(Alk32)；Gln(Alk33)；Gln(Alk34)；Glu(cN1)；Glu(cN2)；Glu(cN3)；Glu(cN4)；Glu(cN5)；Glu(cN6)；Glu(cN7)；Glu(cN8)；Glu(cN9)；Glu(cN10)；Glu(cN11)；Glu(cN12)；Glu(cN13)；Glu(cN14)；Glu(cN15)；Glu(cN16)；Glu(cN17)；Lys(Ar1)；Lys(Ar2)；Lys(Ar3)；Lys(Ar4)；Lys(Ar5)；Lys(Ar6)；Lys(Ar7)；Lys(Ar8)；Lys(Ar9)；Lys(Ar10)；Lys(Ar11)；Lys(Ar12)；Orn(Ar1)；Orn(Ar2)；Orn(Ar3)；Orn(Ar4)；Orn(Ar5)；Orn(Ar6)；Orn(Ar7)；Orn(Ar8)；Orn(Ar9)；Orn(Ar10)；Orn(Ar11)；Orn(Ar12)；Dab(Ar1)；Dab(Ar2)；Dab(Ar3)；Dab(Ar4)；Dab(Ar5)；Dab(Ar6)；Dab(Ar7)；Dab(Ar8)；Dab(Ar9)；Dab(Ar10)；Dab(Ar11)；Dab(Ar12)；Dab(S1)；Dab(S2)；Dab(S3)；Dab(S4)；Dab(S5)；Dab(S6)；Dab(S7)；Dab(S8)；Dab(S9)；Dab(S10)；Dab(S11)；Dab(S12)；Dab(S13)；Dab(S14)；Dab(S15)；Dab(S16)；Dab(S17)；Dab(S18)；Dab(A1)；Dab(A2)；Dab(A3)；Dab(A4)；Dab(A5)；Dab(A6)；Dab(A7)；Dab(A8)；Dab(A9)；Dab(A10)；Dab(A11)；Dab(A12)；Dab(A13)；Dab(A14)；Dab(A15)；Dab(A16)；Dab(A17)；Dab(A18)；Dab(A19)；Dab(A20)；Dab(A21)；Dab(A22)；Dab(A23)；Dab(A24)；Dab(A25)；Dab(A26)；Dab(A27)；Dab(A28)；Dab(A29)；Dab(A30)；Dab(A31)；Dab(A32)；Dab(A33)；Dab(A34)；Dab(A35)；Dab(A36)；Dab(A37)；Dab(A38)；Dab(A39)；Dab(A40)；Dab(A41)；Dab(A42)；Dab(A43)；Dab(A44)；Dab(A45)；Dab(A46)；Dab(A47)；Dab(A48)；Dab(A49)；Dab(A50)；Dab(A51)；Dab(A52)；Dab(A53)；Dab(A54)；Dab(A55)；Orn(A1)；Orn(A2)；Orn(A3)；Orn(A4)；Orn(A5)；Orn(A6)；Orn(A7)；Orn(A8)；Orn(A9)；Orn(A10)；Orn(A11)；Orn(A12)；Orn(A13)；Orn(A14)；Orn(A15)；Orn(A16)；Orn(A17)；Orn(A18)；Orn(A19)；Orn(A20)；Orn(A21)；Orn(A22)；Orn(A23)；Orn(A24)；Orn(A25)；Orn(A26)；Orn(A27)；Orn(A28)；Orn(A29)；Orn(A30)；Orn(A31)；Orn(A32)；Orn(A33)；Orn(A34)；Orn(A35)；Orn(A36)；Orn(A37)；Orn(A38)；Orn(A39)；Orn(A40)；Orn(A41)；Orn(A42)；Orn(A43)；Orn(A44)；Orn(A45)；Orn(A46)；Orn(A47)；Orn(A48)；Orn(A49)；Orn(A50)；Orn(A51)；Orn(A52)；Orn(A53)；Orn(A54)；Orn(A55)；Orn(A56)；Asn(Alk1)；Asn(Alk2)；Asn(Alk3)；Asn(Alk4)；Asn(Alk5)；Asn(Alk6)；Asn(Alk7)；Asn(Alk8)；Asn(Alk9)；Asn(Alk10)；Asn(Alk11)；Asn(Alk12)；Asn(Alk13)；Asn(Alk14)；Asn(Alk15)；Asn(Alk16)；Asn(Alk17)；Asn(Alk18)；Asn(Alk19)；Asn(Alk20)；Asn(Alk21)；Asn(Alk22)；Asn(Alk23)；Asn(Alk24)；Asn(Alk25)；Asn(Alk26)；Asn(Alk27)；Asn(Alk28)；Asn(Alk29)；Asn(Alk30)；Asn(Alk31)；Asn(Alk32)；Asn(Alk33)；Asn(Alk34)；Asp(cN1)；Asp(cN2)；Asp(cN3)；Asp(cN4)；Asp(cN5)；Asp(cN6)；Asp(cN7)；Asp(cN8)；Asp(cN9)；Asp(cN10)；Asp(cN11)；Asp(cN12)；Asp(cN13)；Asp(cN14)；Asp(cN15)；Asp(cN16)；Asp(cN17)；Dap(Ar1)；Dap(Ar2)；Dap(Ar3)；Dap(Ar4)；Dap(Ar5)；Dap(Ar6)；Dap(Ar7)；Dap(Ar8)；Dap(Ar9)；Dap(Ar10)；Dap(Ar11)；Dap(Ar12)；Dap(S1)；Dap(S2)；Dap(S3)；Dap(S4)；Dap(S5)；Dap(S6)；Dap(S7)；Dap(S8)；Dap(S9)；Dap(S10)；Dap(S11)；Dap(S12)；Dap(S13)；Dap(S14)；Dap(S15)；Dap(S16)；Dap(S17)；Dap(S18)；Dap(A1)；Dap(A2) (ii) a Dap (A3); dap (A4); dap (A5); dap (A6); dap (A7); dap (A8); dap (A9); dap (A10); dap (A11); dap (A12); dap (A13); dap (A14); dap (A15); dap (A16); dap (A17); dap (A18); dap (A19); dap (A20); dap (A21); dap (A22); dap (A23); dap (A24); dap (A25); dap (A26); dap (A27); dap (A28); dap (A29); dap (A30); dap (A31); dap (A32); dap (A33); dap (A34); dap (A35); dap (A36); dap (A37); dap (A38); dap (A39); dap (A40); dap (A41); dap (A42); dap (A43); dap (A44); dap (A45); dap (A46); dap (A47); dap (A48); dap (A49); dap (A50); dap (A51); dap (A52); dap (A53); dap (A54); or Dap (A55);

P²is that^DArg；^DhArg；^DAgb；^DLys；^DOrn；^DCit；^DThr；^DDab；^DDab；^DPhe；^DPhe(4CF₃)；^DTrp；^DHis；^DTyr；^D2Pal；^D3Pal；^D4Pal；^DLys(Ar1)；^DLys(Ar2)；^DLys(Ar3)；^DLys(Ar4)；^DLys(Ar5)；^DLys(Ar6)；^DLys(Ar7)；^DLys(Ar8)；^DLys(Ar9)；^DLys(Ar10)；^DLys(Ar11)；^DLys(Ar12)；^DOrn(A41)；^DOrn(A56)；^DOrn(Ar1)；^DOrn(Ar2)；^DOrn(Ar3)；^DOrn(Ar4)；^DOrn(Ar5)；^DOrn(Ar6)；^DOrn(Ar7)；^DOrn(Ar8)；^DOrn(Ar9)；^DOrn(Ar10)；^DOrn(Ar11)；^DOrn(Ar12)；^DDab(Ar1)；^DDab(Ar2)；^DDab(Ar3)；^DDab(Ar4)；^DDab(Ar5)；^DDab(Ar6)；^DDab(Ar7)；^DDab(Ar8)；^DDab(Ar9)；^DDab(Ar10)；^DDab(Ar11)；^DDab(Ar12)；^DDap(Ar1)；^DDap(Ar2)；^DDap(Ar3)；^DDap(Ar4)；^DDap(Ar5)；^DDap(Ar6)；^DDap(Ar7)；^DDap(Ar8)；^DDap(Ar9)；^DDap(Ar10)；^DDap (Ar 11); or^DDap(Ar12)；

And pharmaceutically acceptable salts thereof.

then T²Can also be

Pro; pip; tic; tiq; oic; or Azt;

P¹is Ile; nle; leu; val; chg; cha; abu; ala; ala (cPr); ala (1 Pyraz); ala (tet); trp; 1 Nal; 2 Nal; phe; tyr; 2 Pal; 3 Pal; 4 Pal; thr; his; arg; hArg; agb, respectively; pip; orn (Ar 2); or Orn (a 56);

P²is that^DArg；^DhArg；^DAgb；^DLys；^DOrn；^DCit；^DThr；^DDab；^DDap；^DPhe；^DTrp；^DHis；^DTyr；^D2Pal；^D3 Pal; or^D4Pal；

P³Is Arg; hArg; agb, respectively; agp; lys; orn; orn (a 41); orn (a 56); orn (Ar 2); orn (Ar 4); orn (Ar 7); cit; thr; dab; dap; phe; trp; his; tyr; or Ile

P⁴Is Trp; his; phe; phe (4 CF)₃) (ii) a1 Nal; 2 Nal; tyr; leu; ile; arg; hArg; lys; dab; dap; orn; orn (a 56); or Orn (Ar 7);

and pharmaceutically acceptable salts thereof.

T¹Is that^DPro；^DPip；^DTic；^DPro((4S)OH)；^DPro((4R)NH₂) (ii) a Or^DPro((4S)NH₂)；

T²Is Thr; alloThr; ser; hSer; pro ((3S) OH); (4S) -Hyp (Bn); pro ((4R) NH)₂)；Pro((4S)NH₂) (ii) a Pro ((4S) F); pro ((4S) NHBz); or Mor;

P¹is Ile; nle; leu; val; chg; cha; abu; ala; trp; 1 Nal; tyr; 3 Pal; thr; his; arg; hArg; agb, respectively; pip; ala (1 Pyraz); ala (tet); orn (Ar 2); or Orn (a 56);

P²is that^DArg；^DLys；^DOrn；^DCit；^DThr；^DDab；^DPhe；^DTrp；^DHis; or^D3Pal；

P³Is Arg; hArg; agb, respectively; agp; lys; orn; orn (a 41); orn (a 56); orn (Ar 2); orn (Ar 4); orn (Ar 7); dab; trp; or His;

P⁴is Trp; his; phe；Phe(4CF₃) (ii) a1 Nal; 2 Nal; tyr; ile; arg; hArg; lys; dab; orn; orn (a 56); or Orn (Ar 7);

and pharmaceutically acceptable salts thereof.

A list of abbreviations is provided below, corresponding to commonly employed amino acid abbreviations, the amino acids or residues of amino acids being suitable for the purposes of the present invention and designated herein.

Although these amino acids are specifically indicated, it is still clear to the skilled person that derivatives of these amino acids have similar structural and physicochemical properties, thus having functional analogues of similar biological activity and thus still forming part of the gist of the present invention.

Ala L-alanine

Arg L-arginine

Asn L-asparagine

Asp L-aspartic acid

Cit L-citrulline

Cys L-cysteine

Glu L-glutamic acid

Gln L-Glutamine

Gly glycine

His L-histidine

Ile L-isoleucine

Leu L-leucine

Lys L-lysine

Met L-methionine

Orn L-Ornithine

Phe L-phenylalanine

Pro L-proline

Ser L-serine

Thr L-threonine

Trp L-Tryptophan

Tyr L-tyrosine

Val L-valine

Abu (S) -2-aminobutyric acid

Agb (S) -2-amino-4-guanidinobutyric acid

Agp (S) -2-amino-3-guanidinopropionic acid

Ala (tBu) (S) -2-amino-4, 4-dimethylpentanoic acid

Ala (cPr) (S) -2-amino-3-cyclopropylpropionic acid

Ala (2 furyl) (S) -2-amino-3- (furan-2-yl) propionic acid

Ala (3 furyl) (S) -2-amino-3- (furan-3-yl) propionic acid

Ala (Ppz) (S) -2-amino-3- (piperazin-1-yl) propionic acid

Ala (1Pyraz) (S) -2-amino-3- (1H-pyrazol-1-yl) propionic acid

Ala (2Quin) (S) -2-amino-3- (quinolin-2-yl) propionic acid

Ala (3Quin) (S) -2-amino-3- (quinolin-3-yl) propionic acid

Ala (4Quin) (S) -2-amino-3- (quinolin-4-yl) propionic acid

Ala (Tet) (S) -2-amino-3- (2H-tetrazol-2-yl) propionic acid

Azt (S) -azetidine-2-carboxylic acid

Bbta (S) -2-amino-3- (1-benzothien-3-yl) propionic acid

Bip (S) -2-amino-3- (4-biphenylyl) propionic acid

Cha (S) -2-amino-3-cyclohexylpropionic acid

Dab (S) -2, 4-diaminobutyric acid

Dab (Ac) (S) -4-acetylamino-2-aminobutyric acid

Dab (cPr) (S) -2-amino-4- (cyclopropylamino) butanoic acid

Dab (iPr) (S) -2-amino-4- (isopropylamino) butanoic acid

Dab(4Me₂NPhSO₂) (S) -2-amino-4- (4- (dimethylamino) phenylsulfonylamino) butanoic acid

Dab (MeOEtNCO) (S) -2-amino-4- (3- (2-methoxyethyl) ureido) butanoic acid

Dab (MePpZCO) (S) -2-amino-4- (4-methylpiperazine-1-carboxamide) butanoic acid

Dab(MeSO₂) (S) -2-amino-4- (methylsulfonylamino) butanoic acid

Dab (morphco)(s) -2-amino-4- (morpholine-4-carboxamido) butanoic acid

Dab (1Nal) (S) -2-amino-4- ((S) -2-amino-3- (naphthalen-1-yl) propanamido) -butyric acid

Dab (2Nal) (S) -2-amino-4- ((S) -2-amino-3- (naphthalen-2-yl) -propionamido) -butyric acid

