Oral GLP receptor agonists

Abstract

The disclosures herein relate to novel compounds of formula (1a) or formula (1b): and salts thereof, wherein S, T, W, Z, AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, AA10, AA11, AA12, AA13, AA14, AA15, A16, AA17, AA18, AA19, AA20, AA21, AA22, Sa, Ta, Wa, Xa, Ya, Za, AA1a, AA2a, AA3a, AA4a, AA 5a, AA 6a,AA 7a,AA8a,AA 9a,AA 10a,AA11a,AA 12a,AA13aAA 14a,AA15a,AA 16a, R, R1 and R2 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with Glucagon-like peptide (GLP) receptors.

Description

Oral GLP Receptor Agonists This invention relates to a class of novel orally delivered peptide compounds, their salts, pharmaceutical compositions containing them and their use in therapy of the human body. In particular, the invention is directed to a class of compounds which are agonists of Glucagon- like peptide (GLP) receptors. More particularly, the invention is directed to compounds that are agonists of the Glucagon-like peptide-1 (GLP-1) and Glucagon-like peptide-2 (GLP-2) receptors. More particularly, the invention is directed to compounds that are selective agonists of the Glucagon-like peptide-2 (GLP-2) receptor. The disclosure provides therapeutic methods for treating gastrointestinal diseases through administration of such compounds via the oral route of delivery. The compounds of the invention possess enhanced stability in gastrointestinal relevant fluids. The invention also relates to the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases in which GLP receptors are involved. Background of the Invention Glucagon-like peptide-1 (GLP-1) and Glucagon-like peptide-2 (GLP-2) are highly conserved amino acid peptides that originate from the same precursor protein. These biologically active peptides are encoded by the proglucagon gene which undergoes tissue specific post- translational processing in the pancreas (alpha cells), intestine (L-cells) and the central nervous system (CNS). In the gastrointestinal tract, prohormone convertase 1 / 3 is responsible for cleaving proglucagon to give rise to a number of biologically active peptides including GLP-1, GLP-2, IP2, oxyntomodulin and glicentin. Both GLP-1 and GLP-2 are secreted in response to nutrient ingestion by intestinal L cells localised in the distal ileum and colon and plasma levels of these gut peptides are reported to be increased after food intake in man. The actions of GLP-1 and GLP-2 are mediated through the activation of class B G protein coupled receptors, GLP-1R and GLP-2R, which couple to the Gs protein and stimulate cAMP production via activation of adenylate cyclase. GLP-1R is found expressed in the brain, pancreatic islet cells, heart, kidney and myenteric plexus neurones in the gastrointestinal tract. The expression of GLP-2R on the other hand, is more restricted, and the receptor is largely localised to the CNS and the gastrointestinal tract. A number of cell types have been reported to express GLP-2R in the gut including enteric neurons, subepithelial myofibroblasts and enteroendocrine cells, however the exact cellular distribution remains to be defined. GLP-2 has been reported to be involved in a wide range of physiological functions including gut barrier function, mesenteric blood flow, gastric motility and acid secretion. Exogenous administration of GLP-2 stimulates crypt cell proliferation, enhances intestinal villi length and promotes the growth and repair of the small intestinal mucosa. The potent intestinotrophic activity of GLP-2 has been documented across species including rats, pigs and human. GLP-2 furthermore enhances intestinal absorptive capacity through regulation of intestinal brush border enzymes and solute carriers, highlighting the potential role of this gut hormone in the control of energy homeostasis. Based on the ability to promote potent intestinotrophic effects in the gut, Teduglutide, a GLP-2 analogue has been approved as pharmacological therapy for PN dependent SBS patients and has been shown to reduce PN requirements as well as promote enteral autonomy. In addition to Teduglutide, a number of GLP-2 peptide agonists are in clinical development (e.g. apraglutide, glepaglutide) however all current agents are targeted towards parenteral delivery via subcutaneous injection. GLP peptides that can be given via the oral route of delivery are likely to offer better patient acceptance through convenience of dosing, allow earlier treatment initiation and improve long term compliance. This may particularly be advantageous when considering the development of peptide therapeutics for pediatric patients. However, there are many challenges to the oral delivery of peptides as molecules generally suffer from poor peptide stability (due to extensive proteolytic degradation) as well as low membrane permeability. In the stomach, an orally delivered peptide requires stability in the acidic low pH environment as well as resistance to gastric proteases. In the intestine, the peptides are further subject to degradation from a range of intestinal or pancrealic secreted enzymes as well as brush border membrane bound enzymes. A wide range of biopharmaceutical, formulation and delivery strategies are currently under investigation to overcome some of these barriers. The development of novel potent and stable peptides targeting GLP-2 and GLP-1 receptors suitable for oral delivery remains an attractive strategy and is highly desirable. GLP-1 is a 31 amino acid peptide which is co-released with GLP-2 in response to luminal nutrients (carbohydrates, fats, proteins) and serves as a gut incretin hormone that works in concert with glucose-dependent insulinotropic polypeptide (GIP). GLP-1 plays a key physiological role in pancreatic islet B-cell function, regulating B-cell proliferation as well as postprandial insulin synthesis / release. Studies have furthermore shown that GLP-1 controls the release of other gut peptides such as somatostatin and glucagon. Following its release, somatostatin acts to suppress GLP-1 and GIP secretion thereby establishing a feedback system in enteroendocrine cells. GLP-1 is a key anorexigenic peptide involved in the regulation of satiety and appetite control, and impacts GI function through effects on gastric emptying and gut motility. Several GLP-1 agents are currently marketed for the treatment of type 2 diabetes mellitus and have been successful in improving glycemic control in diabetic patients. One oral formulation of GLP-1 peptide is currently in clinical development (Semaglutide, Ph III) for the treatment of type 2 diabetes. Once daily formulation of oral semaglutide has shown efficacy superior to active comparators and shows comparable safety and tolerability profile to injectable GLP-1 receptor agonists. Intestinal failure (IF) refers to a serious and disabling condition whereby the gut is unable to absorb necessary water, electrolytes, macro- and micronutrients for survival. The causes of IF are varied and can result from obstruction, dysmotility, surgical resection, congenital defect or disease associated loss of absorption. Short bowel syndrome represents the most common cause of intestinal failure and arises from the physical or functional loss of a bowel section, often leading to malnutrition, weight loss, dehydration, diarrhoea, steatorrhoea, fatigue and abdominal pain. Management of SBS requires multidisciplinary care and parenteral nutrition (PN) support to compensate for the extensive fluid loss and to restore nutrient and electrolyte balances. Although critical for survival, long term dependence on parenteral nutrition can negatively impact the patient's quality of life and furthermore increase the risk of life threatening complications such as catheter related sepsis, venous thrombosis and liver damage (e.g. steatosis, cholestasis). The symptoms and severity of SBS can vary depending on the location and length of the remnant bowel. Intestinal motility is known to be influenced by multiple gut hormones including GLP-1, GLP-2 and PYY which are typically produced by L cells in the ileum and proximal colon. Hormones such as GLP-1 act to provide important feedback mechanisms to control the rate of Gl transit for efficient nutrient digestion and absorption. Patients with jejunostomy that have lost the ileal brake have lower fasting GLP-1 and GLP-2 concentrations in plasma and generally suffer rapid gastric emptying and GI transit with high stoma output. Small pilot studies have demonstrated that exenatide or liraglutide (GLP-1 agonists) improve symptoms of diarrhoea in SBS patients and furthermore reduce the requirement for PN. Adding to the complex clinical picture, evidence also exists for a dysregulated enteroinsular axis in patients with bowel resection that results in impaired insulin response in response to oral glucose administration. In addition, hyperglycemia is a frequent complication of parenteral nutrition in hospitalised patients and can increase the risk of death and infectious complications. The prevalence of hyperglycemia in patients receiving specialised nutritional support is estimated to be up to 30% for those receiving enteral nutrition and 50% in patients on parenteral nutrition. It is recognised that continued poor control of hyperglycemia can lead to a decline in pancreatic beta cell function and can contribute to exacerbating complications such as microvascular