Dap (S) -2, 4-diaminopropionic acid

Dap(CONH₂) (S) -2-amino-3-ureidopropionic acid

Dap (MeOEt) (S) -2-amino-3- (2-methoxyethylamino) propionic acid

Dap((MeOEt)₂) (S) -2-amino-3- (bis (2-methoxyethyl) amino) propionic acid

Deg 2-amino-2-ethylbutyric acid

Gly (tBu) (S) -2-amino-3, 3-dimethylbutyric acid

hArg (S) -2-amino-6-guanidinohexanoic acid

hCha (S) -2-amino-4-cyclohexylbutyric acid

hCys (S) -2-amino-4-mercaptobutanoic acid

hHis (S) -2-amino-4- (1H-imidazol-5-yl) butanoic acid

hLys (S) -2, 7-diaminoheptanoic acid

hPhe (S) -2-amino-4-phenylbutyric acid

hSer (S) -2-amino-4-hydroxybutyric acid

hSer (Me) (S) -2-amino-4-methoxybutyric acid

hTRp (S) -2-amino-4- (1H-indol-3-yl) butanoic acid

hTyr (S) -2-amino-4- (4-hydroxyphenyl) butanoic acid

His (Me) -2-amino-3- (1-methyl-1H-imidazol-5-yl) propionic acid

His (Bn) (S) -2-amino-3- (1-benzyl-1H-imidazol-5-yl) propionic acid

Hyp (Bn) (2S, 4R) -4- (benzyloxy) pyrrolidine-2-carboxylic acid

(4S) -Hyp (Bn) (2S, 4S) -4- (benzyloxy) pyrrolidine-2-carboxylic acid

Hyp (4BrBn) (2S, 4R) -4- (4-bromobenzyloxy) pyrrolidine-2-carboxylic acid

Hyp (3CNBn) (2S, 4R) -4- (3-cyanobenzyloxy) pyrrolidine-2-carboxylic acid

Hyp (4CNBn) (2S, 4R) -4- (4-cyanobenzyloxy) pyrrolidine-2-carboxylic acid

Hyp (CONHPh) (2S, 4R) -4- (phenylcarbamoyloxy) pyrrolidine-2-carboxylic acid

Hyp (Ph) (2S, 4R) -4-phenoxypyrrolidine-2-carboxylic acid

Lys (Ac) (S) -6-acetamido-2-aminocaproic acid

Lys (Bz) (S) -2-amino-6-benzoylaminocaproic acid

Lys (cPr) (S) -2-amino-6- (cyclopropylamino) hexanoic acid

Lys (iPr) -2-amino-6- (isopropylamino) hexanoic acid

Lys (Me) -2-amino-6- (methylamino) hexanoic acid

Lys (Nic) (S) -2-amino-6- (nicotinamido) hexanoic acid

Lys ((5R) OH) (2S, 5R) -2, 6-diamino-5-hydroxycaproic acid

Lys (4 oxa) (S) -2-amino-3- (2-aminoethoxy) propionic acid

Met(O₂) (S) -2-amino-4- (methylsulfonyl) butanoic acid

Mor (S) -morpholine-3-carboxylic acid

1Nal (S) -2-amino-3-naphthalen-1-ylpropionic acid

2Nal (S) -2-amino-3-naphthalen-2-ylpropionic acid

Nle (S) -2-amino-hexanoic acid

Nle (6OBn) (S) -2-amino-6- (benzyloxy) hexanoic acid

Octg (S) -2-aminodecanoic acid

Oic (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid

Orn (cPr) (S) -2-amino-5- (cyclopropylamino) pentanoic acid

Orn (iPr) (S) -2-amino-5- (isopropylamino) pentanoic acid

2Pal (S) -2-amino-3- (pyridin-2-yl) -propionic acid

3Pal (S) -2-amino-3- (pyridin-3-yl) -propionic acid

4Pal (S) -2-amino-3- (pyridin-4-yl) -propionic acid

Phe (2Cl) (S) -2-amino-3- (2-chlorophenyl) propionic acid

Phe (3Cl) (S) -2-amino-3- (3-chlorophenyl) propionic acid

Phe (4Cl) (S) -2-amino-3- (4-chlorophenyl) propionic acid

Phe(3，4Cl₂) (S) -2-amino-3- (3, 4-dichlorophenyl) propionic acid

Phe (2F) (S) -2-amino-3- (2-fluorophenyl) propionic acid

Phe (3F) (S) -2-amino-3- (3-fluorophenyl) propionic acid

Phe (4F) (S) -2-amino-3- (4-fluorophenyl) propionic acid

Phe (4CN) (S) -2-amino-3- (4-cyanophenyl) propionic acid

Phe(4CF₃) (S) -2-amino-3- (4- (trifluoromethyl)) propionic acid

Phe (4COOMe) (S) -2-amino-3- (4- (methoxycarbonyl) phenyl) propionic acid

Phg (S) -2-amino-2-phenylacetic acid

Pip (S) -piperidine-2-carboxylic acid

Pro ((4R) Bn) (2S, 4R) -4-benzylpyrrolidine-2-carboxylic acid

Pro ((4S) F) (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid

Pro ((4S) cHex) (2S, 4S) -4-cyclohexylpyrrolidine-2-carboxylic acid

Pro((3R)NH₂) (2S, 3R) -3-Aminopyrrolidine-2-carboxylic acid

Pro((3S)NH₂) (2S, 3S) -3-Aminopyrrolidine-2-carboxylic acid

Pro((4R)NH₂) (2S, 4R) -4-Aminopyrrolidine-2-carboxylic acid

Pro((4S)NH₂) (2S, 4S) -4-Aminopyrrolidine-2-carboxylic acid

Pro ((4S) NHBz) (2S, 4S) -4-benzoylaminopyrrolidine-2-carboxylic acid

Pro(5，5Me₂) (S) -3, 3-dimethylpyrrolidine-2-carboxylic acid

Pro ((3R) OH) (2S, 3R) -3-hydroxypyrrolidine-2-carboxylic acid

Pro ((3S) OH) (2S, 3S) -3-hydroxypyrrolidine-2-carboxylic acid

Ser (Bn) (S) -2-amino-3- (benzyloxy) propionic acid

Ser (Me) (S) -2-amino-3-methoxy-propionic acid

Thi (S) -2-amino-3- (thien-2-yl) propionic acid

alloThr (2S, 3S) -2-amino-3-hydroxybutyric acid

Thr (Bn) (2S, 3R) -2-amino-3- (benzyloxy) butyric acid

Thz (4R) -1, 3-thiazolidine-4-carboxylic acid

Thz(5，5Me₂) (4R) -5, 5-dimethyl-1, 3-thiazolidine-4-carboxylic acid

Tic (3S) -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid

Tic (7OH) (3S) -7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid

Tiq (S) -1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylic acid

Trp (7 aza) (R) -2-amino-3- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) propionic acid

Trp (5Br) (S) -2-amino-3- (5-bromo-1H-indol-3-yl) propionic acid

Trp (6Br) (S) -2-amino-3- (6-bromo-1H-indol-3-yl) propionic acid

Trp(6CF₃) (S) -2-amino-3- (6- (trifluoromethyl) -1H-indol-3-yl) propionic acid

Trp (5Cl) (S) -2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid

Trp (6Cl) (S) -2-amino-3- (6-chloro-1H-indol-3-yl) propionic acid

Trp (5, 6Cl) (S) -2-amino-3- (5, 6-dichloro-1H-indol-3-yl) propionic acid

Trp (5OH) (S) -2-amino-3- (5-hydroxy-1H-indol-3-yl) propionic acid

Tyr (Bn) (S) -2-amino-3- (4- (benzyloxy) phenyl) propionic acid

Tyr (Me) -2-amino-3- (4-methoxyphenyl) propionic acid

Tyr (4MeOCOBn) (S) -2-amino-3- (4- (4- (methoxycarbonyl) benzyloxy) phenyl) -propionic acid

Tyr (Ph) (S) -2-amino-3- (4-phenoxyphenyl) propionic acid

Tyr (4OHPh) (S) -2-amino-3- [4- (4-hydroxyphenoxy) phenyl ] propanoic acid

Tza (S) -2-amino-3- (thiazol-4-yl) propionic acid

Asn (Alk1) (S) -2-amino-4-oxo-4- (2, 2, 2-trifluoroethylamino) butanoic acid

Asn (Alk2) (S) -2-amino-4- (cyclopentylamino) -4-oxobutanoic acid

Asn (Alk3) (S) -2-amino-4- (cyclohexylamino) -4-oxobutanoic acid

Asn (Alk4) (S) -2-amino-4-oxo-4- (tetrahydro-2H-pyran-4-ylamino) butanoic acid

Asn (Alk5) (S) -2-amino-4- (2-hydroxyethylamino) -4-oxobutanoic acid

Asn (Alk6) (S) -2-amino-4- (2-methoxyethylamino) -4-oxobutanoic acid

Asn (Alk7) (S) -2-amino-4- (2-aminoethylamino) -4-oxobutanoic acid

Asn (Alk8) (S) -2-amino-4- (2- (dimethylamino) ethylamino) -4-oxobutanoic acid

Asn (Alk9) (S) -2-amino-4- ((2-methoxyethyl) (methyl) amino) -4-oxobutanoic acid

Asn (Alk10) (S) -2-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -4-oxobutanoic acid

Asn (Alk11) (S) -2-amino-4- (3-aminopropylamino) -4-oxobutanoic acid

Asn (Alk12) (S) -2-amino-4- (3- (dimethylamino) propylamino) -4-oxobutanoic acid

Asn (Alk13) (S) -2-amino-4- ((3- (dimethylamino) propyl) (methyl) amino) -4-oxobutanoic acid

Asn (Alk14) (S) -4- (3-acetamidopropylamino) -2-amino-4-oxobutanoic acid

Asn (Alk15) (S) -2-amino-4-oxo-4- (2- (pyrrolidin-1-yl) ethylamino) butanoic acid

Asn (Alk16) (S) -2-amino-4- (2-morpholinoethylamino) -4-oxobutanoic acid

Asn (Alk17) (S) -2-amino-4- (3-morpholinopropylamino) -4-oxobutanoic acid

Asn (Alk18) (S) -2-amino-4- (1, 3-dihydroxypropan-2-ylamino) -4-oxobutanoic acid

Asn (Alk19) (S) -2-amino-4- (4-hydroxy-3- (hydroxymethyl) butylamino) -4-oxobutanoic acid

Asn (Alk20) (S) -2-amino-4-oxo-4- (piperidin-4-ylmethylamino) butanoic acid

Asn (Alk21) (S) -2-amino-4- (methyl ((tetrahydro-2H-pyran-4-yl) methyl) amino) -4-oxobutanoic acid

Asn (Alk22) (2S) -2-amino-4- (methyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -4-oxobutanoic acid

Asn (Alk23) (S) -2-amino-4-oxo-4- (thiazol-2-ylmethylamino) butanoic acid

Asn (Alk24) (S) -2-amino-4- ((1-methyl-1H-imidazol-4-yl) methylamino) -4-oxobutanoic acid

Asn (Alk25) (S) -2-amino-4- (benzylamino) -4-oxobutanoic acid

Asn (Alk26) (S) -2-amino-4- (4- (methylsulfonyl) benzylamino) -4-oxobutanoic acid

Asn (Alk27) (S) -2-amino-4-oxo-4- (pyridin-3-ylmethylamino) butanoic acid

Asn (Alk28) (S) -2-amino-4-oxo-4- (4- (trifluoromethyl) benzylamino) butanoic acid

Asn (Alk29) (S) -2-amino-4- (2-methoxybenzylamino) -4-oxobutanoic acid

Asn (Alk30) (S) -2-amino-4- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methylamino) -4-oxobutanoic acid

Asn (Alk31) (S) -2-amino-4- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) -methylamino) -4-oxobutanoic acid

Asn (Alk32) (S) -4- (2- (1H-indol-3-yl) ethylamino) -2-amino-4-oxobutanoic acid

Asn (Alk33) (2S) -2-amino-4- (2, 3-dihydro-1H-inden-1-ylamino) -4-oxobutanoic acid

Asn (Alk34) (2S) -2-amino-4-oxo-4- (1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -butyric acid

Asp (cN1) (S) -2-amino-4- (azetidin-1-yl) -4-oxobutanoic acid

Asp (cN2) (S) -2-amino-4-oxo-4- (pyrrolidin-1-yl) butyric acid

Asp (cN3) (S) -2-amino-4-oxo-4- (piperidin-1-yl) butyric acid

Asp (cN4) (S) -2-amino-4-morpholino-4-oxobutanoic acid

Asp (cN5) (S) -2-amino-4-oxo-4- (piperazin-1-yl) butyric acid

Asp (cN6) (S) -2-amino-4- (4-methylpiperazin-1-yl) -4-oxobutanoic acid

Asp (cN7) (S) -2-amino-4- (4-hydroxypiperidin-1-yl) -4-oxobutanoic acid

Asp (cN8) (S) -2-amino-4- (4- (dimethylamino) piperidin-1-yl) -4-oxobutanoic acid

Asp (cN9) (2S) -2-amino-4- (7-methyl-1, 7-diazaspiro [4.4] nonan-1-yl) -4-oxobutanoic acid

Asp (cN10) (S) -2-amino-4- (indolin-1-yl) -4-oxobutanoic acid

Asp (cN11) (S) -2-amino-4- (5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -4-oxobutanoic acid

Asp (cN12) (S) -2-amino-4- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -4-oxobutanoic acid

Asp (cN13) (S) -2-amino-4- (5, 6-dihydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) -4-oxobutanoic acid

Asp (cN14) (S) -4- (4- (1H-imidazol-1-yl) piperidin-1-yl) -2-amino-4-oxobutanoic acid

Asp (cN15) (S) -4- (4- (1H-imidazol-2-yl) piperidin-1-yl) -2-amino-4-oxobutanoic acid

Asp (cN16) (S) -2-amino-4- (1, 4-oxazepan-4-yl) -4-oxobutanoic acid

Asp (cN17) (S) -2-amino-4- (4-methyl-1, 4-diazepan-1-yl) -4-oxobutanoic acid

Gln (Alk1) (S) -2-amino-5-oxo-5- (2, 2, 2-trifluoroethylamino) pentanoic acid

Gln (Alk2) (S) -2-amino-5- (cyclopentylamino) -5-oxopentanoic acid

Gln (Alk3) (S) -2-amino-5- (cyclohexylamino) -5-oxopentanoic acid

Gln (Alk4) (S) -2-amino-5-oxo-5- (tetrahydro-2H-pyran-4-ylamino) pentanoic acid

Gln (Alk5) (S) -2-amino-5- (2-hydroxyethylamino) -5-oxopentanoic acid

Gln (Alk6) (S) -2-amino-5- (2-methoxyethylamino) -5-oxopentanoic acid

Gln (Alk7) (S) -2-amino-5- (2-aminoethylamino) -5-oxopentanoic acid

Gln (Alk8) (S) -2-amino-5- (2- (dimethylamino) ethylamino) -5-oxopentanoic acid

Gln (Alk9) (S) -2-amino-5- ((2-methoxyethyl) (methyl) amino) -5-oxopentanoic acid

Gln (Alk10) (S) -2-amino-5- ((2- (dimethylamino) ethyl) (methyl) amino) -5-oxopentanoic acid

Gln (Alk11) (S) -2-amino-5- (3-aminopropylamino) -5-oxopentanoic acid

Gln (Alk12) (S) -2-amino-5- (3- (dimethylamino) propylamino) -5-oxopentanoic acid

Gln (Alk13) (S) -2-amino-5- ((3- (dimethylamino) propyl) (methyl) amino) -5-oxopentanoic acid

Gln (Alk14) (S) -5- (3-acetamidopropylamino) -2-amino-5-oxopentanoic acid

Gln (Alk15) (S) -2-amino-5-oxo-5- (2- (pyrrolidin-1-yl) ethylamino) pentanoic acid

Gln (Alk16) (S) -2-amino-5- (2-morpholinoethylamino) -5-oxopentanoic acid

Gln (Alk17) (S) -2-amino-5- (3-morpholinopropylamino) -5-oxopentanoic acid

Gln (Alk18) (S) -2-amino-5- (1, 3-dihydroxypropan-2-ylamino) -5-oxopentanoic acid

Gln (Alk19) (S) -2-amino-5- (4-hydroxy-3- (hydroxymethyl) butylamino) -5-oxopentanoic acid

Gln (Alk20) (S) -2-amino-5-oxo-5- (piperidin-4-ylmethyl-amino) pentanoic acid

Gln (Alk21) (S) -2-amino-5- (methyl ((tetrahydro-2H-pyran-4-yl) methyl) amino) -5-oxopentanoic acid

Gln (Alk22) (2S) -2-amino-5- (methyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -5-oxopentanoic acid

Gln (Alk23) (S) -2-amino-5-oxo-5- (thiazol-2-ylmethylamino) pentanoic acid

Gln (Alk24) (S) -2-amino-5- ((1-methyl-1H-imidazol-4-yl) methylamino) -5-oxopentanoic acid

Gln (Alk25) (S) -2-amino-5- (benzylamino) -5-oxopentanoic acid

Gln (Alk26) (S) -2-amino-5- (4- (methylsulfonyl) benzylamino) -5-oxopentanoic acid

Gln (Alk27) (S) -2-amino-5-oxo-5- (pyridin-3-ylmethylamino) pentanoic acid

Gln (Alk28) (S) -2-amino-5-oxo-5- (4- (trifluoromethyl) benzylamino) pentanoic acid

Gln (Alk29) (S) -2-amino-5- (2-methoxybenzylamino) -5-oxopentanoic acid

Gln (Alk30) (S) -2-amino-5- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methylamino) -5-oxopentanoic acid

Gln (Alk31) (S) -2-amino-5- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) -methylamino) -5-oxopentanoic acid

Gln (Alk32) (S) -5- (2- (1H-indol-3-yl) ethylamino) -2-amino-5-oxopentanoic acid

Gln (Alk33) (2S) -2-amino-5- (2, 3-dihydro-1H-inden-1-ylamino) -5-oxopentanoic acid

Gln (Alk34) (2S) -2-amino-5-oxo-5- (1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -pentanoic acid

Glu (cN1) (S) -2-amino-5- (azetidin-1-yl) -5-oxopentanoic acid

Glu (cN2) (S) -2-amino-5-oxo-5- (pyrrolidin-1-yl) pentanoic acid

Glu (cN3) (S) -2-amino-5-oxo-5- (piperidin-1-yl) pentanoic acid

Glu (cN4) (S) -2-amino-5-morpholino-5-oxopentanoic acid

Glu (cN5) (S) -2-amino-5-oxo-5- (piperazin-1-yl) pentanoic acid

Glu (cN6) (S) -2-amino-5- (4-methylpiperazin-1-yl) -5-oxopentanoic acid

Glu (cN7) (S) -2-amino-5- (4-hydroxypiperidin-1-yl) -5-oxopentanoic acid

Glu (cN8) (S) -2-amino-5- (4- (dimethylamino) piperidin-1-yl) -5-oxopentanoic acid

Glu (cN9) (2S) -2-amino-5- (7-methyl-1, 7-diazaspiro [4.4] nonan-1-yl) -5-oxopentanoic acid

Glu (cN10) (S) -2-amino-5- (indolin-1-yl) -5-oxopentanoic acid

Glu (cN11) (S) -2-amino-5- (5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -5-oxopentanoic acid

Glu (cN12) (S) -2-amino-5- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -5-oxopentanoic acid

Glu (cN13) (S) -2-amino-5- (5, 6-dihydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) -5-oxopentanoic acid

Glu (cN14) (S) -5- (4- (1H-imidazol-1-yl) piperidin-1-yl) -2-amino-5-oxopentanoic acid

Glu (cN15) (S) -5- (4- (1H-imidazol-2-yl) piperidin-1-yl) -2-amino-5-oxopentanoic acid

Glu (cN16) (S) -2-amino-5- (1, 4-oxazepan-4-yl) -5-oxopentanoic acid

Glu (cN17) (S) -2-amino-5- (4-methyl-1, 4-diazepan-1-yl) -5-oxopentanoic acid

Lys (Ar1) (S) -2-amino-6- (pyridin-2-ylamino) hexanoic acid

Lys (Ar2) (S) -2-amino-6- (pyrimidin-2-ylamino) hexanoic acid

Lys (Ar3) (S) -2-amino-6- (1, 2, 4-triazin-3-ylamino) hexanoic acid

Lys (Ar4) (S) -2-amino-6- (pyridin-2-ylmethylamino) hexanoic acid

Lys (Ar5) (S) -2-amino-6- (pyrimidin-2-ylmethyl amino) hexanoic acid

Lys (Ar6) (S) -2-amino-6- (di (pyrimidin-2-ylmethyl) amino) hexanoic acid

Lys (Ar7) (S) -2-amino-6- (((1-methyl-1H-imidazol-2-yl) methyl) amino) hexanoic acid

Lys (Ar8) (S) -2-amino-6- (((4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) amino) hexanoic acid

Lys (Ar9) (S) -2-amino-6- (((1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) amino) hexanoic acid

Lys (Ar10) (S) -2-amino-6- (1H-pyrazol-1-yl) hexanoic acid

Lys (Ar11) (S) -2-amino-6- (bis ((1-methyl-1H-imidazol-2-yl) methyl) amino) -hexanoic acid

Lys (Ar12) (S) -2-amino-6- (1H-1, 2, 4-triazol-1-yl) hexanoic acid

Orn (Ar1) (S) -2-amino-5- (pyridin-2-ylamino) pentanoic acid

Orn (Ar2) (S) -2-amino-5- (pyrimidin-2-ylamino) pentanoic acid

Orn (Ar3) (S) -2-amino-5- (1, 2, 4-triazin-3-ylamino) pentanoic acid

Orn (Ar4) (S) -2-amino-5- ((pyridin-2-ylmethyl) amino) pentanoic acid

Orn (Ar5) (S) -2-amino-5- (pyrimidin-2-ylmethylamino) pentanoic acid

Orn (Ar6) (S) -2-amino-5- (di (pyrimidin-2-ylmethyl) amino) pentanoic acid

Orn (Ar7) (S) -2-amino-5- (((1-methyl-1H-imidazol-2-yl) methyl) amino) pentanoic acid

Orn (Ar8) (S) -2-amino-5- (((4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) amino) -pentanoic acid

Orn (Ar9) (S) -2-amino-5- (((1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) amino) -pentanoic acid

Orn (Ar10) (S) -2-amino-5- (1H-pyrazol-1-yl) pentanoic acid

Orn (Ar11) (S) -2-amino-5- (bis ((1-methyl-1H-imidazol-2-yl) methyl) amino) -pentanoic acid

Orn (Ar12) (S) -2-amino-5- (1H-1, 2, 4-triazol-1-yl) pentanoic acid

Orn (A1) (S) -5-acetylamino-2-aminopentanoic acid

Orn (A2) (S) -2-amino-5-propionamidopentanoic acid

Orn (A3) (S) -2-amino-5-isobutyramidovaleric acid

Orn (A4) (S) -2-amino-5- (cyclopropanecarboxamido) pentanoic acid

Orn (A5) (S) -2-amino-5- (3, 3, 3-trifluoropropionylamino) pentanoic acid

Orn (A6) (S) -2-amino-5- (4, 4, 4-trifluorobutanamido) pentanoic acid

Orn (A7) (S) -2-amino-5- (3-aminopropionylamino) pentanoic acid

Orn (A8) (S) -2-amino-5- (4-aminobutyrylamino) pentanoic acid

Orn (A9) (S) -2-amino-5- (5-aminopentanamido) pentanoic acid

Orn (A10) (S) -2-amino-5- (3-methoxypropionylamino) pentanoic acid

Orn (A11) (S) -2-amino-5- (3- (methylamino) propionamido) pentanoic acid

Orn (A12) (S) -2-amino-5- (3- (dimethylamino) propionamido) pentanoic acid

Orn (A13) (S) -2-amino-5- (3- (phenylamino) propionamido) pentanoic acid

Orn (A14) (2S) -2-amino-5- (3-aminobutyrylamino) pentanoic acid

Orn (A15) (S) -2-amino-5- (3-amino-3-methylbutanamido) pentanoic acid

Orn (A16) (S) -2-amino-5- (3- (methylsulfonyl) propionamido) pentanoic acid

Orn (A17) (S) -2-amino-5- (2-cyclopropylacetamido) pentanoic acid

Orn (A18) (2S) -2-amino-5- (2- (pyrrolidin-3-yl) acetylamino) pentanoic acid

Orn (A19) (2S) -2-amino-5- (2- (pyrrolidin-2-yl) acetylamino) pentanoic acid

Orn (A20) (S) -2-amino-5- (2- (piperidin-4-yl) acetylamino) pentanoic acid

Orn (A21) (2S) -2-amino-5- (2- (piperidin-3-yl) acetylamino) pentanoic acid

Orn (A22) (2S) -2-amino-5- (2- (piperidin-2-yl) acetylamino) pentanoic acid

Orn (A23) (S) -2-amino-5- (3- (piperidin-1-yl) propionamido) pentanoic acid

Orn (A24) (S) -2-amino-5- (3- (piperazin-1-yl) propionamido) pentanoic acid

Orn (A25) (S) -2-amino-5- (3- (4-methylpiperazin-1-yl) propionamido) pentanoic acid

Orn (A26) (S) -2-amino-5- (3-morpholinopropionamido) pentanoic acid

Orn (A27) (S) -2-amino-5- (2- (1-aminocyclohexyl) acetylamino) pentanoic acid

Orn (A28) (S) -2-amino-5- (2- (4-aminotetrahydro-2H-pyran-4-yl) acetylamino) -pentanoic acid

Orn (A29) (2S) -2-amino-5- (2, 2-dimethyl-1, 3-dioxolane-4-carboxamido) pentanoic acid

Orn (A30) (S) -2-amino-5-benzoylaminovaleric acid

Orn (A31) (S) -2-amino-5- (isonicotinamido) pentanoic acid

Orn (A32) (S) -2-amino-5- (nicotinamido) pentanoic acid

Orn (A33) (S) -2-amino-5- (picolinamido) pentanoic acid

Orn (A34) (S) -2-amino-5- (6- (trifluoromethyl) nicotinamido) pentanoic acid

Orn (A35) (S) -2-amino-5- (3-methoxybenzamido) pentanoic acid

Orn (A36) (S) -2-amino-5- (3- (difluoromethoxy) benzoylamino) pentanoic acid

Orn (A37) (S) -2-amino-5- (4- (methylsulfonyl) benzoylamino) pentanoic acid

Orn (A38) (S) -2-amino-5- (benzo [ d ] [1, 3] dioxol-5-carboxamido) pentanoic acid

Orn (A39) (S) -2-amino-5- (2- (pyridin-3-yl) acetylamino) pentanoic acid

Orn (A40) (S) -2-amino-5- (pyrimidine-4-carboxamido) pentanoic acid

Orn (A41) (S) -2-amino-5- (pyrazine-2-carboxamide) pentanoic acid

Orn (A42) (S) -2-amino-5- (3-cyanobenzoylamino) pentanoic acid

Orn (A43) (S) -2-amino-5- (thiophene-2-carboxamide) pentanoic acid

Orn (A44) (S) -2-amino-5- (1-methyl-1H-pyrrole-2-carboxamide) pentanoic acid

Orn (A45) (S) -2-amino-5- (thiazole-2-carboxamide) pentanoic acid

Orn (A46) (S) -2-amino-5- (thiazole-4-carboxamide) pentanoic acid

Orn (A47) (S) -2-amino-5- (1-methyl-1H-imidazole-2-carboxamido) pentanoic acid

Orn (A48) (S) -2-amino-5- (1-methyl-1H-imidazole-5-carboxamido) pentanoic acid

Orn (A49) (S) -2-amino-5- (1-methyl-1H-indole-2-carboxamido) pentanoic acid

Orn (A50) (S) -2-amino-5- (benzo [ d ] thiazole-2-carboxamide) pentanoic acid

Orn (A51) (S) -2-amino-5- (quinoxaline-2-carboxamide) pentanoic acid

Orn (A52) (S) -5- (3- (1H-indol-3-yl) propionamido) -2-aminopentanoic acid

Orn (A53) (S) -2-amino-5- (2-aminothiazole-4-carboxamido) pentanoic acid

Orn (A54) (S) -2-amino-5- (2- (2-aminothiazol-4-yl) acetylamino) pentanoic acid

Orn (A55) (S) -2-amino-5- (4-guanidinobutylamido) pentanoic acid

Orn (A56) (S) -2-amino-5- (1, 4, 5, 6-tetrahydropyrimidin-2-ylamino) pentanoic acid

Dab (Ar1) (S) -2-amino-4- (pyridin-2-ylamino) butanoic acid

Dab (Ar2) (S) -2-amino-4- (pyrimidin-2-ylamino) butanoic acid

Dab (Ar3) (S) -2-amino-4- (1, 2, 4-triazin-3-ylamino) butanoic acid

Dab (Ar4) (S) -2-amino-4- (pyridin-2-ylmethylamino) butyric acid

Dab (Ar5) (S) -2-amino-4- (pyrimidin-2-ylmethylamino) butanoic acid

Dab (Ar6) (S) -2-amino-4- (bis (pyrimidin-2-ylmethyl) amino) butanoic acid

Dab (Ar7) (S) -2-amino-4- (((1-methyl-1H-imidazol-2-yl) methyl) amino) butanoic acid

Dab (Ar8) (S) -2-amino-4- (((4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) amino) butanoic acid

Dab (Ar9) (S) -2-amino-4- (((1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) amino) butanoic acid

Dab (Ar10) (S) -2-amino-4- (1H-pyrazol-1-yl) butanoic acid

Dab (Ar11) (S) -2-amino-4- (bis ((1-methyl-1H-imidazol-2-yl) methyl) amino) -butyric acid

Dab (Ar12) (S) -2-amino-4- (1H-1, 2, 4-triazol-1-yl) butanoic acid

Dab (S1) (S) -2-amino-4- (methylsulfonylamino) butanoic acid

Dab (S2) (S) -2-amino-4- (ethylsulfonylamino) butanoic acid

Dab (S3) (S) -2-amino-4- (1-methylethylsulfonylamino) butanoic acid

Dab (S4) (S) -2-amino-4- (cyclopropanesulfonylamino) butanoic acid

Dab (S5) (S) -2-amino-4- (2-methylpropylsulfonylamino) butanoic acid

Dab (S6) (S) -2-amino-4- (2, 2, 2-trifluoroethylsulfonylamino) butanoic acid

Dab (S7) (S) -2-amino-4- (cyclopentanesulfonylamino) butanoic acid

Dab (S8) (S) -2-amino-4- (cyclohexanesulfonylamino) butanoic acid

Dab (S9) (S) -2-amino-4- (tetrahydro-2H-pyran-4-sulfonylamino) butanoic acid

Dab (S10) (S) -2-amino-4- (phenylsulfonylamino) butanoic acid

Dab (S11) (S) -2-amino-4- (4-aminophenylsulfonylamino) butanoic acid

Dab (S12) (S) -2-amino-4- (4- (dimethylamino) phenylsulfonylamino) butanoic acid

Dab (S13) (S) -2-amino-4- (4-morpholinophenylsulfonylamino) butanoic acid

Dab (S14) (S) -2-amino-4- (4-cyanophenylsulfonylamino) butanoic acid

Dab (S15) (S) -2-amino-4- (5-cyanopyridine-2-sulfonylamino) butanoic acid

Dab (S16) (S) -2-amino-4- (1H-pyrazole-4-sulfonylamino) butanoic acid

Dab (S17) (S) -2-amino-4- (1H-1, 2, 4-triazole-5-sulfonylamino) butanoic acid

Dab (S18) (S) -2-amino-4- (1, 1-dimethylethylsulfonylamino) butanoic acid

Dab (A1) (S) -4-acetylamino-2-aminobutanoic acid

Dab (A2) (S) -2-amino-4-propionamidobutyric acid

Dab (A3) (S) -2-amino-4-isobutyramidobutyric acid

Dab (A4) (S) -2-amino-4- (cyclopropanecarboxamido) butanoic acid

Dab (A5) (S) -2-amino-4- (3, 3, 3-trifluoropropionylamino) butanoic acid

Dab (A6) (S) -2-amino-4- (4, 4, 4-trifluorobutanamido) butanoic acid

Dab (A7) (S) -2-amino-4- (3-aminopropionylamino) butanoic acid

Dab (A8) (S) -2-amino-4- (4-aminobutanamido) butanoic acid

Dab (A9) (S) -2-amino-4- (5-aminopentanamide) butanoic acid

Dab (A10) (S) -2-amino-4- (3-methoxypropionylamino) butyric acid

Dab (A11) (S) -2-amino-4- (3- (methylamino) propionamido) butanoic acid

Dab (A12) (S) -2-amino-4- (3- (dimethylamino) propionamido) butanoic acid

Dab (A13) (S) -2-amino-4- (3- (phenylamino) propionamido) butanoic acid

Dab (A14) (2S) -2-amino-4- (3-aminobutyrylamino) butanoic acid

Dab (A15) (S) -2-amino-4- (3-amino-3-methylbutanamido) butanoic acid

Dab (A16) (S) -2-amino-4- (3- (methylsulfonyl) propionamido) butanoic acid

Dab (A17) (S) -2-amino-4- (2-cyclopropylacetamido) butanoic acid

Dab (A18) (2S) -2-amino-4- (2- (pyrrolidin-3-yl) acetylamino) butanoic acid

Dab (A19) (2S) -2-amino-4- (2- (pyrrolidin-2-yl) acetylamino) butanoic acid

Dab (A20) (S) -2-amino-4- (2- (piperidin-4-yl) acetylamino) butanoic acid

Dab (A21) (2S) -2-amino-4- (2- (piperidin-3-yl) acetylamino) butanoic acid

Dab (A22) (2S) -2-amino-4- (2- (piperidin-2-yl) acetylamino) butanoic acid

Dab (A23) (S) -2-amino-4- (3- (piperidin-1-yl) propionamido) butanoic acid

Dab (A24) (S) -2-amino-4- (3- (piperazin-1-yl) propionamido) butanoic acid

Dab (A25) (S) -2-amino-4- (3- (4-methylpiperazin-1-yl) propionamido) butanoic acid

Dab (A26) (S) -2-amino-4- (3-morpholinopropionamido) butanoic acid

Dab (A27) (S) -2-amino-4- (2- (1-aminocyclohexyl) acetylamino) butanoic acid

Dab (A28) (S) -2-amino-4- (2- (4-aminotetrahydro-2H-pyran-4-yl) acetylamino) -butyric acid

Dab (A29) (2S) -2-amino-4- (2, 2-dimethyl-1, 3-dioxolane-4-carboxamido) butanoic acid

Dab (A30) (S) -2-amino-4-benzoylaminobutanoic acid

Dab (A31) (S) -2-amino-4- (isonicotinamido) butanoic acid

Dab (A32) (S) -2-amino-4- (nicotinamido) butanoic acid

Dab (A33) (S) -2-amino-4- (picolinamido) butanoic acid

Dab (A34) (S) -2-amino-4- (6- (trifluoromethyl) nicotinamido) butanoic acid

Dab (A35) (S) -2-amino-4- (3-methoxybenzoylamino) butanoic acid

Dab (A36) (S) -2-amino-4- (3- (difluoromethoxy) benzoylamino) butanoic acid

Dab (A37) (S) -2-amino-4- (4- (methylsulfonyl) benzoylamino) butanoic acid

Dab (A38) (S) -2-amino-4- (benzo [ d ] [1, 3] dioxol-5-carboxamido) butanoic acid