disease, cardiovascular events and hypertension. Patients with hyperglycemia during TPN are at greater risk of being admitted to ICU, have longer hospital stays and higher mortality rates compared to those without hyperglycemia. Based on the known insulinotropic activity of GLP-1 agonists, activation of this mechanism could therefore potentially offer additional benefit in those that develop diminished insulin sensitivity post-surgery and in patients receiving parenteral nutrition. These findings therefore highlight the potential for a combined GLP-2 / GLP-1 pharmacological approach in the management of intestinal failure conditions including SBS. Other intestinal failure conditions where GLP-2 / GLP-1 agonists could provide benefit include rare congenital diarrhoeal diseases such as Tufting enteropathy which presents with early onset severe intractable diarrhoea that persists during fasting. Acute treatment of infants with parenteral nutrition, fluid and electrolyte replacement is critically required to prevent dehydration, electrolyte imbalance and impaired growth resulting from severe malnutrition. Gene encoding the epithelial cell adhesion molecule EpCAM shows association with Tufting enteropathy and to date over 25 EpCAM mutations have been described in the literature. Mutations in the EpCAM gene leads to the loss of cell surface expression, giving rise to the distinctive histological features in the intestinal epithelium, such as focal crowding of enterocytes and formation of ‘tufts’. Mice carrying deletion of exon 4 of the EpCAM gene demonstrate similar morphological defects to Tufting patients with significant morbidity and mortality. EpCAM directly associates with claudin 7, a tight junction molecule and disruptions of this gene leads to poor enterocyte adhesion and impaired gut barrier function, possibly through downregulation of tight junction molecules. Infants with Tufting enteropathy have low IGF-1 levels and depend on parenteral nutrition to compensate for the diminished capacity to absorb nutrients. Currently there are no pharmacological treatments for this debilitating condition and there is pressing need for agents that can improve intestinal function to promote independence from parenteral feeding. Recent analysis of the long term outcome of Tufting patients has revealed that enteral autonomy can successfully be achieved in most patients if they are effectively managed under specialist care settings. Therapies that promote early weaning are expected to lead to a better long term outcome in these patients and improve the quality of life. Agents acting at GLP-2 and GLP-1 receptors may hold promise in repairing barrier function and aiding recovery of intestinal function in this congenital diarrhoeal disease. Summary of the Invention The present invention relates to novel compounds with agonist activity at the GLP-2 and GLP-1 receptor, pharmaceutical compositions comprising these, and use of the compounds for the manufacture of medicaments for treatment of diseases. The present disclosure provides therapeutic methods for treating gastrointestinal diseases through administration of such compounds via the oral route of delivery. The compounds of the invention possess enhanced stability in gastrointestinal relevant fluids by having one or more lactam bridges. Accordingly, in one embodiment the invention provides a compound of the formula (1a): 1 2 Rl R rH ARIAS ARATE AREA AR AAA AAI ARSE AA AAA AA o (1a) wherein; Ris selected from: o © Appx H Oo ath A Hy H 0 NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more R? groups; RY is selected from halogen, hydroxyl, amino or Cy alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis 1to03; R' and R? are independently selected from hydrogen or a Cy alkyl group, or together with the carbon to which they are attached join to form a Cas cycloalkyl or a heterocyclyl group; $% is the sequence -Ser-Phe-; T? is the sequence -Glu-Nie-; W? is the sequence -Ala-Ala-; X? is the sequence -Asp-Phe-lle-; Y? is the sequence -Trp-Leu-ile-; Z° is absent or is the sequence -lle-Thr-; AA" is -NHCHR®CO-; wherein R® is selected from ~(CH,),CONH,, -(CH,),COOH or - (CH,),tetrazolyl; where y is 1 or 2; AA% is -Gly-, -DAla-, -Lys- optionally joined to AA* via a lactam bridge or -Glu- optionally joined to AA™ via a lactam bridge; AA¥ is -Ser- or is -Glu- optionally joined to AA® via a lactam bridge: AA® is -Asp- optionally joined to AA via a lactam bridge, or -Lys- optionally joined to AA% or AA® via a lactam bridge; AA™ is -DPhe-, -Asp- optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA® via a factam bridge; AA is -Thr-, -Asp- optionally joined to AA* or AA® via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA® via a lactam bridge; AA" is -lle- or an a-methyl Leucine residue of formula: Hw © H ¥ i ~ AA® is -Asp- or is -Lys- optionally joined to AA® via a lactam bridge; AA® is -Leu-, -Lys- optionally joined to AA® or AA"? via a lactam bridge, -Asp- optionally joined fo AA® or AA" via a lactam bridge or -Glu- optionally joined to AA'™ via a lactam bridge; AA is -Lys- or is -Glu- optionally joined to AA''® via a lactam bridge; AA" is -Aib-, -Lys- optionally joined to AA®™ or AA™® via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Asp- optionally joined to AA®® via a lactam bridge; AA is -Asn-, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge: AA is .GlIn-, -Asp- optionally joined to AA’? via a lactam bridge or -Lys- optionally joined to AA? via a lactam bridge; AA" is -Thr- or is -Lys- optionally joined to AA via a lactam bridge; AA is -Lys- optionally joined to AA™® via a factam bridge or -Glu- optionally joined to AA™® via a lactam bridge; AA is absent or is -Asp-, -Phe-, -Lys- optionally joined to AA via a lactam bridge or -Glu- optionally joined to AA? or AA'® via a lactam bridge: wherein the AA'™ or AA™® C-terminus is a carboxyl group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains one or two lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof. Accordingly, in one embodiment the invention provides a compound of the formula (1b): Rl R? A AR AREAS AREA ART 80 AA AR AAA ARRAN ART AN AN AE NE 2 o (1b) wherein: R is selected from: 0 H Que Oo athe Au H 0 NH, or Q is phenyl or a monocyclic heteroaryt ring each of which may be optionally substituted with one or more RY groups; RY is selected from halogen, hydroxyl, amino or Cys alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis1to 3: R' and R? are independently selected from hydrogen or a Cy. alkyl group, or together with the carbon to which they are attached join fo form a Ca. cycloalkyl or a heterocyclyl group; S is the sequence -Glu-Nle-; T is the sequence -Phe-lle-; W is the sequence -Trp-Leu-lie-~; Z is absent or is -Pro-; AA" is -NHCHR®CO-; wherein R® is selected from -(CH,),CONH,, (CH), COOH or - (CHy)tetrazolyt; where y is 1 or 2; AA? is -Gly-, -DAla-, -Lys- optionally joined to AA® via a lactam bridge or -Glu- optionally joined to AAS via a lactam bridge; AAS is -Ser-Phe or -Ser-2-F-a-Me-Phe-; AA‘ is -Ser- or -Glu- optionally joined to AA® via a lactam bridge; AA® is -Asp- optionally joined to AA? via a lactam bridge or -Lys- optionally joined to AA? or AA’ via a lactam bridge; AAS is -D-Phe-, -D-u-Me-Phe- or -Lys- optionally joined to AA™ via a lactam bridge; AAT is -Asp- optionally joined to AA® via a lactam bridge, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge: AAS is ~lle or -u-Me-Leu-: AA® is -Leu-Asp- or ~Leu-ACPC-; AA" is -Asp- optionally joined to AA” or AA™ via a lactam bridge, -Glu- optionally joined to AA or AA" via a lactam bridge or -Lys- optionally joined to AA” via a lactam bridge; AA" is -LysR- where LysR is an N-substituted Lysine residue, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA'® via a lactam bridge: AA is -Ala- or -AIB-! AA" is -Ala- or -AIB-: AA" is -AIB- or is -Lys- optionally joined to AA" or AA" via a lactam bridge; AAS is -Asp- optionally joined to AA!" via a lactam bridge or -Glu- optionally joined to AA'™ via a lactam bridge; AA is -Asn-, -ACPC-, -Lys- optionally joined to AA' via a lactam bridge or -Glu- optionally joined to AA! via a lactam bridge; AA" is -GIn-, -ACPC-, -Lys- optionally joined to AA'® via a lactam bridge or -Glu- optionally joined to AA via a lactam bridge; AA is -Thr-, -Lys- optionally joined to AA? via a lactam bridge or -Glu- optionally joined to AA? via a lactam bridge; AA" is -Pro-, -PIPALA-, -Lys- or -Glu- optionally joined to AA? via a lactam bridge; AA? is absent or is -lle-, -a-Me-Leu- or -Pro-; AA?! is absent or is -Thr-: AAZ is absent or is -Lys- optionally joined to AA'™ or AA™ via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; wherein the C-terminus is a carboxyl group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains three, four or five lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof. The GLP-2 / GLP-1 derivatives of this invention can be used in the treatment of various diseases as described below. In one aspect, the present invention provides a method for promoting growth of small bowel tissue in a patient in need thereof, comprising the step of delivering to the patient an intestinotrophic amount of a GLP-2 / GLP-1 analogue of the present invention. In a further aspect the present invention relates to a method for the preparation of a medicament for the treatment of gastrointestinal