Dab (A39) (S) -2-amino-4- (2- (pyridin-3-yl) acetylamino) butanoic acid

Dab (A40) (S) -2-amino-4- (pyrimidine-4-carboxamido) butanoic acid

Dab (A41) (S) -2-amino-4- (pyrazine-2-carboxamide) butanoic acid

Dab (A42) (S) -2-amino-4- (3-cyanobenzoylamino) butyric acid

Dab (A43) (S) -2-amino-4- (thiophene-2-carboxamide) butanoic acid

Dab (A44) (S) -2-amino-4- (1-methyl-1H-pyrrole-2-carboxamide) butanoic acid

Dab (A45) (S) -2-amino-4- (thiazole-2-carboxamide) butanoic acid

Dab (A46) (S) -2-amino-4- (thiazole-4-carboxamide) butanoic acid

Dab (A47) (S) -2-amino-4- (1-methyl-1H-imidazole-2-carboxamide) butanoic acid

Dab (A48) (S) -2-amino-4- (1-methyl-1H-imidazole-5-carboxamido) butanoic acid

Dab (A49) (S) -2-amino-4- (1-methyl-1H-indole-2-carboxamido) butanoic acid

Dab (A50) (S) -2-amino-4- (benzo [ d ] thiazole-2-carboxamide) butanoic acid

Dab (A51) (S) -2-amino-4- (quinoxaline-2-carboxamide) butanoic acid

Dab (A52) (S) -4- (3- (1H-indol-3-yl) propionamido) -2-aminobutyric acid

Dab (A53) (S) -2-amino-4- (2-aminothiazole-4-carboxamide) butanoic acid

Dab (A54) (S) -2-amino-4- (2- (2-aminothiazol-4-yl) acetylamino) butanoic acid

Dab (A55) (S) -2-amino-4- (4-guanidinobutylamido) butanoic acid

Dap (Ar1) (S) -2-amino-3- (pyridin-2-ylamino) propionic acid

Dap (Ar2) (S) -2-amino-3- (pyrimidin-2-ylamino) propionic acid

Dap (Ar3) (S) -2-amino-3- (1, 2, 4-triazin-3-ylamino) propionic acid

Dap (Ar4) (S) -2-amino-3- (pyridin-2-ylmethylamino) propionic acid

Dap (Ar5) (S) -2-amino-3- (pyrimidin-2-ylmethyl-amino) propionic acid

Dap (Ar6) (S) -2-amino-3- (bis (pyrimidin-2-ylmethyl) amino) propionic acid

Dap (Ar7) (S) -2-amino-3- ((1-methyl-1H-imidazol-2-yl) methylamino) propionic acid

Dap (Ar8) (S) -2-amino-3- ((4-methyl-4H-1, 2, 4-triazol-3-yl) methylamino) -propionic acid

Dap (Ar9) (S) -2-amino-3- ((1-methyl-1H-1, 2, 4-triazol-5-yl) methylamino) -propionic acid

Dap (Ar10) (S) -2-amino-3- (1H-pyrazol-1-ylamino) propionic acid

Dap (Ar11) (S) -2-amino-3- (bis ((1-methyl-1H-imidazol-2-yl) methyl) amino) -propionic acid

Dap (Ar12) (S) -2-amino-3- (1H-1, 2, 4-triazol-1-yl) propionic acid

Dap (S1) (S) -2-amino-3- (methylsulfonylamino) propionic acid

Dap (S2) (S) -2-amino-3- (ethylsulfonylamino) propionic acid

Dap (S3) (S) -2-amino-3- (1-methylethylsulfonylamino) propionic acid

Dap (S4) (S) -2-amino-3- (cyclopropanesulfonylamino) propionic acid

Dap (S5) (S) -2-amino-3- (2-methylpropylsulfonylamino) propionic acid

Dap (S6) (S) -2-amino-3- (2, 2, 2-trifluoroethylsulfonylamino) propionic acid

Dap (S7) (S) -2-amino-3- (cyclopentanesulfonylamino) propionic acid

Dap (S8) (S) -2-amino-3- (cyclohexanesulfonylamino) propionic acid

Dap (S9) (S) -2-amino-3- (tetrahydro-2H-pyran-4-sulfonylamino) propionic acid

Dap (S10) (S) -2-amino-3- (phenylsulfonylamino) propionic acid

Dap (S11) (S) -2-amino-3- (4-aminophenylsulfonylamino) propionic acid

Dap (S12) (S) -2-amino-3- (4- (dimethylamino) phenylsulfonylamino) propionic acid

Dap (S13) (S) -2-amino-3- (4-morpholinophenylsulfonylamino) propionic acid

Dap (S14) (S) -2-amino-3- (4-cyanophenylsulfonylamino) propionic acid

Dap (S15) (S) -2-amino-3- (5-cyanopyridine-2-sulfonylamino) propionic acid

Dap (S16) (S) -2-amino-3- (1H-pyrazole-4-sulfonylamino) propionic acid

Dap (S17) (S) -2-amino-3- (1H-1, 2, 4-triazole-5-sulfonylamino) propionic acid

Dap (S18) (S) -2-amino-3- (1, 1-dimethylethylsulfonylamino) propionic acid

Dap (A1) (S) -3-acetylamino-2-aminopropionic acid

Dap (A2) (S) -2-amino-3-propionamido-propionic acid

Dap (A3) (S) -2-amino-3-isobutyramidopropionic acid

Dap (A4) (S) -2-amino-3- (cyclopropanecarboxamido) propionic acid

Dap (A5) (S) -2-amino-3- (3, 3, 3-trifluoropropionylamino) propionic acid

Dap (A6) (S) -2-amino-3- (4, 4, 4-trifluorobutanamido) propionic acid

Dap (A7) (S) -2-amino-3- (3-aminopropionylamino) propionic acid

Dap (A8) (S) -2-amino-3- (4-aminobutanamido) propionic acid

Dap (A9) (S) -2-amino-3- (5-aminopentaneamido) propanoic acid

Dap (A10) (S) -2-amino-3- (3-methoxypropionylamino) propionic acid

Dap (A11) (S) -2-amino-3- (3- (methylamino) propionamido) propanoic acid

Dap (A12) (S) -2-amino-3- (3- (dimethylamino) propionamido) propanoic acid

Dap (A13) (S) -2-amino-3- (3- (phenylamino) propionamido) propionic acid

Dap (A14) (2S) -2-amino-3- (3-aminobutanamido) propionic acid

Dap (A15) (S) -2-amino-3- (3-amino-3-methylbutylamino) propionic acid

Dap (A16) (S) -2-amino-3- (3- (methylsulfonyl) propionamido) propanoic acid

Dap (A17) (S) -2-amino-3- (2-cyclopropylacetamido) propionic acid

Dap (A18) (2S) -2-amino-3- (2- (pyrrolidin-3-yl) acetylamino) propanoic acid

Dap (A19) (2S) -2-amino-3- (2- (pyrrolidin-2-yl) acetylamino) propanoic acid

Dap (A20) (S) -2-amino-3- (2- (piperidin-4-yl) acetylamino) propanoic acid

Dap (A21) (2S) -2-amino-3- (2- (piperidin-3-yl) acetylamino) propanoic acid

Dap (A22) (2S) -2-amino-3- (2- (piperidin-2-yl) acetylamino) propanoic acid

Dap (A23) (S) -2-amino-3- (3- (piperidin-1-yl) propionamido) propanoic acid

Dap (A24) (S) -2-amino-3- (3- (piperazin-1-yl) propionamido) propionic acid

Dap (A25) (S) -2-amino-3- (3- (4-methylpiperazin-1-yl) propionamido) propanoic acid

Dap (A26) (S) -2-amino-3- (3-morpholinopropionamido) propionic acid

Dap (A27) (S) -2-amino-3- (2- (1-aminocyclohexyl) acetylamino) propanoic acid

Dap (A28) (S) -2-amino-3- (2- (4-aminotetrahydro-2H-pyran-4-yl) acetylamino) -propionic acid

Dap (A29) (2S) -2-amino-3- (2, 2-dimethyl-1, 3-dioxolane-4-carboxamido) propionic acid

Dap (A30) (S) -2-amino-3-benzoylaminopropionic acid

Dap (A31) (S) -2-amino-3- (isonicotinamido) propanoic acid

Dap (A32) (S) -2-amino-3- (nicotinamido) propanoic acid

Dap (A33) (S) -2-amino-3- (picolinamido) propionic acid

Dap (A34) (S) -2-amino-3- (6- (trifluoromethyl) nicotinamido) propanoic acid

Dap (A35) (S) -2-amino-3- (3-methoxybenzamido) propionic acid

Dap (A36) (S) -2-amino-3- (3- (difluoromethoxy) benzoylamino) propionic acid

Dap (A37) (S) -2-amino-3- (4- (methylsulfonyl) benzamido) propanoic acid

Dap (A38) (S) -2-amino-3- (benzo [ d ] [1, 3] dioxol-5-carboxamido) propionic acid

Dap (A39) (S) -2-amino-3- (2- (pyridin-3-yl) acetamido) propionic acid

Dap (A40) (S) -2-amino-3- (pyrimidine-4-carboxamido) propionic acid

Dap (A41) (S) -2-amino-3- (pyrazine-2-carboxamide) propionic acid

Dap (A42) (S) -2-amino-3- (3-cyanobenzoylamino) propionic acid

Dap (A43) (S) -2-amino-3- (thiophene-2-carboxamide) propionic acid

Dap (A44) (S) -2-amino-3- (1-methyl-1H-pyrrole-2-carboxamide) propionic acid

Dap (A45) (S) -2-amino-3- (thiazole-2-carboxamide) propionic acid

Dap (A46) (S) -2-amino-3- (thiazole-4-carboxamide) propionic acid

Dap (A47) (S) -2-amino-3- (1-methyl-1H-imidazole-2-carboxamido) propionic acid

Dap (A48) (S) -2-amino-3- (1-methyl-1H-imidazole-5-carboxamido) propionic acid

Dap (A49) (S) -2-amino-3- (1-methyl-1H-indole-2-carboxamido) propionic acid

Dap (A50) (S) -2-amino-3- (benzo [ d ] thiazole-2-carboxamide) propionic acid

Dap (A51) (S) -2-amino-3- (quinoxaline-2-carboxamide) propionic acid

Dap (A52) (S) -3- (3- (1H-indol-3-yl) propionamido) -2-aminopropionic acid

Dap (A53) (S) -2-amino-3- (2-aminothiazole-4-carboxamide) propionic acid

Dap (A54) (S) -2-amino-3- (2- (2-aminothiazol-4-yl) acetylamino) propionic acid

Dap (A55) (S) -2-amino-3- (4-guanidinobutylamido) propionic acid

Abbreviations for D-isomers, e.g.^DLys (Ar1) corresponds to the 2-position epimer of the appropriate amino acid described above.

In a preferred embodiment of the invention, the compound of general formula (I) is selected from:

cyclo (-Ile-^DArg-Arg-Ile-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Tyr-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Lys-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Dab-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DDab-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe-^DPro-Thr-)；

Cyclo (-Ile-^DThr-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-hSer-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-alloThr-)；

Cyclo (-1Nal-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DLys-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DHis-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DCit-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Thr-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-1Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Trp-Arg-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Thr-^DArg-Trp-Arg-^DPro-Thr-)；

Cyclo (-Trp-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Ser-)；

Cyclo (-Ile-^DArg-Agp-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Agb-Trp-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Tyr-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Dab-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Lys-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-His-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Pip-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-hArg-)^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-Agb-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-3Pal-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^D3Pal-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-hArg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4S)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4S)F)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4S)NH₂)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4R)NH₂)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Mor-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Mor-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro-(4S)-Hyp(Bn)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)OH)-(4S)-Hyp(Bn)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-(4S)-Hyp(Bn)-)；

Cyclo (-His-^DTrp-His-Trp-^DPro-Pro((4S)NHBz)-)；

Cyclo (-1Nal-^DArg-Arg-Trp-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro((4S)OH)-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro((4R)NH₂)-Thr-)；

Cyclo (-Val-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Abu-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Chg-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Leu-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Nle-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Cha)^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DOrn-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A41)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-hArg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DTic-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar2)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar7)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar4)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A56)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe(4CF₃)-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPip-Pro((3S)OH)-)；

Cyclo (-Ala (1Pyraz) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala (Tet) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar2) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-Orn (A56) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(Ar7)-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tiq-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tic-)；

And pharmaceutically acceptable salts thereof.

In a most preferred embodiment of the invention, the compound of formula (I) is selected from:

cyclo (-Ile-^DArg-Arg-Trp-^DPip-Thr-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Ser-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Dab-^DPro((4R)NH₂)-Tic-)；

Cyclo (-3Pal-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)OH)-(4S)-Hyp(Bn)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Pro((3S)OH)-)；

Cyclo (-Chg-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-hArg-Trp-^DPro-Thr-)；

And pharmaceutically acceptable salts thereof.

In an alternative most preferred embodiment of the invention, the compound of formula (I) is selected from:

cyclo (-Ile-^DArg-Orn(Ar2)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar7)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar4)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A56)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe(4CF₃)-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPip-Pro((3S)OH)-)；

Cyclo (-Ala (1Pyraz) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala (Tet) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar2) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar56) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(Ar7)-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tiq-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tic-)；

And pharmaceutically acceptable salts thereof.

A further embodiment of the invention relates to the preparation of a β -hairpin peptidomimetic according to the invention by a process comprising the steps of:

(a) coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid located at position T as defined above in the desired end product¹Or T²Or P¹To P⁴(ii) a Any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;

(b) removing the N-protecting group from the product obtained in step (a);

(c) coupling the product thus obtained with a suitably N-protected derivative of an amino acid located in the desired end product at the position of the next element (T or P) following-COOH to-NH according to formula (I)₂A counterclockwise or clockwise order of orientation; any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) until all amino acid residues have been introduced;

(f) selectively deprotecting one or several protected functional groups present in the molecule and appropriately substituting the reactive groups thus liberated, if desired;

(g) removing the product thus obtained from the solid support;

(h) cyclizing the product cleaved from the solid support;

(i) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, if desired, any protecting groups that may be additionally present in the molecule; and is

(j) If desired, performing additional chemical transformations on one or more reactive groups present in the molecule; and/or

(k) If desired, the product thus obtained is converted into a pharmaceutically acceptable salt or a pharmaceutically acceptable or unacceptable salt thus obtained is converted into the corresponding free compound of formula (I) or into a different pharmaceutically acceptable salt.

The methods of the invention can advantageously be performed in parallel array synthesis to generate libraries of template-immobilized β -hairpin peptidomimetics of the general formula (I) described above. The parallel synthesis allows to obtain a large number (generally 24 to 192, generally 96) of compounds of general formula (I) in an array with high yields and defined purity, wherein the formation of dimers and polymeric by-products is minimized. Thus, proper selection of the functionalized solid support (i.e., solid support and linker molecule), the template and site for cyclization plays a key role.

The functionalized solid support is conveniently derived from polystyrene crosslinked with preferably 1-5% divinylbenzene; polystyrene coated with polyethylene glycol spacerAnd polyacrylamide resins (see also Obrecht, D.; Villalgordo, J. -M, "Solid-supported combinatorial and Parallel Synthesis of Small-Molecular-weight Compounds", Tetrahedron Organic Chemistry Series, Vol.17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by a linker, which is a bifunctional spacer molecule containing at one end an immobilization group for attachment to the solid support and at the other end a selectively cleavable functional group for subsequent chemical conversion and cleavage procedures. For the purposes of the present invention, 2 types of linkers were used:

type 1 linkers are designed to release the amide group under acidic conditions (Rink H, Tetrahedron Lett.1987, 28, 3783-. This type of linker forms an amide of the carboxyl group of the amino acid; examples of resins functionalized by the linker structure include 4- [ ((((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] PS resin, 4- [ (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] -4-methylbenzhydrylamine PS resin (Rink amide MBHA PS resin), and 4- [ ((((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] benzhydrylamine PS-resin (Rink amide BHA PS resin). Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene, and functionalized by a 4- (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl group under acidic conditions. This type of linker forms esters of the carboxyl group of acid labile amino acids, typically the acid labile benzyl, benzhydryl and trityl esters; examples of the linker structure include 2-methoxy-4-hydroxymethylphenoxyLinker), 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid (HMPB linker), trityl and 2-chlorotrityl. Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene and functionalized by a 2-chlorotrityl linker.

In the case of parallel array synthesis, the process of the invention can advantageously be carried out as described below, but it will be readily apparent to the skilled person how to adapt these procedures in the case where it is desired to synthesize individual compounds of formula (I) as described above.

To a number of reaction vessels equal to the total number of compounds to be synthesized by the parallel method (generally 24 to 192, generally 96), 25 to 1000mg, preferably 100mg, of a suitably functionalized solid support, preferably derived from polystyrene crosslinked with 1 to 3% of divinylbenzene, or derived from Tentagel resin, are loaded.

The solvent used must be capable of swelling the resin and includes, but is not limited to, Dichloromethane (DCM), Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, Tetrahydrofuran (THF), ethanol (EtOH), Trifluoroethanol (TFE), isopropyl alcohol, and the like. Solvent mixtures containing a polar solvent as at least one component (e.g., 20% TFE/DCM, 35% THF/NMP) are advantageous for ensuring high reactivity and solvation of resin-bound peptide chains (Fields, G.B., Fields, C.G., J.Am.chem.Soc.1991, 113, 4202-.

With the development of various linkers that release a C-terminal carboxylic acid group under mildly acidic conditions without affecting the acid labile groups protecting the functional groups in the side chains, the synthesis of protected peptide fragments has made significant progress. 2-methoxy-4-hydroxybenzyl alcohol-derived linkersMergler et al, Tetrahedron Lett.1988, 294005-4008) can be cleaved with dilute trifluoroacetic acid (0.5-1% TFA in DCM) and are stable to Fmoc deprotection conditions during peptide synthesis, and additional protecting groups of the Boc/tBu-type are also suitable for this protection scheme. Other linkers suitable for the method of the invention include 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy-linker which is very labile to superacids (Rink linker, Rink, H.tetrahedron Lett.1987, 28, 3787-; 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid-derived linker (HMPB-linker,&riniker, Peptides 1991, 1990131) which is also cleaved with 1% TFA/DCM to yield peptide fragments containing all acid-labile side chain protecting groups; and, 2-chlorotrityl chloride linker (Barlos et al, Tetrahedron Lett.1989, 30, 3943-.

Suitable protecting groups for amino acids and their respective residues are for example,

for amino groups (e.g. also including lysine side chain amino groups)

Cbz benzyloxycarbonyl

Boc tert-butyloxycarbonyl

Fmoc 9-fluorenylmethoxycarbonyl

Alloc allyloxycarbonyl radical

Teoc trimethylsilyl ethoxycarbonyl

Tc Trichloroethoxycarbonyl

Nps O-Nitrophenylsulphonyl radical

Trt triphenylmethyl or trityl

For carboxyl groups (for example also including aspartic acid and glutamic acid side chain carboxyl groups): conversion into esters with alcoholic components

tBu tert-butyl

Bn benzyl group

Me methyl group

Ph phenyl

Pac phenacyl

Allyl radical

Tse Trimethylsilylethyl group

Tce Trichloroethyl

For guanidino (e.g. also including arginine side chain guanidino)

Pmc 2, 2, 5, 7, 8-pentamethyl chroman-6-sulfonyl

Ts tosyl (i.e. p-tosyl)

Cbz benzyloxycarbonyl

Pbf 2, 2, 4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl

For hydroxyl groups (e.g. also including threonine and serine side chain hydroxyl groups)

tBu tert-butyl

Bn benzyl group

Trt trityl radical

And for thiol groups (e.g. also including cysteine side chain thiol groups)

Acm acetylaminomethyl

tBu tert-butyl

Bn benzyl group

Trt trityl radical

Mtr 4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivative is preferably used as building block for the construction of template-fixed beta-hairpin loop mimetics of formula (I). For deprotection, i.e. cleavage to remove the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF may be used.

The amount of reactants, i.e., amino acid derivatives, is typically 1 to 20 equivalents based on the functionalized solid support initially weighed into the reaction tube (typically 0.1 to 2.85meq/g for polystyrene resins) in milliequivalents per gram (meq/g) loading. Additional equivalents of reactants can be used to drive the reaction to completion in a reasonable time, if desired. The reaction tubes combined with the scaffold portion and manifold were reinserted into the reservoir portion and the devices were fastened together. The gas stream is first provided through a manifold to provide a controlled environment, such as nitrogen, argon, air, etc. The gas stream may also be heated or cooled prior to flowing through the manifold. The heating or cooling of the reaction hole is achieved by heating the reaction portion or cooling it with isopropyl alcohol/dry ice or the like from the outside to cause the desired synthesis reaction. Agitation is achieved by shaking or magnetic stirring (in the reaction tube). Preferred workstations, without limitation, are Labsource's Combi-chemistry workstation and MultiSynTech's-Syro synthesizer.

Amide bond formation requires activation of the alpha-carboxyl group in the acylation step. If the activation is by means of a generally used carbodiimide, for example dicyclohexylcarbodiimide (DCC, Sheehan)&Hess, j.am.chem.soc.1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al biochem.biophysis.res.commun.1976, 73, 336-342), the dicyclohexylurea and diisopropylurea obtained are insoluble and soluble, respectively, in the solvents generally used. In a variant of the carbodiimide process, 1-hydroxybenzotriazole (HOBt,&geiger, chem. Ber1970, 103, 788-798) as an additive to the coupling mixture. HOBt prevents dehydration, inhibits racemization of activated amino acids and acts as a catalyst to promote slow coupling reactions. Certain phosphonium reagents have been used as direct coupling agents, for example benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP, Castro et al, Tetrahedron Lett.1975, 14, 1219-; these phosphonium and uronium reagents are also suitable for forming HOBt esters in situ with protected amino acid derivatives. More recently, diphenoxyphosphoryl azide (DPPA) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TATU) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino et al, Tetrahedron Lett.1994, 35, 2279-.

Since a near quantitative coupling reaction is required, it is desirable to have experimental evidence showing completion of the reaction. After each coupling step, the ninhydrin test (Kaiser et al, anal. biochemistry 1970, 34, 595) can be easily and quickly performed, where a positive colorimetric reaction on a resin-bound peptide aliquot qualitatively indicates the presence of a primary amine. The chemical nature of Fmoc allows spectrophotometric detection of the Fmoc chromophore with base release (Meienhofer et al, int.J.Peptideprotein Res.1979, 13, 35-42).

Excess reagents, solvents and byproducts were washed from the resin-bound intermediate in each reaction tube by repeated exposure to pure solvent.

The washing procedure is repeated up to about 30 times (preferably about 5 times), and the removal efficiency of the reagents, solvents and by-products is monitored by various methods such as TLC, GC, LC-MS or examination of the washings.

The above procedure was repeated for each successive transformation: the resin-bound compound is reacted with a reagent in a reaction well, followed by removal of excess reagent, byproducts, and solvent until the final resin-bound fully protected linear peptide is obtained.

Before the fully protected linear peptide is removed from the solid support, one or more protected functional groups in the molecule may be selectively deprotected and the reactive groups thus released appropriately substituted, if desired. To achieve this effect, the functional group concerned must initially be protected by a protecting group and be able to be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example of the amino protecting group, which can be for example by Pd ° and phenylsilane/CH₂Cl₂Selectively removed without affecting the remaining protecting groups present in the molecule, such as Fmoc. The reactive groups thus released can then be treated with reagents suitable for introducing the desired substituents. Thus, for example, an amino group can be acylated by an acylating agent corresponding to the acyl substituent to be introduced.

After detachment of the fully protected linear peptide from the solid support, the individual solutions/extracts are then manipulated as needed to isolate the final compound. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.

The solution containing the fully protected linear peptide derivative which has been cleaved from the solid support is neutralized with a base and evaporated. The cyclization is then carried out in a solution using a solvent such as DCM, DMF, dioxane, THF, etc. A variety of coupling agents as mentioned previously can be used for the cyclization. The duration of the cyclization is about 6 to 48 hours, preferably about 16 hours. The reaction is followed, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a water immiscible solvent such as DCM, and the solution is extracted with water or a mixture of water miscible solvents to remove any excess coupling agent.

Finally, the fully protected peptide derivative was treated with 95% TFA, 2.5% H₂O, 2.5% TIS or other combined treatments of capture agents for cleavage of the protecting group. The cleavage reaction time is generally 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles were evaporated to dryness and the crude peptide was dissolved in 20% AcOH/water and extracted with isopropyl ether or other suitable solvent. The water layer was collected and evaporated to dryness to obtain the fully deprotected cyclic peptide derivative of formula (I) as the final product.

Certain compounds of the invention of formula (I) require additional synthetic steps. These transformations can be applied to partially deprotected cyclic or linear peptides attached to or released from a solid support, or to the final deprotected molecules exemplified below.

Depending on their purity, the peptide derivatives can be used directly in biological tests or they have to be further purified, for example by preparative HPLC.

As indicated above, the thus obtained fully deprotected product of formula (I) may be converted into a pharmaceutically acceptable salt, or the thus obtained pharmaceutically acceptable or unacceptable salt may be converted into the corresponding free compound of formula (I) or into a different pharmaceutically acceptable salt, if desired. Any of these manipulations can be performed by methods well known in the art.

The building blocks generally used in the peptidomimetics of the invention can be synthesized according to literature methods (examples are described below) or are known to those skilled in the art and/or are commercially available. The present invention has been subjected to some additional novel syntheses, which are described in the examples. All other corresponding amino acids have been described as unprotected or Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It will be appreciated that the unprotected amino acid building blocks can be readily converted to the corresponding Fmoc-protected amino acid building blocks required in the present invention by standard protecting group manipulations. A review describing the general method of synthesizing alpha-amino acids includes: duthaler, Tetrahedron (report)1994, 349, 1540-1650, R.M.Williams, "Synthesis of optional active α -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989. Particularly useful methods for the Synthesis of optically active alpha-amino acids relevant to the present invention include kinetic resolution with hydrolases (M.A. Verhovskaya, I.A. Yamskov, Russian chem.Rev.1991, 60, 1163-1179; R.M.Williams, "Synthesis of aqueous active alpha-amino acids", tetrahedron organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989, Chapter 7, p.257-279). Hydrolases involve the hydrolysis of amides and nitriles by aminopeptidases or nitrilases, the cleavage of N-acyl groups by acyltransferases, and ester hydrolysis by lipases or proteases. It is widely described that certain enzymes result in particular in the pure (L) -enantiomer, while others produce the corresponding (D) -enantiomer (e.g.: R.Duthaler, Tetrahedron report 1994, 349, 1540 1650; R.M.Williams, "Synthesis of optically active. alpha. -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989).

The beta-hairpin peptidomimetics of the present invention can be used in a wide range of applications to selectively modulate the activity of the CXCR7 receptor, for the treatment of a variety of diseases and disorders mediated by or sustained by CXCR7 activity or for drug therapy supporting specific disease conditions of substantially different causes, such as but not limited to dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastrointestinal disorders, urological diseases, ocular diseases, oral diseases, hematological diseases and the field of cancer, or for stem cell activation in humans or other mammals of similar etiology.

In particular, they can be used as agents for the treatment and/or prevention of the following diseases or conditions: such as but not limited to HIV infection, Epstein-Barr virus infection; diabetes (type I and/or type II); conjunctivitis, scleritis, uveitis, sinusitis, Whim syndrome, lupus erythematosus, osteoarthritis, rheumatoid arthritis, synovitis, psoriasis, multiple sclerosis, crohn's disease, inflammatory bowel disease, mixed connective tissue disease, chronic lymphocytic thyroiditis, graves ' disease, graft versus host disease, sjogren's syndrome; dry eye syndrome, glaucoma, age-related macular degeneration; pulmonary hypertension, pulmonary hypoxia, atherosclerosis, myocarditis, heart failure, such as myocardial infarction, arterial thrombosis, stroke, angiogenesis; chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma; sarcomas, such as osteosarcoma, rhabdomyosarcoma, kaposi's sarcoma, synovial sarcoma; lipomas, such as angiolipoma; glioblastoma multiforme, astrocytoma, neuroblastoma; cancer, such as adenocarcinoma; malignant epithelial and mucoepidermoid tumors, thyroid tumors, sex adenomas, prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer; a solid tumor; lymphomas such as Birkitt lymphoma, hodgkin lymphoma, non-hodgkin lymphoma; multiple myeloma and leukemia; transferring; for inhibiting neointima formation; for stem cell activation of peripheral blood stem cells and/or mesenchymal stem cells; for activation of endothelial or neuronal progenitor cells; or for the repair of different types of tissue in humans or other mammals.

For use as a medicament, the β -hairpin peptidomimetics can be administered alone, as a mixture of several β -hairpin peptidomimetics or in combination with other pharmaceutically active agents. The β -hairpin peptidomimetic may be administered as such or as a pharmaceutical formulation, e.g., an appropriate formulation together with carriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising the β -hairpin peptidomimetics of the invention can be prepared by: conventional mixing, dissolving, granulating, making coated tablet, grinding, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical compositions may be formulated in conventional manner: one or more physiologically acceptable carriers, diluents, excipients or adjuvants are used which facilitate processing of the active β -hairpin peptidomimetics into pharmaceutically useful formulations. Suitable formulations depend on the chosen method of administration.

For topical administration, the β -hairpin peptidomimetics of the present invention may be formulated as solutions, gels, ointments, creams, suspensions, and the like, as is known in the art.

Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

For injections, the β -hairpin peptidomimetics of the invention can be formulated in suitable solutions, preferably in physiologically compatible buffers such as Hank's solution, ringer's solution, or physiological saline solution. The solution may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, as is known in the art.

For oral administration, complexes can be readily formulated by combining the active β -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. The carrier allows the beta-hairpin peptidomimetics of the invention to be formulated as tablets, pills, troches, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral formulations such as powders, capsules and tablets, suitable excipients include fillers such as sugars, for example lactose, sucrose, mannitol and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agent; and a binder. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The solid dosage forms may be sugar coated or enteric coated using standard techniques, if desired.

For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, and the like. In addition, a flavoring agent, a preservative, a coloring agent, and the like may be added.

For buccal administration, the compositions may be in the form of conventionally formulated tablets, lozenges, and the like.

For administration by inhalation, the β -hairpin peptidomimetics of the invention are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer, using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to administer a metered amount. Capsules and cartridges of, for example, gelatin, containing a powder mix of a β -hairpin peptidomimetic of the invention and a suitable powder base such as lactose or starch may be formulated for use in an inhaler or insufflator.

The compounds may also be formulated in rectal or vaginal compositions such as solutions for enema or suppositories with a suitable suppository base such as cocoa butter or other glycerides.

In addition to the formulations described above, the β -hairpin peptidomimetics of the invention can also be formulated as depot preparations. The long acting formulation may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. To prepare the depot formulations, the β -hairpin peptidomimetics of the invention can be formulated with suitable polymeric or hydrophobic substances (e.g., emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble salts.

In addition, other drug delivery systems such as liposomes and emulsions well known in the art may be used. Certain organic solvents such as dimethylsulfoxide also can be used. Additionally, the β -hairpin peptidomimetics of the invention can be delivered using a sustained release system such as a semipermeable matrix of a solid polymer containing the therapeutic agent. A variety of sustained release materials are identified and known to those skilled in the art. Depending on the chemical nature, sustained release capsules can release the compound for weeks up to 3 years. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization may be used.

Since the β -hairpin peptidomimetics of the invention may contain charged residues, they may be included in the above formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in water and other protic solvents than the corresponding free base forms.

Furthermore, the compounds of the present invention and their pharmaceutically acceptable salts may be used as such or in any suitable formulation in solid form of different forms, which may or may not contain varying amounts of solvents, such as hydrates, remaining from the crystallization process.

The β -hairpin peptidomimetics of the invention, or compositions thereof, are generally used in an amount effective to achieve the desired purpose. It is understood that the amount depends on the particular application.

For use in treating or preventing diseases or disorders whose etiology includes increased or decreased activity of or associated with the CXCR7 receptor and its ligands (e.g., CXCL11 and CXCL12), the beta-hairpin peptidomimetics of the invention or compositions thereof are administered or administered in therapeutically effective amounts. One skilled in the art will be able to determine a therapeutically effective amount, particularly after reviewing the detailed disclosure provided herein.

The effective dosage of the active ingredient employed may vary depending upon the particular compound or pharmaceutical formulation employed, the mode of administration and the severity and type of the condition being treated. Thus, the dosage regimen will be selected in accordance with factors including the route of administration and the route of clearance, such as the renal and hepatic function of the patient. A physician, clinician or veterinarian in the art can readily determine and prescribe the amount of the individual active ingredients required to prevent, ameliorate or stop the condition or disease progression. Optimal precision in achieving concentration of the active ingredient without toxicity requires a regimen based on the kinetics of the active ingredient's availability to the target site. This involves considerations of active ingredient distribution, equilibrium and elimination.

In the case of topical administration or selective administration, the effective local concentration of the β -hairpin peptidomimetics of the invention may not be related to the plasma concentration. One skilled in the art would be able to optimize therapeutically effective dosages without undue experimentation.

The invention is further described below with examples, which are intended to be illustrative only and not to limit the scope of the invention in any way.