diseases that include intestinal failure or other conditions leading to nutrient malabsorption and intestinal insufficiency. Examples of such diseases may include small bowel syndrome, diarrhoeal diseases, inflammatory bowel syndrome, Crohn's disease, Ulcerative colitis, pouchitis, radiation induced bowel damage, Celiac disease (gluten sensitive enteropathy), NSAID-induced gastrointestinal damage, cancer treatment induced tissue damage (e.g. chemotherapy induced enteritis), Parkinson's disease, parenteral nutrition induced mucosal atrophy, intestinal failure in preborn infants, necrotizing enterocolitis, neonatal feeding intolerance, congenital diarrhoeal diseases, congenital or acquired digestion and absorption disorders, tissue damage induced by vascular obstruction, trauma or ischemia. A further aspect of the invention is a method for treating the symptoms of, or treating rare congenital diarrheal diseases in a patient in need thereof, by delivering a GLP-2 / GLP-1 analogue of the present invention in a therapeutically effective amount. Persistent uncontrolled diarrhoea can cause severe dehydration, electrolyte imbalance, malnutrition and failure to thrive which, if left untreated, could lead to life threatening condition including death. In a further aspect, the present invention provides the use of a compound as outlined above for the preparation of a medicament for the treatment of Tufting enteropathy, a rare congenital diarrhoeal disease characterised by early onset severe and intractable diarrhoea that often leads to intestinal failure. A further aspect of the invention is a method for treating metabolic diseases and syndromes in a patient in need thereof, by delivering a GLP-2 / GLP-1 analogue of the present invention in a therapeutically effective amount, In one embodiment metabolic disease and syndromes include obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, hyperglycemia, insulin resistance, glucose intolerance. It is envisaged that treatment with a GLP-2 / GLP-1 analogue may restore glycemic control and insulin sensitivity. This could be beneficial for the management of hyperglycemia during enteral and parenteral nutrition therapy in patients with intestinal failure, insufficiency or malabsorption disorders. Detailed Description of the Invention This invention relates to novel compounds. The invention also relates to the use of novel compounds as agonists of GLP receptors. The invention further relates to the use of novel compounds in the manufacture of medicaments for use as GLP receptor agonists or for the treatment of gastrointestinal and metabolic disorders. The invention further relates to compounds, compositions and medicaments which are selective GLP-2 receptor agonists. The present disclosure provides therapeutic methods for treating gastrointestinal diseases through administration of such compounds via the oral route of delivery. The compounds of the invention possess enhanced stability in gastrointestinal relevant fluids. Compounds of the invention contain one of more lactam bridges. Accordingly, in one embodiment the invention provides a compound of the formula (1a): Rl R? RO ARTES ARATE AEA aA AAI AK AA AAA 0 (1a) wherein; R is selected from: i o App o ath Any H 0 NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more R? groups; RY is selected from halogen, hydroxyl, amino or Cys alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nistto3: R' and R? are independently selected from hydrogen or a Cy alkyl group, or together with the carbon to which they are attached join fo form a Cag cycloalkyl or a heterocyclyl group; S$? is the sequence -Ser-Phe-; T? is the sequence -Glu-Nie-; W? is the sequence -Ala-Ala-; X? is the sequence -Asp-Phe-lle-; Y? is the sequence -Trp-Leu-ile-; 2% is absent or is the sequence -lle-Thr-; AA" is -NHCHR®CO-; wherein R® is selected from -(CHu),CONH,, -(CHz),COOH or - (CHy),tetrazolyl; where y is 1 or 2; AAZ is -Gly-, -DAla-, -Lys- optionally joined to AA* via a lactam bridge or -Glu- optionally joined to AA* via a lactam bridge; AA js -Ser- or is -Glu- optionally joined to AA® via a lactam bridge; AA* is -Asp- optionally joined to AA? via a lactam bridge, or -Lys- optionally joined to AA? or AA® via a lactam bridge; AA* is -DPhe-, -Asp- optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA® via a lactam bridge; AA® is -Thr-, -Asp- optionally joined to AA* or AA% via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA®® via a lactam bridge; AA" is -lle- or an a-methyl Leucine residue of formula: Hw © H 1 iL ~ AA™ is -Asp- or is -Lys- optionally joined to AA® via a lactam bridge; AA* is -Leu-, -Lys- optionally joined to AA® or AA via a lactam bridge, -Asp- optionally joined to AA® or AA via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; AA is .Lys- or is -Glu- optionally joined to AA!" via a lactam bridge; AA is -Aib-, -Lys- optionally joined to AA® or AA'® via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Asp- optionally joined to AA®® via a factam bridge; AA'® is -Asn-, -Glu- optionally joined to AA? via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge: AA's -GIn-, -Asp- optionally joined to AA’? via a factam bridge or -Lys- optionally joined to AA? via a lactam bridge; AA is -Thr- or is -Lys- optionally joined to AA" via a lactam bridge; AA" is .Lys- optionally joined to AA*® via a lactam bridge or -Glu- optionally joined to AA™® via a lactam bridge: AA ig absent or is -Asp-, -Phe-, -Lys- optionally joined to AA via a lactam bridge or -Glu- optionally joined to AA™2 or AA via a factam bridge; wherein the AA'® or AA C-terminus is a carboxyl group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains one or two lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof. Accordingly, in one embodiment the invention provides a compound of the formuta (1b): rl R? LA | AAZARS ARS ARS. ARC. ANT Anand ant antl aa an anti an’ 5 rAn Ewan TAA! 8 pal 9 An an?! A027 0 (1b) wherein; R is selected from: oO H Ae Oo arth no H oO NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more R? groups; RY is selected from halogen, hydroxyt, amino or Cys alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis1to 3: R' and R? are independently selected from hydrogen or a Cy. alkyl group, or together with the carbon to which they are attached join to form a Cs cycloalky! or a heterocyclyl group; S is the sequence -Glu-Nle-; T is the sequence -Phe-lle-; W is the sequence -Trp-Leu-lie-: Z is absent or is -Pro-: AA" is -NHCHRYCO-; wherein R® is selected from -(CH,),CONH,, -(CH,),COOH or - (CH,)tetrazolyl; where y is 1 or 2; AA? is -Gly-, -DAla-, -Lys- optionally joined to AA® via a lactam bridge or -Glu- optionally joined to AA® via a lactam bridge; AA3 is -Ser-Phe or -Ser-2-F-a-Me-Phe-: AA‘ is -Ser- or -Glu- optionally joined to AA® via a lactam bridge: AA’ is -Asp- optionally joined to AA? via a lactam bridge or -Lys- optionally joined to AA? or AA’ via a lactam bridge; AA® is -D-Phe-, D-a-Me-Phe or -Lys- optionally joined to AA™ via a lactam bridge; AA’ is -Asp- optionally joined to AA® via a lactam bridge, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA™ via a lactam bridge; AAS is lle or -a-Me-Leu-: AA® is -Leu-Asp- or —Leu-ACPC-; AA is -Asp- optionally joined to AA” or AA™ via a lactam bridge, -Glu- optionally joined to AA’ or AA™ via a lactam bridge or -Lys- optionally joined to AA’ via a lactam bridge; AA" is -LysR- where LysR is an N-substituted Lysine residue, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA" via a lactam bridge; AA's -Ala- or -AlB-: AA" is -Ala- or -AIB-: AA" is -AIB- or is -Lys- optionally joined to AA or AA" via a lactam bridge; AA" is -Asp- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA™ via a lactam bridge; AA is -Asn-, -ACPC-, -Lys- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; AA" is -GIn-, -ACPC-, -Lys- optionally joined to AA'® via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; AA™ is -Thr-, -Lys- optionally joined to AA? via a lactam bridge or -Glu- optionally joined to AA? via a lactam bridge; AA" is -Pro-, -PIPALA-, -Lys- or -Glu- optionally joined to AA? via a lactam bridge; AA? is absent or is -lle-, -a-Me-Leu- or -Pro-; AA?! is absent or is -Thr-! AAZ is absent or is -Lys- optionally joined to AA" or AA™ via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; wherein the C-terminus is a carboxyl group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains three, four or five lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof. All compounds described herein may contain at least one lactam bridges to internally cyclise the peptide sequence All compounds described herein may contain one, two, three, four or five lactam bridges to internally cyclise the peptide sequence. The lactam bridge can be between the side chain amino group of a lysine moiety and the side chain carboxylate group of aspartic acid or glutamic acid. Specifically the lysine can be at positions AA%, AA*®, AA®, AA®E AA AAS AATIE AATZE ANTE AAME AATSS or AAT The aspartic acid or glutamic acid can be at positions AA%, AA™, AA AA™ AA® AA%E AAO ARTE AATZ AATSE AAT or AA'®. The compounds must include one or two lactam bridges between the amino acid pairs shown below: AAZ_AA%: AAR_AAS: AAA: AAT_AARR: AAAS: AAA AA'%E_AAME. AA'Z_ AATE: AAT ANTES AAT ANTES With the proviso that the compounds at least one lactam bridges, the amino acids can be independently selected from each of the groups shown below. AA" can be -NHCHR®CO-; wherein R® is -(CH),tetrazolyl, where y is 1. AA'™ can be -NHCHR®CO-; wherein R® is -(CH,),tetrazolyl, where y is 2. AA can be -NHCHR®CO-; wherein R® is -(CH,),COOH, where y is 1. AA can be -NHCHR®CO-; wherein R® is -(CH,),COOH, where y is 2. R?