The following abbreviations are used:

boc tert-butyloxycarbonyl

DBV divinylbenzene

DIPEA diisopropylethylamine

Fmoc fluorenylmethyloxycarbonyl

HATU O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HCTU O- (6-chlorobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HOAt 7-aza-1-hydroxybenzotriazole

HOBt 1-hydroxybenzotriazole

(benzotriazol-1-yloxy) trispyrrolidinylphosphonium hexafluorophosphates

TATU O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

TBTU 2- (1H-benzotriazol-1-yl-) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate

TIS Triisopropylsilane

TPP triphenylphosphine

rt Room temperature

Retention time of RT

Examples

1. Peptide synthesis

1.1 general synthetic procedure

Two general methods for synthesizing peptidomimetics of the present invention, method A and method B, are illustrated below. This is intended to illustrate the concept in principle and not to limit or restrict the invention in any way. The skilled person can easily modify these procedures, in particular but not limited to, selecting different starting positions within the ring system, which all allow the preparation of the claimed cyclic peptidomimetic compounds of the invention.

Coupling the first protected amino acid residue to the resin

The method A comprises the following steps:

0.5g of 2-chlorotrityl chloride resin (Barlos et al tetrahedron Lett.1989, 30, 3943-Mesh, polystyrene, 1% DBV crosslinked, 1.4mmol/g loading, 0.7mmol) was charged to the dry flask. Suspending the resin in CH₂Cl₂(2.5ml) and allowed to swell at room temperature for 30 minutes. The resin was washed with 0.43mmol (0.6 equiv.) of the first suitably protected amino acid residue and 488. mu.l (4 equiv.) of Diisopropylethylamine (DIPEA) in CH₂Cl₂(2.5ml) and the mixture was shaken at 25 ℃ for 4 hours. CH for resin₂Cl₂(1x)，DMF(1x)，CH₂Cl₂(1x)，DMF(1x)，CH₂Cl₂(2x) washing. In 30ml of CH₂Cl₂The resin was shaken for 30 min in MeOH/DIPEA (17: 2: 1); then using CH₂Cl₂(1x)，DMF(1x)，CH₂Cl₂(1x)，MeOH(1x)，CH₂Cl₂(1x)，MeOH(1x)，CH₂Cl₂(2x)，Et₂O (2X) was washed in the following order and dried under vacuum for 6 hours.

The method B comprises the following steps:

in a dry flask, 2-chlorotrityl chloride resin (100-mesh 200-mesh, polystyrene, 1% DBV crosslinked, 1.4mmol/g loading) was placed in anhydrous CH₂Cl₂Medium swelling for 30 min (7ml CH)₂Cl₂Per g resin). 0.8 equivalent of Fmoc-AA-OH for appropriate side chain protection and 6 equivalents of DIPEA in dry CH was added₂Cl₂Solution in DMF (4: 1) (10ml per g of resin). After shaking for 2-4 hours at room temperature, the resin was filtered, successively with CH₂Cl₂，DMF，CH₂Cl₂DMF and CH₂Cl₂And (6) washing. Then, anhydrous CH was added₂Cl₂A solution of/MeOH/DIPEA (17: 2: 1) (10ml per g of resin). After shaking for 3X 30 min, the resin was filtered in a pre-weighed sinter funnel, successively with CH₂Cl₂，DMF，CH₂Cl₂，MeOH，CH₂Cl₂，MeOH，CH₂Cl₂(2x) and Et₂O (2x) wash. The resin was dried under high vacuum overnight. The final mass of the resin was calculated prior to quality control.

The following pre-loaded resins were prepared: Fmoc-Ile-2-chloroTrityl resin, Fmoc-Arg-2-chlorotrityl resin, Fmoc-Trp-2-chlorotrityl resin, Fmoc-Thr-2-chlorotrityl resin, Fmoc-^DPro-2-chlorotrityl resin, Fmoc-Ser-2-chlorotrityl resin, Fmoc-Agp-2-chlorotrityl resin, Fmoc-Agb-2-chlorotrityl resin, Fmoc-Tic-2-chlorotrityl resin, Fmoc-Tiq-2-chlorotrityl resin, Fmoc-Oic-2-chlorotrityl resin, Fmoc- (4S) -Hyp (Bn) -2-chlorotrityl resin, Fmoc-Pro ((4S) NHBz) -2-chlorotrityl resin, Fmoc-^DPip-2-Chlorotribenzyl resin, Fmoc-^DPro ((3S) OH-2-chlorotrityl resin.

Synthesis of fully protected peptide fragments

The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) with 24 to 96 reaction vessels. In each vessel, approximately 60mg (method A) or 80mg (method B) of the above resin (resin weight before loading) was placed. The following reaction cycles were programmed and performed:

the method A comprises the following steps:

steps 3 to 6 are repeated to add each amino acid residue.

The method B comprises the following steps:

steps 3 to 6 are repeated to add each amino acid residue.

After the synthesis of the fully protected peptide fragment is terminated, the cleavage, cyclization and work-up procedures described below are used to prepare the final compound.

Cleavage, backbone cyclization and deprotection of peptides

After assembly of the linear peptide, the resin was suspended in 1ml of 1% TFA/CH₂Cl₂(v/v; 0.14mmol) for 3 minutes, filtered and the filtrate taken up in 1ml of 20% DIPEA/CH₂Cl₂(v/v; 1.15mmol) of the resulting mixture. This procedure was repeated four times to ensure that the cleavage was complete. 1mlCH for resin₂Cl₂Washed three times. Will contain CH of the product₂Cl₂The layer was evaporated to dryness.

The fully protected linear peptide was dissolved in 8ml anhydrous DMF. Then, 2 equivalents of HATU in dry DMF (1-2ml) and 4 equivalents of DIPEA in dry DMF (1-2ml) were added to the peptide followed by stirring for 16 hours. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7mlCH₂Cl₂Extracted three times with 4.5ml 10% acetonitrile/water (v/v). Will CH₂Cl₂The layer was evaporated to dryness.

To completely deprotect the peptide, 4-7ml of cleavage mix TFA/TIS/H was added₂O (95: 2.5), the mixture is kept at room temperature for 2.5-4 hours until the reaction is complete. The reaction mixture was evaporated to dryness and the crude peptide was dissolved in 7ml of 20% AcOH/water (v/v) and extracted three times with 4ml of diisopropyl ether. The water layer was collected, evaporated to dryness and the residue was purified by preparative reverse phase LC-MS.

Purification procedure (preparative reverse phase LC-MS)

The compounds were purified by reverse phase chromatography using Vydac 218MS column, 30x150mm (Cat No.218MS103015), 10 μm, or Waters XBridge C18, 30x150mm, 5 μm (Cat No. 186002982).

The mobile phases used were:

a: 0.1% TFA in water/acetonitrile 95: 5(v/v)

B: 0.1% TFA/acetonitrile

The gradient slope of the preparative mode was adjusted each time based on the analytical LC-MS analysis of the synthesized crude product. For example, a typical operation (purified ex.29) is performed as follows: flow rate 35ml/min, gradient from 0-2 min 25% B, 6.5 min 45% B to final 6.6-10.7 min 100% B (retention time: 4.99 min in this case).

And (3) detection: MS and UV220nm

The collected fractions were evaporated using a Genevac HT4 evaporator or a Buchi system.

Alternatively, for larger quantities, the following LC-purification system was used:

column: vydac 218MS, 10 μm, 50X150mm

Mobile phase A: 0.1% TFA/water

Mobile phase B: 0.1% TFA/acetonitrile

Flow rate: 150ml/min

And (3) detection: UV220nm

After lyophilization, the product was obtained as a white to off-white powder and analyzed by HPLC-ESI-MS as described below. Analytical data after preparative HPLC purification are shown in table 1.

1.2 analytical methods

Analytical method A:

analytical HPLC retention time (RT, min) was determined as follows: using a Gemini NX column, 50X2.0mm, (cod.00B-4453-B0-Phenomenex), the following solvent A (H) was used₂O +0.1% TFA) and B (CH)₃CN +0.085% TFA), and gradient: 0-0.1 min: 97% A, 3% B; 2.7 minutes: 3% A97% B; 2.7-3 minutes: 3% a, 97% B; 3.05-3.3 min: 97% A, 3% B. Flow rate =0.8ml/min at 45 ℃.

Analysis method B:

analytical HPLC retention time (RT, min) was determined as follows: using an Xbridge C18 column, 50X2.0mm, (cod.186003084-Waters), theUsing the following solvent A (H)₂O +0.1% TFA) and B (CH)₃CN +0.085% TFA), and gradient: 0-0.05 min: 97% A, 3% B; 3 minutes: 3% A97% B; 3-3.6 min: 3% a, 97% B; 3.6-4.3 minutes: 97% A, 3% B. Flow rate =0.5ml/min at 45 ℃.

Analysis method C:

analytical HPLC retention time (RT, min) was determined as follows: using an Ascentis ExpressC18 column, 50X3.0mm, (cod.53811-U-Supelco) with the following solvent A (H)₂O +0.1% TFA) and B (CH)₃CN +0.085% TFA), and gradient: 0-0.05 min: 97% A, 3% B; 2.95 minutes: 3% A97% B; 2.95-3.15 minutes: 3% a, 97% B; 3.17-3.2 min: 97% A, 3% B. Flow rate =1.3ml/min at 45 ℃.

Analytical method C':

similar to method C, but operating at 55 ℃.

Analysis method D:

analytical HPLC retention time (RT, min) was determined as follows: using an Ascentis ExpressC18 column, 50X3.0mm, (cod.53811-U-Supelco), the following solvent A (H)₂O +0.1% TFA) and B (CH)₃CN +0.085% TFA), and gradient: 0-0.05 min: 97% A, 3% B; 3.4 min: 33% a 67% B; 3.45-3.65 minutes: 3% a, 97% B; 3.67-3.7 minutes: 97% A, 3% B. Flow rate =1.3ml/min at 55 ℃.

1.3 Synthesis of peptide sequences

Examples 1-5 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-isoleucine, which was grafted onto a resin (Fmoc-Ile-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Ile-Thr-^DPro-P⁴-P³-P². The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analytical method a described above. See ex.1, 2, 3, 4, 5 in table 1 for analytical data.

Examples 6, 7 and 67 are shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-arginine, which was grafted onto a resin (Fmoc-Arg-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Arg-P²-P¹-T²-T¹-P⁴. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.6, 7, 67 in table 1 for analytical data.

Examples 8 and 9 are shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-tryptophan, which was grafted onto a resin (Fmoc-Trp-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Trp-Arg-^DArg-Ile-T²-T¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.8, 9 in table 1 for analytical data.

Examples 10-16 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-threonine, which was grafted onto a resin (Fmoc-Thr-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Thr-T¹-P⁴-P³-P²-P¹. As described above, the product is cleaved, cyclized, and desolventized from the resinProtection and purification by preparative reverse phase LC-MS.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analytical method a described above. See ex.10, 11, 12, 13, 14, 15, 16 in table 1 for analytical data.

Examples 17-20 are shown in Table 1.

The peptide was synthesized according to general procedure A starting from the amino acid D-proline grafted onto the resin (Fmoc-^DPro-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-^DPro-P⁴-P³-P²-P¹-T¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a above, but ex.20 by analytical method B. See ex.17, 18, 19, 20 in table 1 for analytical data.

Examples 21, 52 and 53 are shown in Table 1.

The peptide was synthesized according to general procedure B starting from the amino acid D-proline grafted onto the resin (Fmoc-^DPro-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-^DPro-P⁴-P³-P²-P¹-T¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method C above, but ex.21 by analytical method a. See ex.21, 52, 53 in table 1 for analytical data.

Example 22 is shown in Table 1.

The peptide was synthesized according to general method B, starting from the amino acid L-serine, soThe amino acids described above were grafted onto a resin (Fmoc-Ser-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Ser-^DPro-Trp-Arg-^DArg-Ile. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.22 in table 1 for analytical data.

Example 23 is shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid (S) -2-amino-3-guanidinopropionic acid, which was grafted onto a resin (Fmoc-Agp-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Agp-^DArg-Ile-Thr-^DPro-Trp. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.23 in table 1 for analytical data.

Example 24 is shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid (S) -2-amino-4-guanidinobutyric acid, which was grafted onto a resin (Fmoc-Agb-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Agb-^DArg-Ile-Thr-^DPro-Trp. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.24 in table 1 for analytical data.

Examples 25-40, 74, 75 and 78 are shown in Table 1.

According to the generalMethod B the peptide was synthesized starting from the amino acid (3S) -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid, which was grafted onto a resin (Fmoc-Tic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Tic-T¹-P⁴-P³-P²-P¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analytical method C as described above, but ex.25 and 26 were characterized by analytical method a, while ex.74, 75 and 78 were characterized by analytical method D. See table 1 for ex.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 74, 75, 78 for analytical data.

Examples 41 and 42 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid, which was grafted onto a resin (Fmoc-Oic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Oic-^DPro((4R)NH₂)-Arg-Trp-^DPhe-P¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder and characterized by HPLC-MS analytical method C described above. See ex.41, 42 in table 1 for analytical data.

Examples 43-46 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-tryptophan, which was grafted onto a resin (Fmoc-Trp-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Trp-^DPhe-Trp-T²-T¹-P⁴. The product is cleaved from the resin, cyclized, deprotected and purified as described aboveAnd (5) purifying the preparative reverse phase LC-MS.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analysis method C described above. See ex.43, 44, 45, 46 in table 1 for analytical data.

Example 47 is shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-tryptophan, which was grafted onto a resin (Fmoc-Trp-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Trp-Arg-^DArg-Ile-Mor-^DPro. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method C described above. See ex.47 in table 1 for analytical data.

Examples 48-50 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid (2S, 4S) -4- (benzyloxy) pyrrolidine-2-carboxylic acid, which was grafted onto a resin (Fmoc- (4S) -hyp (bn) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin- (4S) -Hyp (Bn) -T¹-P⁴-P³-P²-P¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white to off-white powder and characterized by HPLC-MS analysis method C described above. See ex.48, 49, 50 in table 1 for analytical data.

Example 51 is shown in table 1.

The peptide was synthesized according to general procedure a, starting from the amino acid (2S, 4S) -4-benzoylaminopyrrolidine-2-carboxylic acid, which was grafted onto a resin (Fmoc-Pro ((4S) NHBz) -2-chlorotrityl resin). According to the above descriptionThe procedure described above synthesizes a linear peptide on a solid support with the following sequence: resin-Pro ((4S) NHBz) -^DPro-Trp-His-^DTpr-His. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method a described above. See ex.51 in table 1 for analytical data.

Example 54 is shown in table 1.

The peptide was synthesized according to general procedure B starting from the amino acid (R) -piperidine-2-carboxylic acid, which was grafted onto the resin (Fmoc-^DPip-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-^DPip-Trp-Arg-^DArg-Ile-Pro ((3S) OH). The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method C described above. See ex.54 in table 1 for analytical data.

Example 55 is shown in table 1.

The peptide was synthesized according to general procedure B starting from the amino acid (2R, 3S) -3-hydroxypyrrolidine-2-carboxylic acid, which was grafted onto a resin (Fmoc-^DPro ((3S) OH-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-^DPro((3S)OH-Trp-Arg-^DArg-Ile-Thr). The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method C described above. See ex.55 in table 1 for analytical data.

Examples 56-66, 69, 70 and 72 are shown in Table 1.

According to a general formulaMethod B the peptide was synthesized starting from the amino acid L-threonine, which was grafted onto a resin (Fmoc-Thr-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Thr-T¹-P⁴-P³-P²-P¹. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analytical method C as described above, but ex.69 and 70 were characterized by analytical method C' and ex.72 by analytical method D. See ex.56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 70, 72 in table 1 for analytical data.

Examples 71, 73, 77, 79 and 80 are shown in Table 1.

The peptide was synthesized according to general procedure B, starting from position T according to Table 1²Or in position T in the case of Ex.73¹Appropriately protected amino acids grafted onto resin (Fmoc-T)²Chlorotrityl resin and Fmoc-T¹Chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-T²-T¹-P⁴-P³-P²-P¹And resin-T¹-P⁴-P³-P²-P¹-T². Fmoc-protected (S) -2-amino-5- (pyrimidin-2-ylamino) pentanoic acid is used as starting material at the position where the final amino acid Orn (A56) is desired. The product is cleaved from the resin and cyclized. Following the standard procedure described above with TFA/TIS/H₂Deprotection of O results in the reduction of the desired molecule containing the Orn (A56) residue. The compound was then purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS analytical method D above, but ex.71 by analytical method C'. See ex.71, 73, 77, 79, 80 in table 1 for analytical data.

Example 68 is shown in table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid L-threonine, which was grafted onto a resin (Fmoc-Thr-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Thr-^DPro-Trp-Orn(Ar2)-^DArg-Ile. The product is cleaved from the resin and cyclized. Unlike the general procedure described above, TFA/H was used for deprotection²The mixture of O (95: 5) was completed (avoiding TIS) and monitored for completion. The compounds were purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method D described above. See ex.68 in table 1 for analytical data.

Example 76 is shown in Table 1.

The peptide was synthesized according to general procedure B, starting from the amino acid (3S) -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid, which was grafted onto a resin (Fmoc-Tic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above with the following sequence: resin-Tic-^DPro((4R)NH₂)-Arg-Trp-^DPhe-Orn (Ar 2). The product is cleaved from the resin and cyclized. Unlike the general procedure described above, TFA/H was used for deprotection₂The O (95: 5) mixture was completed (avoiding TIS) and monitored for completion. The compounds were purified by preparative reverse phase LC-MS as described above.

The product was obtained after lyophilization as a white powder, characterized by HPLC-MS analytical method D described above. See ex.76 in table 1 for analytical data.

2. Biological method

2.1 preparation of peptide samples.

The lyophilized peptides were weighed on a microbalance (Mettler MX5) and dissolved in DMSO to a final concentration of 10mM unless otherwise indicated. The stock solution was kept at +4 ℃ protected from light.

2.2CXCR7 beta-arrestin recruitment assay

PathHunter CHO-CXCR7(discover X) testing was performed according to the manufacturer's protocol. Briefly, CHO CXCR7 β -arrestin cells were seeded at 5000 cells/well density in 40 μ l F12 medium in black 96-half volume well plates at 37 ℃ in 5% CO₂Incubated overnight in a humid atmosphere. The next day, serial dilutions of PEM compounds were prepared in DMSO, followed by dilution in HBSS buffer containing 0.1% BSA.

For the agonistic assay, 10. mu.l of compound solution or a solution of stromal cell derived factor-1 (SDF-1) as a positive control was added to the cells, with a final DMSO concentration of 1% (v/v). 5% CO in an incubator at 37 ℃₂The plates were incubated for 90 minutes, gently shaken (300rpm), followed by the addition of 40ul of detection reagent per well. The reaction was carried out for 90 minutes at room temperature with shaking out of the light and the chemiluminescence was measured using a Topcount (Perkin Elmer) luminometer.

2.3 results

Table 2: biological results

nd = not determined

Claims

1. A compound of the general formula (I)

-

T¹Is an alpha-amino acid residue of one of the formulae

While

T²Is an alpha-amino acid residue of one of the formulae

-or

T¹Is an alpha-amino acid residue of one of the formulae

While

T²Is an alpha-amino acid residue of one of the formulae AA11 to AA17 as described above, or an alpha-amino acid residue of one of the formulae

P¹，P³And P⁴Independently is

-NR¹CH(R²⁹)CO-；-NR¹CH(R³⁰) CO-; or-NR¹CH(R³¹)CO-；

P²Is an alpha-amino acid residue of one of the formulae

A is O; NR (nitrogen to noise ratio)¹⁷(ii) a S; SO; or SO₂；

X is OH; NH (NH)₂；OR¹⁶；NR¹R¹⁶(ii) a Or NR¹⁷R¹⁸；

Y is NH₂；F；OR¹⁶；NR¹R¹⁶(ii) a Or NR¹⁷R¹⁸；

R¹，R²And R³Independently is

R⁴，R⁵，R⁶，R⁷and R⁸Independently is

-(CHR¹⁵)_oSR¹⁷；-(CHR¹⁵)_oNR¹⁷R¹⁸；-(CHR¹⁵)_oOCONR¹⁷R¹⁸；-(CHR¹⁵)_oNR¹CONR¹⁷R¹⁸；-(CHR¹⁵)_oNR¹COR¹⁷；-(CHR¹⁵)_oCOOR¹⁷；-(CHR¹⁵)_oCONR¹⁷R¹⁸；-(CHR¹⁵)_oPO(OR¹)₂；-(CHR¹⁵)_oSO₂R¹⁷；-(CHR¹⁵)_oNR¹SO₂R¹⁷；-(CHR¹⁵)_oSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_oR³⁵(ii) a Or- (CHR)¹)_nO(CHR²)_mR³⁵(ii) a Or

R⁴And R²Together can form

R⁴And R⁵Independently is X;

R⁹，R¹⁰，R¹¹and R¹²Independently is

-(CHR¹⁵)_rSR¹⁷；-(CHR¹⁵)_rNR¹⁷R¹⁸；-(CHR¹⁵)_rOCONR¹⁷R¹⁸；-(CHR¹⁵)_rNR¹CONR¹⁷R¹⁸；-(CHR¹⁵)_rNR¹COR¹⁷；-(CHR¹⁵)_oCOOR¹⁷；-(CHR¹⁵)_oCONR¹⁷R¹⁸；-(CHR¹⁵)_rPO(OR¹)₂；-(CHR¹⁵)_rSO₂R¹⁷；-(CHR¹⁵)_rNR¹SO₂R¹⁷；-(CHR¹⁵)_rSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_oR³⁵(ii) a Or- (CHR)¹)_rO(CHR¹)_oR³⁵(ii) a Or

R¹¹And R¹²Together can form

= O; or = NR¹；

R¹³And R¹⁴Independently is

H；F；Cl；Br；CF₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹⁵)_oOR¹⁷；-(CHR¹⁵)_oSR¹⁷；-(CHR¹⁵)_oNR¹⁷R¹⁸；-(CHR¹⁵)_oOCONR¹⁷R¹⁸；-(CHR¹⁵)_oNR¹CONR¹⁷R¹⁸；-(CHR¹⁵)_oNR¹COR¹⁷；-(CHR¹⁵)_oCOOR¹⁷；-(CHR¹⁵)_oCONR¹⁷R¹⁸；-(CHR¹⁵)_oPO(OR¹)₂；-(CHR¹⁵)_oSO₂R¹⁷；-(CHR¹⁵)_oNR¹SO₂R¹⁷；-(CHR¹⁵)_oSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_oR³⁵(ii) a Or- (CHR)¹)_rO(CHR¹)_oR³⁵；

R¹⁵Is H; f; CF (compact flash)₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；-(CHR¹)_oSR¹⁷；-(CHR¹)_oNR¹⁷R¹⁸；-(CHR¹)_oNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR¹⁷R¹⁸；-(CHR¹)_oSO₂R¹⁷(ii) a Or- (CHR)¹)_oSO₂NR¹⁷R¹⁸；

R¹⁶Is CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl; - (CHR)¹)_sOR¹⁷；-(CHR¹)_sSR¹⁷；-(CHR¹)_sNR¹⁷R¹⁸；-(CHR¹)_oCOR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR¹⁷R¹⁸(ii) a Or- (CHR)¹)_oSO₂R¹⁷；

R¹⁷，R¹⁸，R¹⁹And R²⁰Independently is

cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl; or

Structural element-NR¹⁷R¹⁸and-NR¹⁹R²⁰Can independently form:

or a radical of one of the formulae

Z, Z 'and Z' are independently

-CR³⁹(ii) a Or N;

R²¹，R²²，R²³and R²⁴Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；-(CHR¹)_oSR¹⁷；-(CHR¹)_oNR²R¹⁷；-(CHR¹)_oOCONR²R¹⁷；-(CHR¹)_oNR²CONR³R¹⁷；-(CHR¹)_oNR²COR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR²R¹⁷；-(CHR¹)_oPO(OR²)₂；-(CHR¹)_oSO₂R¹⁷；-(CHR¹)_oNR²SO₂R¹⁷；-(CHR¹)_oSO₂NR²R¹⁷；-(CR¹R²)_oR³⁸(ii) a Or- (CHR)¹)_nO(CHR²)_mR³⁸；

R²⁵And R²⁶Independently is

H；F；CF₃(ii) a A lower alkyl group; lower alkenyl; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_rOR¹⁷；-(CHR¹)_rSR¹⁷；-(CHR¹)_rNR²R¹⁷；-(CHR¹)_rOCONR²R¹⁷；-(CHR¹)_rNR²CONR³R¹⁷；-(CHR¹)_rNR²COR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR²R¹⁷；-(CHR¹)_rPO(OR²)₂；-(CHR¹)_rSO₂R¹⁷；-(CHR¹)_rNR²SO₂R¹⁷；-(CHR¹)_rSO₂NR²R¹⁷；-(CR¹R²)_oR³⁸(ii) a Or- (CHR)¹)_rO(CHR²)_oR³⁸；

R²⁷Is H; f; cl; br; CF (compact flash)₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CHR)¹)_oOR¹⁷；-(CHR¹)_oSR¹⁷；-(CHR¹)_oNR²R¹⁷；-(CHR¹)_oOCONR²R¹⁷；-(CHR¹)_oNR²CONR³R¹⁷；-(CHR¹)_oNR²COR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR²R¹⁷；-(CHR¹)_oPO(OR²)₂；-(CHR¹)_oSO₂R¹⁷；-(CHR¹)_oNR²SO₂R¹⁷；-(CHR¹)_oSO₂NR²R¹⁷；-(CR¹R²)_oR³⁸(ii) a Or- (CHR)¹)_rO(CHR²)_oR³⁸；

R²⁹Is H; an alkyl group; an alkenyl group; cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; - (CHR)⁴)_oOR¹⁷；-(CHR⁴)_oSR¹⁷(ii) a Or- (CHR)⁴)_rNR¹⁷R¹⁸；

R³¹Is an alkyl group; an alkenyl group; - (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²R¹⁶；-(CR¹R¹⁵)_qNR¹⁷R³²；-(CR¹R¹⁵)_qNR¹⁷COR¹⁸；-(CH₂)_qC(=NR¹⁵)NR¹⁷R¹⁸；-(CH₂)_qC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_qC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qOR¹⁷；-(CR¹R¹⁵)_qOR³²；-(CR¹R¹⁵)_qSR¹⁷；-(CR¹R¹⁵)_qSO₂R¹⁷；-(CR¹R¹⁵)_qNR¹⁷SO₂R¹⁸；-(CR¹R¹⁵)_qSO₂NR²R¹⁶；-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR¹⁹SO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qPO(OR²)₂；-(CH₂)_nO(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qCOOR¹⁷；-(CR¹R¹⁵)_qCONR¹⁷R¹⁸(ii) a Or- (CR)¹R¹⁵)_qCOR³³；

R³²is-COR²⁹；-COR³⁰；-CO(CR¹R¹⁵)_oR¹⁷；-CO(CR¹R¹⁵)_oOR¹⁷；-CO(CR¹R¹⁵)_oNR¹⁷R¹⁸；-CO(CR¹R¹⁵)_oNR²R¹⁶；-CO(CR¹R²⁹)NR¹⁷R¹⁸；-CO(CR¹R³⁰)NR¹⁷R¹⁸；-CO(CR¹R³⁴)NR¹⁷R¹⁸；-CO(CHR¹)_oCONR¹⁷R¹⁸；-CO(CHR¹)_oCONR¹⁷SO₂R¹⁸；-CO(CR¹R¹⁵)_oNR¹⁷SO₂R¹⁸；-CONR¹(CHR¹⁷)_nNR²(CHR¹⁵)_mR¹⁶；-CO(CHR¹⁷)_nO(CHR¹⁵)_mR¹⁶；-CONR¹(CHR¹⁷)_nO(CHR¹⁵)_mR¹⁶；-SO₂R²⁹；-SO₂R³⁰；-SO₂(CR¹R¹⁵)_oR¹⁷(ii) a or-SO₂(CR¹R¹⁵)_oNR¹⁷R¹⁸；

R³³is-NR¹C(R²)(R²⁹)COOR¹⁷；-NR¹C(R²)(R²⁹)CONR¹⁷R¹⁸；-NR¹C(R²)(R³⁰)COOR¹⁷；-NR¹C(R²)(R³⁰)CONR¹⁷R¹⁸；-NR¹C(R²)(R³⁴)COOR¹⁷(ii) a or-NR¹C(R²)(R³⁴)CONR¹⁷R¹⁸；R³⁴Is- (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CH₂)_qC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_qC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_qC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qNR²C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qOR¹⁷；-(CR¹R¹⁵)_qSR¹⁷；-(CR¹R¹⁵)_qSO₂R¹⁷；-(CR¹R¹⁵)_qNR¹⁷SO₂R¹⁸；-(CR¹R¹⁵)_qSO₂NR¹R¹⁶；-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²SO₂NR¹⁷R¹⁸；-(CR¹R¹⁵)_qPO(OR¹)₂；-(CH₂)_nO(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NOR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mC(=NNR¹⁷R¹⁸)NR¹⁹R²⁰；-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mN=C(NR¹⁷R¹⁸)NR¹⁹R²⁰；-(CR¹R¹⁵)_qCOOR¹⁷(ii) a Or- (CR)¹R¹⁵)_qCONR¹⁷R¹⁸；

R³⁵Is an aryl radical of one of the formulae

Or a heteroaryl group of one of the formulae

R³⁶And R³⁷Independently is

H；F；Cl；Br；CF₃；OCF₃；OCHF₂；CN；NO₂(ii) a A lower alkyl group; lower alkenyl; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH)₂)_oR³⁸；-(CH₂)_oOR¹⁷；-O(CH₂)_oR³⁸；-(CH₂)_oSR¹⁷；-(CH₂)_oNR¹⁷R¹⁸；-(CH₂)_oOCONR¹⁷R¹⁸；-(CH₂)_oNR¹CONR¹⁷R¹⁸；-(CH₂)_oNR¹COR¹⁷；-(CH₂)_oCOOR¹⁷；-(CH₂)_oCONR¹⁷R¹⁸；-(CH₂)_oPO(OR¹)₂；-(CH₂)_oSO₂R¹⁶(ii) a Or- (CH)₂)_oCOR¹⁷；

R³⁸Is an aryl radical of the formula

R³⁹，R⁴⁰And R⁴¹Independently is

R⁴²is H; a lower alkyl group; or aryl-lower alkyl;

n and m are independently integers from 0 to 5, provided that n + m.ltoreq.6;

o is 0 to 4; p is 2 to 6; q is 1 to 6; r is 1 to 3; s is 0 to 4

And pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein

-(CHR¹)_sNR¹⁷R¹⁸；-(CHR¹)_oCOR¹⁷；-(CHR¹)_oCOOR¹⁷；-(CHR¹)_oCONR¹⁷R¹⁸(ii) a Or- (CHR)¹)_oSO₂R¹⁷；

R¹⁷，R¹⁸，R¹⁹And R²⁰Independently is

aryl-lower alkyl; or heteroaryl-lower alkyl; or

Structural element-NR¹⁷R¹⁸and-NR¹⁹R²⁰Can independently form:

or a group of one of the above formulae C1 to C8;

R³¹is an alkyl group; an alkenyl group; - (CR)¹R¹⁵)_qNR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²R¹⁶；-(CR¹R¹⁵)_qNR¹⁷COR¹⁸；-(CH₂)_qC(=NR¹⁵)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qOR¹⁷；-(CR¹R¹⁵)_qSR¹⁷；-(CR¹R¹⁵)_qSO₂R¹⁷；-(CR¹R¹⁵)_qNR¹⁷SO₂R¹⁸；-(CR¹R¹⁵)_qSO₂NR²R¹⁶；

-(CR¹R¹⁵)_qSO₂NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mC(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR²⁰C(=NR¹⁹)NR¹⁷R¹⁸；-(CR¹R¹⁵)_qCONR¹⁷R¹⁸(ii) a Or- (CR)¹R¹⁵)_qCOR³³；

s is 2-4

And pharmaceutically acceptable salts thereof.