® can be -CH,COOH. AA'2 can be oO H NH ~~ ZN N=pN AA can be -Asp-. AA" can be an aspartic acid residue. AA™ can be oO H H 3 ~¢° OH Q can be an imidazole ring. Q can be: ncanbe 1. ncanbe 2. ncan be 3. R' and R? may be independently selected from hydrogen or a Cy alkyl group. R' can be hydrogen or a Cy alkyl group. R? can be hydrogen or a C. alkyl group. R' and R? can both be methyl. R' can be methyl. R? can be methyl. R® can be ~CH.tetrazolyl. R® can be -CH,COOH. AA® can be -Gly-. AA® can be -DAla-. AA can be -Lys-. The lysine can optionally be joined to AA* via a lactam bridge. AA® can be -Glu-. The glutamic acid can optionally be joined to AA* via a lactam bridge. AA® can be -Ser-. AA* can be -Glu-. The glutamic acid can optionally be joined to AA® via a factam bridge. AA* can be -Asp-. The aspartic acid can optionally be joined to AA? via a lactam bridge. AA can be -Lys-. The lysine can optionally be joined to AA? or AA® via a lactam bridge. AA® can be -DPhe-. AA®® can be -Asp-. The aspartic acid can optionally be joined to AA® via a lactam bridge. AA® can be -Lys- the lysine can optionally be joined to AA® via a lactam bridge. AA® can be -Thr-. AA® can be -Asp-. The aspartic acid can optionally be joined to AA* via a lactam bridge. The aspartic acid can optionally be joined to AA®® via a lactam bridge. AA® can be -Glu-. The glutamic acid can optionally be joined to AA™ via a lactam bridge. AA®® can be -Lys-. The lysine can optionally be joined to AA® via a lactam bridge. AA can be -lle-. AA™ can be an a-methyl Leucine residue of formula: H oO CA N77 AA® can be -Asp-. AA®™ can be -Lys-. The lysine can be optionally joined to AA® via a lactam bridge. AA® can be -Leu-. AA® can be -Lys-. The lysine can be optionally joined to AA® via a lactam bridge. The lysine can be optionally joined to AA'™ via a factam bridge. AA can be - Asp-. The aspartic acid can optionally be joined to AA®® via a lactam bridge. The aspartic acid can optionally be joined to AA™™ via a lactam bridge. AA* can be -Glu-. The glutamic acid can optionally be joined to AA" via a lactam bridge. AA" can be -Lys-. AA'® can be -Glu-. The glutamic acid can be optionally joined to AA'* via a lactam bridge. AA can be -Aib-. AA'™ can be -Lys-. The lysine can be optionally joined to AA* via a lactam bridge. The lysine can be optionally joined to AA'® via a factam bridge. AA'" can be -Glu-. The glutamic acid can be optionally joined to AA® via a lactam bridge. AA" can be - Asp-. The aspartic acid can be optionally joined to AA* via a lactam bridge. AA"? can be -Asn-. AA" can be -Glu-. The glutamic acid can be optionally joined to AA™® via a lactam bridge. AA" can be -Lys-. The lysine can be optionally joined to AA'* via a lactam bridge. AA'™ can be -GIn-. AA™® can be -Asp-. The aspartic acid can be optionally joined to AA’? via a lactam bridge. AA' can be -Lys-. The lysine can be optionally joined to AA via a lactam bridge. AA can be -Thr-. AA' can be -Lys-. The lysine can be optionally joined to AA" via a lactam bridge. AA" can be -Lys-. The lysine can be optionally joined to AA™® via a lactam bridge. AA™™® can be -Glu-. The glutamic acid can be optionally joined to AA via a lactam bridge. AA can be absent. Where AA'™ is present AA™® can be -Asp-, Where AA'® is present AA can be -Phe-. Where AA'™ is present AA'® can be -Lys-. The lysine can be optionally joined to AA" via a lactam bridge. Where AA'™® is present AA can be -Glu-. The glutamic acid can be optionally joined to AA™2 or AA" via a lactam bridge. The glutamic acid can be optionally joined to AA™? or AAS? via a lactam bridge. 2Z® can be absent. Z® can be the sequence -lle-Thr-. The AA™® or AA™® C-terminus can be a carboxyl group. The AA'™® or AA C-terminus can be a carboxamide group. The AA'™® or AA™® C-terminus can be adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups. The compound can be selected from any one of Examples 82 to 117 shown in Table 1a. Compounds described herein may contain three, four or five lactam bridges to internally cyclise the peptide sequence. The lactam bridge can be between the side chain amino group of a lysine moiety and the side chain carboxylate group of aspartic acid or glutamic acid. Specifically the lysine can be at positions AA?, AA®, AA®, AA7, AAT? AA™", AA™ AA™® AAT, AA or AA, The aspartic acid or glutamic acid can be at positions AA? AAS, AAT, AA™, AA" AAS AA’ AA AAS AA" or AAZ, The compounds may include three, four or five lactam bridges between the amino acid pairs shown below: AAZAAS AASAAS AASAAT AABAAT: AAT.AAT AAT AA™M. AAT_AA™. AATAATS AAG AAT: AATBAAZ or AATS-AAZ: Exemplary compounds having three bridges include compounds having a first bridge from position AAS-AA’; a second bridge from position AA'-AA' and a third bridge from position AATS.AAZ Exemplary compounds having three bridges include compounds having a first bridge from position AA%-AA®; a second bridge from position AA’-AA' and a third bridge from position AAB.AATT Exemplary compounds having three bridges include compounds having a first bridge from position AA®-AA’; a second bridge from position AA-AA' and a third bridge from position AATB.AA2Z Exemplary compounds having three bridges include compounds having a first bridge from position AA%-AA®; a second bridge from position AA-AA' and a third bridge from position AATB.AAZZ Exemplary compounds having four bridges include compounds having a first bridge from position AA%-AA®; a second bridge from position AA’-AA; a third bridge from position AA'®- AA"and a fourth bridge from position AA'®-AAZ, Exemplary compounds having four bridges include compounds having a first bridge from position AAS-AA’; a second bridge from position AA™-AA™; a third bridge from position AA'™- AA'"and a fourth bridge from position AA'®-AAZ, Exemplary compounds having four bridges include compounds having a first bridge from position AA%-AA®; a second bridge from position AA’-AA'; a third bridge from position AA'®- AA"and a fourth bridge from position AA'®-AA%, Exemplary compounds having four bridges include compounds having a first bridge from position AA®-AA’; a second bridge from position AA'-AA; a third bridge from position AA- AA'and a fourth bridge from position AA'®-AAZ, Exemplary compounds having four bridges include compounds having a first bridge from position AA’-AA'’; a second bridge from position AA''-AA™; a third bridge from position AA.AA"7and a fourth bridge from position AA'8-AAZ, Exemplary compounds having four bridges include compounds having a first bridge from position AA’-AA™; a second bridge from position AA''-AA'; a third bridge from position AA'_AA'and a fourth bridge from position AA'8-AAZ. Exemplary compounds having four bridges include compounds having a first bridge from position AA%-AAS; a second bridge from position AA'°-AA'; a third bridge from position AA™- AA'and a fourth bridge from position AA'*-AA%, Exemplary compounds having five bridges include compounds having a first bridge from either position AA%-AA® or position AA*-AA%; a second bridge from position AA"-AA™ a third bridge from either position AA''-AA'™ or AA'"-AA™S; a fourth bridge from position AA"®-AA™ and a fifth bridge from position AA'™8-AA%, Exemplary compounds having five bridges include compounds having a first bridge from position AA2-AA®, a second bridge from position AA’-AA" a third bridge from position AA" AA™, a fourth bridge from position AA'®-AA' and a fifth bridge from position AA'6-AAZ, Exemplary compounds having five bridges include compounds having a first bridge from position AA%-AA®; a second bridge from position AA’-AA" a third bridge from position AA''- AA", a fourth bridge from position AA'®-AA" and a fifth bridge from position AA'8-AAZ. Exemplary compounds having five bridges include compounds having a first bridge from position AA®-AA®; a second bridge from position AA’-AA" a third bridge from position AA" AA™, a fourth bridge from position AA'®-AA" and a fifth bridge from position AA'8-AAZ, Exemplary compounds having five bridges include compounds having a first bridge from position AA®-AA®; a second bridge from position AA’-AA" a third bridge from position AA''- AA", a fourth bridge from position AA'®-AA' and a fifth bridge from position AA'8-AAZ, With the proviso that the compounds contain three, four or five lactam bridges, the amino acids can be independently selected from each of the groups shown below. AA! can be -NHCHR3CO-; wherein R® is -(CHp)\tetrazolyl, where y is 1. AA can be -NHCHR®CO-; wherein R? is -(CH,),tetrazolyl, where y is 2. AA can be -NHCHR®CO-; wherein R® is -(CH,),COOH, where y is 1. AA" can be -NHCHR®CO-; wherein R® is -(CH2),COOH, where y is 2. R® can be -CH,COOH. AA! can be 0 H ‘NH Se ZN N=pN AA! can be -Asp-. AA! can be an aspartic acid residue. AA’ can be uy © ~p° OH Q can be an imidazole ring. Q can be: ncanbe 1. ncan be 2. ncan be 3. R' and R? may be independently selected from hydrogen or a Ci, alkyl group. R' can be hydrogen or a Cy. alkyl group. R? can be hydrogen or a C. alkyl group. R' and R? can both be methyl. R* can be methyl. R? can be methyl. R® can be -CHytetrazolyl. R® can be ~-CH,COOH. AA? can be -Gly-. AA? can be -DAla-, AA? can be -Lys-. The lysine can be optionally joined to AAS via a lactam bridge. AA? can be -Glu-. The glutamic acid can be optionally joined to AA® via a lactam bridge. AA? can be -Ser-Phe-. AA? can be -Ser-2-Fluoro-o.