3. A compound according to claim 1, wherein

then T²Can also be

Pro; pip; tic; tiq; oic; or Azt;

P¹，P³and P⁴Independently is

Ala; arg; asn; asp; cit; cys; glu; gln; gly; his; ile; leu; lys; met; orn; phe; pro; ser; thr; trp; tyr; val; abu; agb, respectively; agp; ala (tBu); ala (cPr); ala (2 furyl); ala (3 furyl); ala (Ppz); ala (1 Pyraz); ala (2 Quin); ala (3 Quin); ala (4 Quin); ala (tet); azt; bbta; bip; cha; chg; dab; dab (ac); dab (cPr); dab (ipr); dab (4 Me)₂NPhSO₂)；Dab(MeOEtNCO)；Dab(MePpzCO)；Dab(MeSO₂)；Dab(morphCO)；Dab(1Nal)；Dab(2Nal)；Dap；Dap(CONH₂)；Dap(MeOEt)；Dap((MeOEt)₂) (ii) a Deg, respectively; gly (tbu); hArg; hRha; hCys; hHis; hLys; hPhe; hSer; hSer (Me); an hTRp; hTyr; his (Me); his (Bn); hyp (Bn); (4S) -Hyp (Bn); hyp (4 BrBn); hyp (3 CNBn); hyp (4 CNBn); hyp (conhph); hyp (Ph); lys (ac); lys (bz); lys (cpr); lys (ipr); lys (Me); lys (Nic); lys ((5R) OH); lys (4 oxa); met (O)₂)；1Nal；2Nal；Nle；Nle(6OBn)；OctG；Oic；Orn(cPr)；Orn(iPr)；2Pal；3Pal；4Pal；Phe(2Cl)；Phe(3Cl)；Phe(4Cl)；Phe(3，4Cl₂)；Phe(2F)；Phe(3F)；Phe(4F)；Phe(4CN)；Phe(4CF₃)；Phe(4COOMe)；Phg；Pip；Pro((4R)Bn)；Pro((4S)F)；Pro((4S)cHex)；Pro(5，5Me₂)；Ser(Bn)；Ser(Me)；Thi；alloThr；Thr(Bn)；Thz；Thz(5，5Me₂) (ii) a Tic; tic (7 OH); trp (7 aza); trp (5 Br); trp (6 Br); trp (6 CF)₃)；Trp(5Cl)；Trp(6Cl)；Trp(5，6Cl)；Trp(5OH)；Tyr(Bn)；Tyr(Me)；Tyr(4MeOCOBn)；Tyr(Ph)；Tyr(4OHPh)；Tza；Gln(Alk1)；Gln(Alk2)；Gln(Alk3)；Gln(Alk4)；Gln(Alk5)；Gln(Alk6)；Gln(Alk7)；Gln(Alk8)；Gln(Alk9)；Gln(Alk10)；Gln(Alk11)；Gln(Alk12)；Gln(Alk13)；Gln(Alk14)；Gln(Alk15)；Gln(Alk16)；Gln(Alk17)；Gln(Alk18)；Gln(Alk19)；Gln(Alk20)；Gln(Alk21)；Gln(Alk22)；Gln(Alk23)；Gln(Alk24)；Gln(Alk25)；Gln(Alk26)；Gln(Alk27)；Gln(Alk28)；Gln(Alk29)；Gln(Alk30)；Gln(Alk31)；Gln(Alk32)；Gln(Alk33)；Gln(Alk34)；Glu(cN1)；Glu(cN2)；Glu(cN3)；Glu(cN4)；Glu(cN5)；Glu(cN6)；Glu(cN7)；Glu(cN8)；Glu(cN9)；Glu(cN10)；Glu(cN11)；Glu(cN12)；Glu(cN13)；Glu(cN14)；Glu(cN15)；Glu(cN16)；Glu(cN17)；Lys(Ar1)；Lys(Ar2)；Lys(Ar3)；Lys(Ar4)；Lys(Ar5)；Lys(Ar6)；Lys(Ar7)；Lys(Ar8)；Lys(Ar9)；Lys(Ar10)；Lys(Ar11)；Lys(Ar12)；Orn(Ar1)；Orn(Ar2)；Orn(Ar3)；Orn(Ar4)；Orn(Ar5)；Orn(Ar6)；Orn(Ar7)；Orn(Ar8)；Orn(Ar9)；Orn(Ar10)；Orn(Ar11)；Orn(Ar12)；Dab(Ar1)；Dab(Ar2)；Dab(Ar3)；Dab(Ar4)；Dab(Ar5)；Dab(Ar6)；Dab(Ar7)；Dab(Ar8)；Dab(Ar9)；Dab(Ar10)；Dab(Ar11)；Dab(Ar12)；Dab(S1)；Dab(S2)；Dab(S3)；Dab(S4)；Dab(S5)；Dab(S6)；Dab(S7)；Dab(S8)；Dab(S9)；Dab(S10)；Dab(S11)；Dab(S12)；Dab(S13)；Dab(S14)；Dab(S15)；Dab(S16)；Dab(S17)；Dab(S18)；Dab(A1)；Dab(A2)；Dab(A3)；Dab(A4)；Dab(A5)；Dab(A6)；Dab(A7)；Dab(A8)；Dab(A9)；Dab(A10)；Dab(A11)；Dab(A12)；Dab(A13)；Dab(A14)；Dab(A15)；Dab(A16)；Dab(A17)；Dab(A18)；Dab(A19)；Dab(A20)；Dab(A21)；Dab(A22)；Dab(A23)；Dab(A24)；Dab(A25)；Dab(A26)；Dab(A27)；Dab(A28)；Dab(A29)；Dab(A30)；Dab(A31)；Dab(A32)；Dab(A33)；Dab(A34)；Dab(A35)；Dab(A36)；Dab(A37)；Dab(A38)；Dab(A39)；Dab(A40)；Dab(A41)；Dab(A42)；Dab(A43)；Dab(A44)；Dab(A45)；Dab(A46)；Dab(A47)；Dab(A48)；Dab(A49)；Dab(A50)；Dab(A51)；Dab(A52)；Dab(A53)；Dab(A54)；Dab(A55)；Orn(A1)；Orn(A2)；Orn(A3)；Orn(A4)；Orn(A5)；Orn(A6)；Orn(A7)；Orn(A8)；Orn(A9)；Orn(A10)；Orn(A11)；Orn(A12)；Orn(A13)；Orn(A14)；Orn(A15)；Orn(A16)；Orn(A17)；Orn(A18)；Orn(A19)；Orn(A20)；Orn(A21)；Orn(A22)；Orn(A23)；Orn(A24)；Orn(A25)；Orn(A26)；Orn(A27)；Orn(A28)；Orn(A29)；Orn(A30)；Orn(A31)；Orn(A32)；Orn(A33)；Orn(A34)；Orn(A35)；Orn(A36)；Orn(A37)；Orn(A38)；Orn(A39)；Orn(A40)；Orn(A41)；Orn(A42)；Orn(A43)；Orn(A44)；Orn(A45)；Orn(A46)；Orn(A47)；Orn(A48)；Orn(A49)；Orn(A50)；Orn(A51)；Orn(A52)；Orn(A53)；Orn(A54)；Orn(A55)；Orn(A56)；Asn(Alk1)；Asn(Alk2)；Asn(Alk3)；Asn(Alk4)；Asn(Alk5)；Asn(Alk6)；Asn(Alk7)；Asn(Alk8)；Asn(Alk9)；Asn(Alk10)；Asn(Alk11)；Asn(Alk12)；Asn(Alk13)；Asn(Alk14)；Asn(Alk15)；Asn(Alk16)；Asn(Alk17)；Asn(Alk18)；Asn(Alk19)；Asn(Alk20)；Asn(Alk21)；Asn(Alk22)；Asn(Alk23)；Asn(Alk24)；Asn(Alk25)；Asn(Alk26)；Asn(Alk27)；Asn(Alk28)；Asn(Alk29)；Asn(Alk30)；Asn(Alk31)；Asn(Alk32)；Asn(Alk33)；Asn(Alk34)；Asp(cN1)；Asp(cN2)；Asp(cN3)；Asp(cN4)；Asp(cN5)；Asp(cN6)；Asp(cN7)；Asp(cN8)；Asp(cN9)；Asp(cN10)；Asp(cN11)；Asp(cN12)；Asp(cN13)；Asp(cN14)；Asp(cN15)；Asp(cN16)；Asp(cN17)；Dap(Ar1)；Dap(Ar2)；Dap(Ar3)；Dap(Ar4)；Dap(Ar5)；Dap(Ar6)；Dap(Ar7)；Dap(Ar8)；Dap(Ar9)；Dap(Ar10)；Dap(Ar11)；Dap(Ar12)；Dap(S1)；Dap(S2)；Dap(S3)；Dap(S4)；Dap(S5)；Dap(S6)；Dap(S7)；Dap(S8)；Dap(S9)；Dap(S10)；Dap(S11)；Dap(S12)；Dap(S13)；Dap(S14)；Dap(S15)；Dap(S16)；Dap(S17)；Dap(S18)；Dap(A1)；Dap(A2)；Dap(A3)；Dap(A4)；Dap(A5)；Dap(A6)；Dap(A7)；Dap(A8)；Dap(A9)；Dap(A10)；Dap(A11)；Dap(A12)；Dap(A13)；Dap(A14)；Dap(A15)；Dap(A16)；Dap(A17)；Dap(A18)；Dap(A19)；Dap(A20)；Dap(A21)；Dap(A22)；Dap(A23)；Dap(A24)；Dap(A25)；Dap(A26)；Dap(A27)；Dap(A28)；Dap(A29)；Dap(A30)；Dap(A31)；Dap(A32)；Dap(A33)；Dap(A34)；Dap(A35)；Dap(A36)；Dap(A37)；Dap(A38)；Dap (A39); dap (A40); dap (A41); dap (A42); dap (A43); dap (A44); dap (A45); dap (A46); dap (A47); dap (A48); dap (A49); dap (A50); dap (A51); dap (A52); dap (A53); dap (A54); or Dap (A55);

P²is that^DArg；^DhArg；^DAgb；^DLys；^DOrn；^DCit；^DThr；^DDab；^DDab；^DPhe；^DPhe(4CF₃)；^DTrp；^DHis；^DTyr；^D2Pal；^D3Pal；^D4Pal；^DLys(Ar1)；^DLys(Ar2)；^DLys(Ar3)；^DLys(Ar4)；^DLys(Ar5)；^DLys(Ar6)；^DLys(Ar7)；^DLys(Ar8)；^DLys(Ar9)；^DLys(Ar10)；^DLys(Ar11)；^DLys(Ar12)；^DOrn(A41)；^DOrn(A56)；^DOrn(Ar1)；^DOrn(Ar2)；^DOrn(Ar3)；^DOrn(Ar4)；^DOrn(Ar5)；^DOrn(Ar6)；^DOrn(Ar7)；^DOrn(Ar8)；^DOrn(Ar9)；^DOrn(Ar10)；^DOrn(Ar11)；^DOrn(Ar12)；^DDab(Ar1)；DDab(Ar2)；^DDab(Ar3)；^DDab(Ar4)；^DDab(Ar5)；^DDab(Ar6)；^DDab(Ar7)；^DDab(Ar8)；^DDab(Ar9)；^DDab(Ar10)；^DDab(Ar11)；^DDab(Ar12)；^DDap(Ar1)；^DDap(Ar2)；^DDap(Ar3)；^DDap(Ar4)；^DDap(Ar5)；^DDap(Ar6)；^DDap(Ar7)；^DDap(Ar8)；^DDap(Ar9)；^DDap(Ar10)；^DDap (Ar 11); or^DDap(Ar12)；

And pharmaceutically acceptable salts thereof.

4. A compound according to claim 1, wherein

then T²Can also be

Pro; pip; tic; tiq; oic; or Azt;

and pharmaceutically acceptable salts thereof.

5. A compound according to claim 1, wherein

P⁴is Trp; his; phe; phe (4 CF)₃) (ii) a1 Nal; 2 Nal; tyr; ile; arg; hArg; lys; dab; orn; orn (a 56); or Orn (Ar 7);

and pharmaceutically acceptable salts thereof.

6. A compound according to claim 1 selected from

Cyclo (-Ile-^DArg-Arg-Ile-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Tyr-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Lys-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Dab-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DDab-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe-^DPro-Thr-)；

Cyclo (-Ile-^DThr-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-hSer-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-alloThr-)；

Cyclo (-1Nal-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DLys-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DHis-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DCit-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Thr-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-1Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Trp-Arg-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Thr-^DArg-Trp-Arg-^DPro-Thr-)；

Cyclo (-Trp-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Ser-)；

Cyclo (-Ile-^DArg-Agp-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Agb-Trp-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (A)-Tyr-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Dab-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Lys-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-His-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Pip-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-hArg-)^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-Agb-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-3Pal-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^D3Pal-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-hArg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4S)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4S)F)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4S)NH₂)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Pro((4R)NH₂)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro-Mor-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Mor-)；

Cyclo (-Arg-^DPhe-Trp-Arg-^DPro-(4S)-Hyp(Bn)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)OH)-(4S)-Hyp(Bn)-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-(4S)-Hyp(Bn)-)；

Cyclo (-His-^DTrp-His-Trp-^DPro-Pro((4S)NHBz)-)；

Cyclo (-1Nal-^DArg-Arg-Trp-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Pro((3S)OH)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro((4S)OH)-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro((4R)NH₂)-Thr-)；

Cyclo (-Val-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Abu-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Chg-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Leu-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Nle-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Cha)^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DOrn-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A41)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-hArg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DTic-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar2)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar7)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar4)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A56)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe(4CF₃)-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPip-Pro((3S)OH)-)；

Cyclo (-Ala (1Pyraz) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala (Tet) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar2) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Ring (-Orn (A56) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(Ar7)-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tiq-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tic-)；

And pharmaceutically acceptable salts thereof.

7. A compound according to claim 6 selected from

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Thr-)；

Cyclo (-Ile-^DArg-Arg-2Nal-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPro-Ser-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Dab-^DPro((4R)NH₂)-Tic-)；

Cyclo (-3Pal-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4R)NH₂)-Oic-)；

Cyclo (-Trp-^DPhe-Trp-Arg-^DPro((4S)OH)-(4S)-Hyp(Bn)-)；

Cyclo (-Ile-^DArg-Arg-Trp-^DPip-Pro((3S)OH)-)；

Cyclo (-Chg-^DArg-Arg-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-hArg-Trp-^DPro-Thr-)；

And pharmaceutically acceptable salts thereof.

8. A compound according to claim 6 selected from

Cyclo (-Ile-^DArg-Orn(Ar2)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar7)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(Ar4)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Orn(A56)-Trp-^DPro-Thr-)；

Cyclo (-Ile-^DArg-Arg-Phe(4CF₃)-^DPro-Thr-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPip-Pro((3S)OH)-)；

Cyclo (-Ala (1Pyraz) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Ala (Tet) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar2) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Orn (Ar56) -^DPhe-Trp-Arg-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(Ar7)-^DPro((4R)NH₂)-Tic-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tiq-)；

Cyclo (-Trp-^DPhe-Trp-Orn(A56)-^DPro((4R)NH₂)-Tic-)；

And pharmaceutically acceptable salts thereof.

9. Epimers and diastereomers of the compound of formula (I) as defined in claim 1, which are based on one or more chiral centers not explicitly specified in formula (I).

10. A compound according to any one of claims 1 to 9 for use as therapeutically active substance, in particular for use as therapeutically active substance against a disease or condition mediated or maintained by the activity of CXCR 7.

11. Compounds according to any one of claims 1 to 9, which have modulatory activity towards the CXCR7 receptor, in particular selectively interfering with the natural activity of the CXCR7 receptor and its natural ligands CXCL11 and/or CXCL 12.

12. A pharmaceutical composition comprising a compound or mixture of compounds according to any one of claims 1 to 9 and a pharmaceutically inert carrier.

13. A composition according to claim 12, which is in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, particularly in the form of tablets, lozenges, capsules, solutions, liquids, gels, plasters, creams, ointments, syrups, slurries, suspensions, sprays, nebulisers or suppositories.

14. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament thereof as sole active pharmaceutical ingredient or in combination with other active pharmaceutical ingredients.

15. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the therapeutic, prophylactic or supportive treatment of a disease or condition involving CXCR7 activity in the fields of dermatology, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastrointestinal disorders, urological diseases, ocular diseases, oral diseases, hematologic diseases and oncology, or for stem cell activation,

in particular for the preparation of a medicament for the therapeutic, prophylactic or supportive treatment of a disease or condition, such as an HIV infection, an Epstein-Barr virus infection; diabetes (type I and/or type II); conjunctivitis, scleritis, uveitis, sinusitis, Whim syndrome, lupus erythematosus, osteoarthritis, rheumatoid arthritis, synovitis, psoriasis, multiple sclerosis, crohn's disease, inflammatory bowel disease, mixed connective tissue disease, chronic lymphocytic thyroiditis, graves ' disease, graft versus host disease, sjogren's syndrome; dry eye syndrome, glaucoma, age-related macular degeneration; pulmonary hypertension, pulmonary hypoxia, atherosclerosis, myocarditis, heart failure, such as myocardial infarction, arterial thrombosis, stroke, angiogenesis; chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma; sarcomas, such as osteosarcoma, rhabdomyosarcoma, kaposi's sarcoma, synovial sarcoma; lipomas, such as angiolipoma; glioblastoma multiforme, astrocytoma, neuroblastoma; cancer, such as adenocarcinoma; malignant epithelial and mucoepidermoid tumors, thyroid tumors, sex adenomas, prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer; a solid tumor; lymphomas such as Birkitt lymphoma, hodgkin lymphoma, non-hodgkin lymphoma; multiple myeloma and leukemia; transferring; for inhibiting neointima formation; for stem cell activation of peripheral blood stem cells and/or mesenchymal stem cells; for activation of endothelial or neuronal progenitor cells; or for different types of tissue repair in humans or other mammals.

16. A process for the preparation of a compound according to any one of claims 1 to 9, which comprises

(b) removing the N-protecting group from the product obtained in step (a);

(d) removing the N-protecting group from the product thus obtained;

(g) removing the product thus obtained from the solid support;

(h) cyclizing the product cleaved from the solid support;