-Me-Phe-. AA* can be -Ser-. AA* can be -Glu-. The glutamic acid can be optionally joined to AA® via a lactam bridge. AA® can be -Asp-. The aspartic acid can be optionally joined to AA? via a lactam bridge. AA® can be -Lys-. The lysine can be optionally joined to AA? or AA via a lactam bridge. AA® can be -D-Phe-. AA® can be -D-a-Me-Phe. AA® can be -Lys- The lysine can be optionally joined to AA via a lactam bridge. AA’ can be -Asp-. The aspartic acid can be optionally joined to AA® via a lactam bridge. AA” can be -Glu-. The glutamic acid can be optionally joined to AA™ via a lactam bridge. AA” can be or -Lys-. The lysine can be optionally joined to AA via a lactam bridge. AA® can be —lle-. AA® can be -g-Me-Leu-. AA? can be -Leu-Asp-. AA® can be —Leu-ACPC-, AA can be -Asp-. The aspartic acid can be optionally joined to AA via a lactam bridge. The aspartic acid can be optionally joined to AA via a lactam bridge. AA' can be -Glu-. The glutamic acid can be optionally joined to AA™ via a lactam bridge. The glutamic acid can be optionally joined to AA’ via a lactam bridge. AA™ can be -Lys-. The lysine can be optionally joined to AA’ via a lactam bridge; AA" can be -LysR- where LysR is an N-substituted Lysine residue. AA'" can be -Glu-. The glutamic acid can be optionally joined to AA™ via a lactam bridge. AA" can be -Lys-. The lysine can be optionally joined to AA via a lactam bridge; LysR can be an N-substituted Lysine residue, wherein the N-substituent is selected from: - CO(CH_){CHs; -CO(CH,)CO-H; -CO(CH2)qCHCH; -COO(CH,)CHs; -COO(CH,),CO.H and -COO(CH,),CHCH_; where q is 1 to 22. LysR can be an N-substituted Lysine residue, wherein the N-substituent is - COO(CHz),CHCH;; where q is 1 to 22. LysR can be an N-substituted Lysine residue, wherein the N-substituent is -COO(CH.),CHCH,; where q is 1. LysR can be an N-substituted Lysine residue, wherein the N-substituent is -COOCH,CHCH,. Lys R can be HN 0 Nyt oF LysR can be an N-substituted Lysine residue, wherein the N-substituent is a wherein L is selected from the group consisting of: Oo Oo CO.H o H 0 H 1" H ns H Mo N o Pan ; hg No ro ~N 5 pS oO 80H CoH 0 H o noo goon Amon Onli 0 o H 0 H 1 Rn FT sho Aon MA # Bd H i H Hey tt oa mr oO dh: Oo 0 Oo H o H 1 H n H Jo N No sg No foo hi < o oo o . H 00 NT H Sse shoot me N Hoot Ty 0 H o mr 0 COH o “ o COH Jodo ma fonoF iy momo o Ng 1 o H o JOT . 0 ~~ o Ay A oN Ny No “oy , : HOC © & H oo a: HH 1 i o *H yo,c o COH B San 0 COH oO EO “Di Nx and G is selected from the group consisting of: o oOo 0 eo o oO 0 COH oo 0 nn 1 3 att JA AA yor AAA com 4 OH YM oo rR \ = OH CF KH LE a EL 3 Rd . rH ard rH where mis 1 to 23; pistto3; ris 1 $0 20; sis0to3; tisQto 4; andwis0Oto4 LysR can be HN" 0 » 0 H o H HN" 0 o H H PNA mony mor Oy AN 0 + H o H Sd, HOC ASS LysR can be HN 0 0 NNN AA’? can be -Ala-. AA? can be -AlB-. AA’ can be -Ala-. AA" can be -AlB-. AA" can be -AIB-. AA" can be -Lys-. The lysine can be optionally joined to AA via a lactam bridge. The lysine can be optionally joined to AA!" via a lactam bridge. AA'™ can be -Asp-. The aspartic acid can be optionally joined to AA" via a lactam bridge. AA" can be -Glu-. The glutamic acid can be optionally joined to AA' via a lactam bridge. AA can be -Asn-. AA" can be -ACPC-. AA™ can be -Lys-. The lysine can be optionally joined to AA" via a lactam bridge. AA™ can be -Glu-. The glutamic acid can be optionally joined to AA" via a lactam bridge. AA" can be -GIn-. AA" can be -ACPC-. AA" can be -Lys-. The lysine can be optionally joined to AA™ via a lactam bridge. AA" can be -Glu-, The glutamic acid can be optionally joined to AA'® via a lactam bridge. AA™ can be -Thr-, AA" can be -Lys-. The lysine can be optionally joined to AA? via a lactam bridge. AA™ can be -Glu-. The glutamic acid can be optionally joined to AA? via a lactam bridge. AA can be -Pro-. AA™ can be -PIPALA-. AA™ can be -Lys-. AA™ can be or -Glu-. The glutamic acid can be optionally joined to AA? via a lactam bridge. AA? can be absent such that AA™ is the C-terminus. AA? can be -lle-. AA? can be -a-Me- Leu-. AAZ can be -Pro-. AA?" can be absent such that AA" or AAZ is the C-terminus. AA?! can be -Thr-. AA? can be absent such that AA™®, AA? or AA?" is the C-terminus. AA? can be -Lys-. The lysine can be optionally joined to AA™ via a lactam bridge. The lysine can be optionally joined to AA'™ via a lactam bridge. AA? can be -Glu-. The glutamic acid can be optionally joined to AA via a lactam bridge. The C terminus can be a carboxyl group. The C terminus can be a carboxamide group. The C terminus can be adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups. The compound can be selected from any one of Examples 1 to 81 shown in Table 1. The compound can be selected from any one of Examples 1 to 117 shown in Table 1 and Table 1a. Specific examples of compounds include compounds having GLP receptor agonist activity. Specific examples of compounds include compounds having GLP-1 and / or GLP-2- receptor agonist activity. Specific examples of compounds include compounds that have higher GLP-2 receptor agonist activity compared to GLP-1 receptor agonist activity. The compounds of the invention may be used in a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. The compounds of the invention may be used in medicine. The compounds of the invention may be used in the treatment of disorders associated with GLP receptors. The compounds of the invention may be used in the treatment of disorders associated with the GLP-1 and / or GLP-2 receptor. The present invention provides the use of a GLP-2 / GLP-1 analogue compound for the preparation of a medicament for treating gastrointestinal and metabolic diseases. GLP- 2 / GLP-1 analogues as defined herein may be useful for promoting intestinal recovery and nutritional status of patients with malabsorption disorders, intestinal failure, intestinal insufficiency, diarrheal diseases and chronic inflammatory bowel disorders. In addition, therapeutic freatment with a GLP-2 / GLP-1 analogue may improve mucosal barrier function, ameliorate gut inflammation and reduce intestinal permeability which could improve symptoms in patients with inflammatory disorders, celiac disease, congenital and acquired digestion and malabsorption syndromes, chronic diarrhoeal diseases, conditions caused by mucosal damage (e.g. cancer treatment). A GLP-2 / GLP-1 analogue of the present invention is anticipated to restore glycemic control and insulin sensitivity. This could be beneficial for the management of hyperglycemia during enteral and parenteral nutrition therapy in patients with intestinal failure, insufficiency or malabsorption disorders. In a further aspect, the present invention provides a methods of treating one of the group consisting of gastrointestinal injury, diarrheal diseases, intestinal insufficiency, intestinal failure, acid-induced intestinal injury, arginine deficiency, obesity, celiac disease, chemotherapy-induced enteritis, diabetes, obesity, fat malabsorption, steatorrhea, autoimmune diseases, food allergies, gastric ulcers, gastrointestinal barrier disorders, Parkinson's disease, sepsis, bacterial peritonitis, inflammatory bowel disease, chemotherapy-associated tissue damage, bowel trauma, bowel ischemia, mesenteric ischemia, short bowel syndrome, malnutrition, necrotizing enterocolitis, necrotizing pancreatitis, neonatal feeding intolerance, NSAID-induced gastrointestinal damage, nutritional insufficiency, total parenteral nutrition damage to gastrointestinal tract, neonatal nutritional insufficiency, radiation-induced enteritis, radiation-induced injury to the intestines, mucositis, pouchitis, ischemia, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), nonaicoholic steatohepatitis (NASH), insulin resislance, hyperglycemia, insulin resistance, glucose intolerance. Specifically, it is suggested that congenital diarrheal diseases which are characterised by severe diarrhoea, fluid and electrolyte loss, malabsorption and impairment of nutritional transport could be ameliorated by treatment with GLP-2 / and GLP-1 analogues of this invention. In particular, Tufting enteropathy is a condition associated with disrupted villus morphological architecture, that results in impaired nutrient absorption and enhanced intestinal permeability. Agents that can improve fluid and nutritional absorption, as well as correct the gut barrier impairment may offer value in promoting early weaning from parenteral nutrition. Other examples of congenital diarrheal diseases that may be treated with a peptide of the invention includes brush border enzyme deficiencies (congenital lactase deficiency, congenital sucrase-isomaltase deficiency, congenital maltase-glucoamylase-deficiency), defects of membrane carriers (glucose-galactose-malabsorption, fructose malabsorption, Acrodermatitis enteropathica, Congenital chloride / sodium diarrhoea, Primary biliary malabsorption, cystic fibrosis), lipid / lipoprotein metabolism defects (chylomicron retention disease, abetalipoproteinemia), defects of enterocyte differentiation or cellular polarisation (Microvillous atrophy, Tufting enteropathy, Trichohepatoenteric syndrome,) and defects of enteroendocrine cells (Congenital malabsorptive diarrhoea, anendocrinosis, protein- convertase 1 / 3 deficiency). The compounds of the invention may be used in the treatment of Tufting enteropathy. Definitions In this application, the following definitions apply, unless indicated otherwise. The term “alkyl”, “aryl”, “halogen”, “alkoxy”, “cycloalkyl”, "heterocyclyl" and “heteroaryl” are used in their conventional sense (e.g. as defined in the IUPAC Gold Book) unless indicated otherwise. The term “treatment”, in relation to the uses of any of the compounds described herein, including those of the formula (1a) and (1b), is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term “treatment” covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed. The term “effective therapeutic amount” as used herein (for example in relation to methods of treatment of a disorder, disease or condition) refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain. To the extent that any of the compounds described have chiral centres, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt. Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2- dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2- sulfonic, naphthalene-1,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L-ascorbic), L- aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (t)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L- malic), malonic, ()-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L- tartaric), thiocyanic, undecylenic and valeric acids. Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monochydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn ef al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3. The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 'H, 2H (D), and °H (T). Similarly, references to carbon and oxygen include within their scope respectively 2C, "°C and "C and ®0 and "0. In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). The isotopes may be radioactive or non-radioactive. Therapeutic dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. In general, the daily dose range may be from about 10 ug to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 ug to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 pg to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 ug to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 pg to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 pg to about 1 mg per kg of body weight of a human and non-human animal. Pharmaceutical Formulations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). Accordingly, in another embodiment of the invention, there is provided a pharmaceutical composition comprising at least one compound of the formula (1a) and (1b) as defined above together with at least one pharmaceutically acceptable excipient. The composition may be a tablet composition. The composition may be a capsule composition. The composition may be a composition suitable for injection. The injection may be intra- venous (IV) or subcutaneous. The composition may be supplied in a sterile buffer solution or as a solid which can be suspended or dissolved in sterile buffer for injection. The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicity- adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing compounds of the formula (1a) and (1b) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches. Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract. The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95%, preferably% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragées, powders, tablets or capsules. Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition typically contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers. Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-89% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils. The pharmaceutical formulations may be presented to a patient in “patient packs" containing an entire course of treatment in a single package, usually a blister pack. The compounds of the formula (1a) and (1b) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient). For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound. The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures. Biological activity The in vitro GLP-2 assay results for compounds illustrated in Table 1 were in the range from about 0.001 nM to about 1 nM. The GLP-2 analogues of the invention demonstrate activity at both GLP-2 and GLP-1 receptors, with greater activity demonstrated at the GLP-2 receptor. EXAMPLES The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. a slg ]a|e |e 4 legs y dete] 4 =| £ tee] E te] ¢ E zee] e ree =e glee s|s|s|g]s wo ow oy | oy yy | yy wo ow ow ow ow www wa y tla br nnn ese]: ¥ | t] el = |2|e 8&8 |R |N|R|(X|Q& 8&8 & | RR | R |B |5 | 8 | 88 3 = I = = = = = I EO A- | us Ys Ya |Y4> | 43 | 4> us | 4s Ya | Ya wa Ya Ya Ya ys | w= Ya §2 Y lel ge] ge| syle ly| syle l9g]y]y fu | zw | Fu Fu] Fu |Fo| Fu | Fo |Fu| Fe | Fo | Fo | Fo | Zu | ue | Fu | Fu ga 3 2< 2< 48LE 2 | sss (888888 28 ||| 28 12 (5282 l0elee lie te oe 02022) iz tage 0 2] 2 Za Yo [exe 818 [sas $22 847 [sas] gap [us] 3ap [as

[452] 353 | ar 3a | [=] 2e [z= 2x = Jom[ = [ee [om [2m [oe [on [ze | 2: | [eee] elee]elelelel eel] ss gaa) e es [s]m]s ss ]e]s]s]2] re | = Tor Jap] op vu sa ecb dis becbecaleceepcbebed gy [gleeful eleu[elolelslalulely | se Tor or oer Toe | soe [oe Lo [oe [oe or] oe [= [ee [oe [en [ee] oe [men ee [en] mn [ee en [oe [on [on [=e [oe | EB s[nlEue Gene GEE 5s g [ea ]u]y]y] [als TeleTalalalaly Be | ge | ge [ee] ae [oe] BEER EERIE ze [ge ze [oe] 2e [oe] 2s [ae [ae] me [2e | 2a [2o [oe

[488] zo | 4: | Ble ae a ole ieee nln =< 2< | I< [2<] #< [2] < #< [ae] =< 2< | d< | d< | d< | de | I< | F< ex [we [ee [ae] we [ae] ee [ee [ae] te [ae | ae ae [2e [2s [= | 2e exile |x [see] ow [s]s fe se mes] Bese nlnnn snes ss eee lolele ele jwfele lee feel] To Tooele [so oe ee To To [oe [odo [so odo 2 | 2 |) [a |e |ofe|ode of) 2 lo e [oge) su 3 89 i gz Za 3 | § | 8 [eg |egefegm| 2 | 2 3) 8 [4 [2 egm|ege edz] 2 [8] 8 [ego] 2] tlre n[nlnsenle] enunn | ot [4g] of [og] ar [or] op [or [op] ap [or | ator |ar]ot] or] wo | go | gu [au] ge [au] aa | we [du] du [ae | gu | au | ge [du [ae | ae | ¥s | as | 2s

[32] 82

[32] 52 | 3= [a3] 30 [32 30 32 [32 [32 | 32 | 52 | . : | #e [w= [ox [ux] ue [un a= ge [ue um [ue |e [ue [ae [un [0m [ae KE ENE ENNEREE EA a AE EE ER EE EES bts ds loads [od 8 [Be [oa] [0 [8 [5 | 5 [ot] e(efelelelelelelelele oleae] tlafefe]afselsslelale slalele]s]|s] zo | za zo | | | HE zo | 20 | zo | za a ss |s|s|e|s|e|e|ls|ele|z|a]le]|s]s gg lplele|l ¢&¢ eg lelel 2g pg | Bg |B |g 8g |g Woow yyy [ow Woy | yoy Woy ow oy ow wow Yo wo ow www] ow ow www www ww wu Fw | Fw | Fu | Fw | Fw | Fw | Fu 9a | 92 | Ye | 92 | 92 | 92 | Yo fo | $2 [$2 fe |8e Be | Hi 2< | d< | F< | #< | d< | F< | F< 2 Ys Yow ly wud ago | ago | Y (age Y 5 | 8 | ¢ | ¥ | E| ®B ® |E a¥ | a | al | a | WH | gE | gk El tu | ge |g su de | || ds | 22 | g> | g>2| E> | d> | @= 5 | § ¥ > x3 Ga Sx | 8 Fo 8 |g |slg / 8] 5&5 B88 B|8| 8 8&8 |3|3|8 | 8 & |8 Ya | Yo fo | fe |8¢|¢ |Be|e Be ¢ [fgg [88 sus [gan] gun [ us [a03

[533] 09a

[892] 832 82 [432 [893 [z= [oe [=] #= [on [ze [om] on [on [2 oe [2a [2x | |elelele se|e|s|s|e eles] FF rs oo 2 4 4 4 4 4 2 g 4 4 2 4 4 4s Ya =] Ya Ea EE EE] EE] Be Ya | 4a EE] | [ze (ellen [en [ee Joc fee [2 [oo [re onze [oe | ee eo] 3 4 4 4 4 4 4 4 4 4 4 4 4 4 go ge [me | ge | Ee me ge | me |e [Ee Ee Ee | me ge | 2a | ge | 2s | go | ge 20 2: [83s] 2 [$5 lee eee as $ g < | 2< | E< i= q< F< | << | d< | d< | F< | F< | F< | F< 2< | 2< [2 | ae | ae | ae | de | ae | ac | ac | ae | 2c | ae | ae] ac| es |e builtin 2 B28 ene fio 0 000 ne ee EE | [22 [2a [4a | ue fuse |e [ua [us [us | us so | se ego) oie [ge | a le leu lye aly] a¥ | ad rele): of |B BB BEB BE sop |ox| or | of [ara] te] ore] so [ge [| gu | gu [gu | gu] a du | du | du | gu 2 | a> | @» fo do Be) fo Bo BB bt EE EY a= [ue [ue | ux | ue [we [ae [$93

[892] a= | ue

[332] 80 e |e oe] sew Teel elelele|e]| #s | 32 3 | 32 do 82 [4a] 92 [= 82 | 82 [82 | en | BEER RB ENNCOCNN [#= [oe [=| w= [ux [ue [a= [a82]a8] 5 | o- [a5o]083 Cala eee Te oe Loe [oe [oe [ow [oe EEEERIEERREENE exon [er [er [en Je [oe [a2 [or [om [or [er wel lo [o [eas awn ole] Eo Zn Ew Ew 8s elr| nx e|x|e|e|r|r]e]s]s ®#8%% 0% 80% 58s uBelnls ¥en ay Bley isle elle [Hp] [paler pelp cpa 2x pale elraleapalaalrulze pola] 2a [rufa] 7e [2e 2x [2x] (al=] esa a]e ale [a]sfafslaleelas 2 2 fala]e]e]z [2] |B ro 883 no] lne nologies olor fo lo a8 oe $5388 52 53 Rlelelelee / eieielz eles e ele eee [xe] e 2 ]¢] ns] 5 |a]a)s 55 a] x [a]a]sa]s]z]s[smme 5 [a]s]5 2 i]s [nl] []afelalalu] x [alalu]slalu]elals]aa]ule]z ys] lor bbb oe] lc a a a od ae mE EM ER EN =e] e gle axe ee e[e[e[a)a)a saan nee] e |e es (R|=[ 8 [oss a]e als [a]sfafsfafsefas 2 a fas]e]e]:]s] [Aen joule p-le le ole ea jeulefeule pulelenlee pula oe feufen 2 [2a 2a

[20] [AiJee] 2 [ae]ae zeae ine ge] ae gangs gelaorela ge ae 2 faafae ae [an [2 22] 2s |= [sles ]s]e tx [spose pee x x Japale |x 8e)ae [Je] te aac ze mcr ae acfeclefacleclaciacfa ae a ae pee] ze [ac aca] [8 Jae] [acfaefeela lela] 2 aafafeslecfeslacfelaczac] ae feee]ze [ae 2 [2] nlelelelelelelele] x elele]e]e]e else ex [eee Je x |2]2|2 |2|2 2 grata = jtaala | pape 2 pepe 2 1a ale alafafelairnanjaaalannalanenfaaale oj EE Ee Foo ot ce dc od ES Ee El a t| 4 |2]2]2]e]2 1 y |2]2|2|2|2]e]2]2|2[¢] 3 HE y 4 | tx] |i] [o[sn]e wane nee oe |e me x x x [ns ae 1 | 1 Ca ed al Re ee be

[82] s=lg=le=le = 8=la=] d= [¢=s=[s=]e==la=lt=la=la=1o=] 4= [gala] a [d= = = ele pre nn ala fafalalalalalaann a faalte]e us) cd ca ed om dl Cd Cc lc lc coc co ccc cc ll Ed 8 ||] 8 [seu sss aa [afa[s[s[s[e[s]s as] [s[s[se] a [5 [5] 8 [mle]er rele elated] on frledleslae-efecanleclad a felon [or g[n[elo-lefele ieee] x lmle[eeipslele[e 2 2 [ale] [an ana) Bo] Jefeleefelee] [e]efe] | [e]e]efe]efele[e] 1 [| Blg|alalalelsalals|s|alals|s|s|a|als zs a|z|a|z|s 2s 2 rl “i o & 9 a oT ZT 2 z={ ‘=o & zx ~ Sell Ye ee = 1 NN, 2 Ss He T SL = . 4 Yr = a CX # Oo ¢ 5 KX ot - DT a NY oy I LB oA HEHE EERE 37 / a x, rz = y.8 o= 2T / Zz Cc \ E \ =o go F o x , ° > A= 2 Tz oO / Oo HA 2 A A C © oO o={ ZT 7 NX - Z— So x T 08 < eX TI zx > a. Zt Nir os 8 < -£ zT 3 : : : o° =z | | —a =0 ZL = he i [=> © i; © z oN 5 ud x ot. S QO He QQ = fo) a Zz" a = a 5 «% 5 £5 § KH | oe =| To | =f ex Wad I eX F ol | Bo Sx © QQ o=_ [] o= Q Fa QQ a F TB 1A IN a =o a fF 0H FX 5 or 8 £ LE 2 £ EE EE ot 1 z “~ Ta Lg General procedures Where no preparative routes are included, the relevant intermediate is commercially available. Commercial reagents were utilized without further purification. Room temperature (rt) refers to approximately 20-27°C. 'H NMR spectra were recorded at 400 MHz on a Bruker instrument. Chemical shift values are expressed in parts per million (ppm), i.e. (8)-values. The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt= triplet of triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets, ddt=doublet of doublet of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using 60 — 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. Analytical Methods LCMS analysis of compounds was performed under electrospray conditions. LCMS Method A Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1 x 100 mm; Gradient [time (min) / solvent B in A (%)]: 0.00 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10; Solvents: solvent A = 0.1% trifluoroacetic acid in water; solvent B = acetonitrile; Injection volume 1pL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL per min. LCMS Method B LCMS: Agilent 1200 HPLC&6410B Triple Quad, Column: Xbridge C18 3.5 ym 2.1*30mm. Gradient [time (min) / solvent B(%)]:0.0 / 10,0.9 / 80,1.5 / 90,8.5 / 5,1.51 / 10. (Solvent A=1mL of TFA in 1000 mL Water; Solvent B=1mL of TFA in 1000 mL of MeCN); Injection volume 5 pL; UV detection 220 nm 254 nm 210 nm; Column temperature 25°C; 1.0 mL / min. Analytical Method C MS ion determined using LCMS method below under electrospray conditions, HPLC retention time (Rr) determined using HPLC method below, purity > 95% by HPLC unless indicated. LCMS: Agilent 1200 HPLC&6410B Triple Quad, Column: Xbridge C18 3.5um 2.1*30mm. Gradient [time (min) / solvent B(%)]:0.0 / 10,0.9 / 80,1.5 / 90,8.5 / 5,1.51 / 10. (Solvent A=1mL of TFA in 1000 mL Water; Solvent B=1mL of TFA in 1000 mL of MeCN); injection volume 5 uL (may vary); UV detection 220 nm 254 nm 210 nm; Column temperature 25°C; 1.0 mL / min. HPLC: Agilent Technologies 1200, Column: Gemini-NX C18 5um 110A 150"4.6mm. Gradient [time (min) / solvent B(%)]:0.0 / 30,20 / 60,20.1 / 90,23 / 90. (Solvent A=1mL of TFA in 1000 mL Water; Solvent B=1mL of TFA in 1000 mL of MeCN); Injection volume 5 pL (may vary); UV detection 220 nm 254 nm; Column temperature 25°C; 1.0 mL / min. Analytical Method D Instrument: Thermo Scientific Orbitrap Fusion; Column: Phenomenex Luna Omega C18 100 A, 1.6 ym, 2.1 x 50 mm; Gradient {time (min) / solvent B in A (%)]: 0.00 / 10, 0.30 / 10, 0.40 / 60, 1.10 / 90, 1.70 / 90, 1.75 / 10, 1.89 / 10, 2.00 / 10; Solvents: Solvent A = 0.1% formic acid in water; Solvent B = 0.1% formic acid in acetonitrile; Injection volume 5 pL; Column temperature 25 °C: Flow rate 0.8 mL / min. Synthesis of Intermediates and Compounds The following examples are provided to fllustrate preferred aspects of the invention and are not intended to limit the scope of the invention. Synthesis of Intermediates Alf Fmoc-amino acids are commercially available except for intermediates 1, 2 and the Fmoc-cyclic peptide building blocks (intermediates 3 to 21) Synthesis of 2,2-dimethyi-3-0x0-3-{{2-(1-trityl-1H-imidazol-4-yi)ethyl)Jamino}propanoic acid (Intermediate 1) 1. Ethyl trifiuoroacetate, EtsN. MeOH. 0°Ctort, 4 h NN A IF ds OC =, NS 2 3 oO etate, “= 4h ~ | oT of. mem, F eOH, 0°Ctort, — NRA ! “ro Step-2 | 2 en ” o ni Mel, KoCOa, ACN, reflux, 10h on = Too 5 NY = i 5 Ny pe JT {ToS steps EN, tcluene, 75°C, 3h o 0 - | Too | : py a wa WE ea Ng HN TH Log 8 Step-4 Se? YN ~ NY, Ny =O =C Oy-oH {HC HN {oe Intermediate 1 Step-1: Synthesis of 2,2,2-trifluoro-N-(2-(1-trityl-1H-imidazoi-4-yl)ethyl)acetamide (2): To a solution of 2-(1H-imidazoi-4-yl)ethan-1-amine dihydrochioride (1, 25.0 g, 136.6 mmol) in MeOH (100 mL), EtsN (67 mL, 464.4 mmol) was added at rt and the reaction mixture was cooled to 0 °C. A solution of ethyl trifluoroacetate (20 mL, 164.0 mmol) in MeOH (50 mL) was added to the reaction mixture over 30 min at 0 °C and the reaction mixture was stirred at rt for 4 h. This reaction mixture was diluted with dry DCM (200 mL) and Et;N (60 mL, 409.8 mmol) and the reaction mixture was cooled to 0 °C. Tr-Cl (76 g, 273.2 mmol) was added portion wise and the resulting reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was quenched with water (300 mL) and the aq layer was extracted with chloroform (3 x 150 mL). The organic layers were combined, dried (Na;SO.) and concentrated in vacuo. The crude residue was triturated with n-hexane to give 2,2,2- trifluoro-N-(2-(1-trityl-1H-imidazol-4-yl)ethyl)acetamide (2, 50.10 g, 81%) as a white solid. MS (ESI +ve): 450 H-NMR (400 MHz; CDCl,): 52.75 (t, J = 5.9 Hz, 2H), 3.60 - 3.65 (m, 2H), 6.61 (s, 1H), 7.08 - 7.15 (m, 6H), 7.31 - 7.38 (m, 9H), 7.40 (s, 1H), 8.41 (bs, 1H). Step-2: Synthesis of 2-(1-trityl-1H-imidazol-4-yl)ethan-1-amine (3): To a solution of 2,2,2-trifluoro-N-(2-(1-trityl-1 H-imidazol-4-yl)ethyl)acetamide (2, 50.0 g, 111.3 mmol) in THF (150 mL) and MeOH (180 mL), NaOH (22.0 g, 556.7 mmol) in water (100 mL) was slowly added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was quenched with water (300 mL) and the aq layer was extracted with chloroform (3 x 150 mL). The organic layers were combined, dried (Na,SO,) and concentrated in vacuo to give 2-(1-trityl-1H-imidazol-4-yl)ethan-1-amine (3, 34.0 g, 86%) as a yellowish sticky solid. The crude residue was used for the next step without further purification. MS (ESI +ve): 354 H-NMR (400 MHz; CDCl): & 1.53 (bs, 2H), 2.65 (t, J = 6.5 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 6.58 (s, 1H), 7.11 - 7.16 (m, 6H), 7.26 - 7.38 (m, 10H). Step-3: Synthesis of 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (5): To a solution of 2,2- dimethyl-1,3-dioxane-4,6-dione (4, 20.0 g, 138.8 mmol) in ACN (200 mL), K.CO; (96 g, 694.0 mmol) and Mel (26 mL, 416.6 mmol) were added at rt and reaction mixture was refluxed for 10 h. After completion, the reaction mixture was cooled to room temperature, filterd through a pad of celite, washed with EtOAc (3 x 50 mL). The organic layer was washed with 10% aq Na,S,03 (100 mL), dried, (Na,SO,) and concentrated in vacuo to give 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (5, 21 g, 88%) as a yellow sold. The crude residue was used for the next step without further purification. H-NMR (400 MHz; CDCly): 51.63 (s, 6H), 1.73 (s, 6H). Step-4: Synthesis of 2,2-dimethyl-3-0x0-3-{(2-{1-trityl-1H-imidazol-4-yl)ethyl)amino) propanoic acid (Intermediate 1): A solution of 2-(1-trityl-1H-imidazol-4-yl)ethan-1-amineto (3, 8.0 g, 22.6 mmol) and Et;N (16.0 mL, 113.0 mmol} in toluene (100 mL) was added drop wise over 60 min to a solution of 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (5, 5.8 g, 29.76 mmol} in toluene (50 mL) at 75 °C. The reaction mixture was further stirred at same temperature was 3 h. After completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (100 mL) and washed with 10% aq citric acid (pH ~ 6 - 6.5). The organic layer was dried (Na,SOs) and concentrated in vacuo. The crude residue obtained was triturated with hot chloroform (150 mL} and n-hexane (75 mL) and the suspension was stirred at rt for 16 h. The solid was filtered, washed with chloroform : n- hexane (1:1, 2 x 50 mt) and dried in vacuo to give 2,2-dimethyl-3-ox0-3-((2-(1-trityl-1H- imidazol-4-yl)ethyl)amino)propanoic acid (Intermediate 1, 6.8 g, 64%) as a white solid. LCMS (Method A): m / z 468 [M+H]" (ES), at 5.38 min, 99.31% "H-NMR (400 MHz; DMSO-ds): 51.21 (s, 6H), 2.57 (t, J = 6.8 Hz, 2H), 3.22 - 3.27 (m, 2H), 6.66 (s, 1H), 7.06 - 7.11 (m, 6H), 7.28 (s, 1H), 7.35 - 7.42 (m, 8H), 7.64 (t, J = 5.4 Hz, 1H), 8.31 (s, 1H), 12.44 (bs, 1H). Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-trityl-2H-tetrazol- 5-yl)propanoic acid {intermediate 2) toluene, reflux, 15min N pemrzh Step-1 NY ~ Step3 p- NY Step-2 mou? sepa CN TMSN;, (BukSnO, toluene, reflux, 15 ri Foc, OH —————— NY Step-2 Q DCC. Py, ~ 0°Cton, NH: sn Fmoc N OH Step! 0 N=N i, NH Tec EN in N pom'm2h i OH “eps 8 8 8 Intermediate 2 Step-1: Synthesis of (S)-2-(({{9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- cyanopropanoic acid (7): To a suspension of (({SH-fluoren-8-yl)methoxy)carbonyl)-L- asparagine (7, 50.0 g, 423.7 mmol) in pyridine (200 mL) was added DCC (34.0 g, 466.1 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was carefully quenched with aq. 2N HCI tiff pH became acidic and extracted with diethyl ether (3 x 500 mL). The organic layers were combined and washed with brine, dried (Na,S0,) and concentrated in vacuo. The residue was triturated with pentane to give (S)-2- (({(9H-fluoren-9-yl)methoxy)carbonyl}aminc)-3-cyanopropanoic acid (7, 96 g, 68%) as a white solid. MS (ESI -ve): 335. "H-NMR (400 MHz; DMSO-d): 52.85 - 3.05 (m, 2H), 4.22 - 4.39 (m, 4H), 7.33 {t, J = 7.6 Hz, 2H), 7.42 {t, J = 7.6 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H). Step-2: Synthesis of (S)-2-({{(9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2H-tetrazol- 5-yl)propanoic acid 8: To a suspension of (S)-2-((({(9H-fluoren-9- yi)methoxy)carbonyl)amino)-3-cyanopropanoic acid (7, 48.0 g, 142.8 mmol) in toluene (50 mL), dibutyltin oxide (21.0 g, 85.6 mmol) was added and the reaction mixture was stirred for 15 min. To this reaction mixture trimethylsilyl azide (61 mL, 422.8 mmol) was added and reaction mixture was refluxed at 120° C for 15 min. After cooling the reaction mixture to room temperature, the resultant solid formed was filtered and washed with diethyl ether. The solid residue was triturated with 5% MeOH / DCM (500 mL) to give (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(2H-tetrazol-5-yl)propanoic acid (8, 32.5 g, 60%) as an off white solid. MS (ESI +ve): 380 H-NMR (400 MHz; DMSO-ds): £3.22-3.41 (m, 2H), 4.18 - 4.28 (m, 3H), 4.41 - 4.48 (m, 1H), 7.31 (t J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H). Step-3: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-{2-trityl-2H- tetrazol-5-yl)propanoic acid (Intermediate 2): To a solution of (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(2H-tetrazol-5-yl)propanoic acid (8, 12 x 5 g, 12 x 13.0 mmol) in DCM (12 x 456 mL), Et;N (12 x 5.6 mL, 12 x 39.0 mmol) was added at 0 °C. After stirring for 5 min, trityl chloride (12 x 4.0 g, 12 x 14.0 mmol) was added and the reaction mixture was stirred at the same temperature for 2 h. Reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 100 mL) (12 times). The organic layers were combined and washed with brine, dried (Na,SO,) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 1% to 5% methanol in DCM] to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-trityl-2H- tetrazol-5-yl)propanoic acid (Intermediate 2, 41 g, 41% ) as a white solid. LCMS (Method A); m / z 620 [M-H]* (ES"), at 5.99 min, 86.85% "H-NMR (400 MHz; CDCls): 53.44 - 3.62 (m, 2H), 4.12 - 4.20 (m, 1H), 4.25 - 4.32 (m, 1H), 4.36 - 4.44 (m, 1H), 4.82 - 4.88 (m, 1H), 7.02 - 7.12 (m, 6H), 7.24 - 7.32 (m, 11 H), 7.34 - 7.42 (m, 2H), 7.44 - 7.48 (m, 1H), 7.49 - 7.58 (m, 2H), 7.74 (d, J = 6.6 Hz, 2H). Used in solid phase peptide synthesis without further purification Method for the synthesis of Fmoc-cyclic peptide building blocks, Exemplified by the Synthesis of Intermediate 8, Fmoc-[Asp-lle-Leu-Lys] 1) Add DCM to the vessel containing CTC Resin (3 mmol, 3 g, 1.0 mmol / g) and Fmoc- Lys(Alloc)-OH (1.35 g, 3 mmol, 1 eq) agitate with N, bubbling. 2) Add DIEA (4.0 eq) dropwise and agitate with N, bubbling for 2 hours 3) Add MeOH (3 mL) and agitate with N, bubbling for 30 min. 4) Drain and wash resin with DMF (5 times, drain between each wash). 5) A solution of 20% piperidine in DMF was added and resin agitated with N, bubbling for 30 min. 6) Drain and wash with DMF (5 times, drain between each wash). 7) Add Fmoc-amino acid solution (3.0 equivalents in DMF) and agitate with N, bubbling for 30 seconds, then add activation buffer (HBTU (2.85 equivalents) and DIEA (6 equivalents) in DMF), agitate with N; bubbling for 1 hour. 8) The coupling reaction was monitored by ninhydrin test 9) If required repeat steps 6 to 8 for same amino acid coupling if inefficient coupling occurs 10) Repeat steps 3 to 8 for next amino acid coupling. Note: for the acids in the table below different protecting groups and / or coupling agents were used Amino acid site from resin Materials Coupling reagents Amino acid site from resin Materials Coupling reagents 2 Fmog-Lys(Alioc)-OH (1.0 eq DIEA (4.0 eq 4 Fmoc-Glu(OAlf)-OH (3.0 eq HBTU (2.85 eq) and DIEA (6.0 eq Peptide sidechain deprotection cyclisation: 1) Add DCM to the resin and agitate with N, bubbling, then add PhSiH; (10 eq), Pd(PPha)s (0.2 eq) agitate with N for 15 mins for 3 times. 2) The resin was washed with DCM three times and then DMF three times. 3) The resin was washed with 0.5% Sodium diethyidithiocarbamate trihydrate DMF and 0.5% DIEA in DMF for ten times. 4) HATU (2 eq) and DIEA {4 eq) was added to the resin in DMF and agitate with N; bubbling for 1 hour. 3) The resin was washed with MeOH three times and dried in vacuo. 4) The resin was added to a solution of 20% HFiP / 80% DCM and stir for 30 mins, filtered and repeated. 5) Organic layers were combined and the solvent was removed in vacuo. 8) The peptide was washed with H,O twice. 7) Peptide re-dissolved and lyophilize fo give Intermediate 8 (1.5 g, 55.6% yield) as a solid. Intermediates 3 to 21 were synthesized using the above procedure, analytical data is given below: Structure ESI (LCMS Method B) 2 OH 3 oH HY Mass not observed Intermediate Structure TG pe NEN Le A, So 3 Cla Ne pag EI 0 ay B% i Ha 833.3 [M-tBu+MeCNJ’ EE #0 © I y 0 Foc” “NN 0 : HN A Xr oH HN So on On Te Mass not observed oH HN So NP “rte crt: eee eo P——e as 991.7 [M-HY LI Gm NR a BE (2 3 orn dw TER hn PA hl ‘Nr 7% 692.1 (M+H]" | a Sa a) oO =O HN Ny f So ed. 977.8 [M-HI A onl Sn Hin = He wr > Nn en re _— FL 7 ot fs ] 898.7 [M-HT Bu H - Bt Swit OY ie = PENH GN NS tBu 977.7 [M-HJ 0 Bh Q 3 Ia lt & is) 0 a | wound { SN 930.7 [M-HJ' oy ” 2 NH WS Ng Or ~ pL ¥ Vaio “Bu Cu 3 A 3 end < A oy A . ons apd Se 977.7 [M-H}' r 'S) * ea ~ i Oy Ny 50s) Y 821.7 [M-HY =1 oo Q - 009 ed ~L | ©: ®))~aNH { Ji ow ho QQ NH | a is Hy Ue a - 00 I wr = 00 = Nyy od nF } Ndi Ja yd SE FE & ay 0 OH Toh ow ~ oF 912.7 [M-HY 835.6 [M-HI” & pd vu ST | 7 od Ne 7 948.7 [M-HJ’ pe PEN toy 0 SS a SA 3 HN 2 0 $s | PE 912.7 [M-H] Sy PY Nh I 7 § 5 OS A) 0 a W— ot, et TES 3 ¢ - Ee 8 835.6 [M-H oly wpe LD | ol’ Frege i 7 18 | £.3 = io 048.7 [M-HJ 5 oo ALS - H Neds So Apt pa Hp Th od TRL O NEE Ls io 8 or | = 8 x es — Ll N} Ya 19 Cow {M0 VE 862.7 [M-HI" 10 | PHL ~X o={ Mn - oo m / N fa! os enNP Jong lo a ~ Y _ 0 | o=g, En “A Wa HN NA / J Res 9 Np pl 20 IS Jef md 749.6 [M-tBu+MeCN]" 5] Re Nols @ 8 o 4 ‘a rel Be oC JN » Lo om =. ow Sw 21 FEATS #0 Ay 913.7 [M-HY 20 | Synthesis of Examples 1-81 Standard Fmoc solid phase peptide synthesis (SPPS) was used to synthesize the peptides which were then cleaved from the resin and purified. General method for Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry. Method a — Exemplified by the Synthesis of Example 1 Peptide Synthesis 1) Add DCM to the vessel containing Rink Amide MBHA Resin (sub: 0.35 mmol / g, 0.15 mmol, 0.42 g) and swell for 2 hours. 2) Drain and then wash with DMF (5 times, drain between each wash). 3) A solution of 20% piperidine in DMF was added agitate with N; bubbling for 30 min. 4) Drain and wash with DMF (5 times, drain between each wash). 5) Add Fmoc-amino acid solution (3.0 equivalents in DMF) and mix for 30 seconds, then add activation buffer (HBTU (2.85 equivalents) and DIEA (6 equivalents) in DMF), agitate with N; bubbling for 1 hour. 6) The coupling reaction was monitored by ninhydrin test 7) If required repeat steps 4 to 6 for same amino acid coupling if inefficient coupling occurs 8) Repeat steps 2 to 6 for next amino acid coupling. Note: for the acids in the table below different protecting groups and / or coupling agents were used Step Materials Coupling reagents 1 Intermediate 5 (2.0 eq) DIC (2.0 eq) and HOBT (2.0 eq) 1 Intermediate 4 (2.0 eq) DIC (2.0 eq) and HOBT (2.0 eq) 15 Intermediate 3 (2.0 eq) DIC (2.0 eq) and HOBT (2.0 eq) 20 Intermediate 2 (2.0 eq) DIC (2.0 eq) HOBT (2.0 eq) 21 Intermediate 1(1.5 eq) DIC (1.5 eq) HOBT (1.5 eq) 9) The resin was washed with DMF five times and MeOH three times and dried in vacuo. Peptide Cleavage and Purification: 1) Add cleavage buffer (92.5%TFA / 2.5%EDT / 2.5%TIS / 2.5%H,0) to the flask containing the side chain protected peptide on resin at room temperature and stir for 3 hours. 2) Filter and collect the peptide solution. 3) The peptide is precipitated with cold tert-butyl methyl ether and centrifuged (3 min at 3000 rpm). 4) Residue washed with tert-butyl methyl ether (2 times). 5) Crude peptide dried under vacuum for 2 hours. 6) The crude peptide was purified by prep-HPLC. Prep-HPLC Conditions: Instrument: Gilson 281. Solvent: A - 0.1% TFA in H20, B - acetonitrile, Column: Luna C18 (200x25 mm; 10 um) and Gemini C18 (150*30 mm; 5 um) in series. Gradient [time (min) / solvent B (%)]:0.0 / 25, 60.0 / 55, 60.1 / 90, 70 / 80, 70.1 / 10, at 20 mL / min with UV detection (wave length = 215 / 254 nm). Residue was re-purified by prep-HPLC. Prep-HPLC Conditions: Instrument; Gilson 281. Solvent; A - 0.08% NH,HCO; in H,O, B - acetonitrile, Column: Luna C18 (200%25 mm; 10 um) and Gemini C18 (150*30 mm; 5 um) in series. Gradient [time (min) / solvent B (%)]:0.0 / 20, 60.0 / 55, 60.1 / 90, 70 / 90, 70.1 / 10, at 20 mL / min with UV detection (wave length = 215 / 254 nm) and then lyophilized to give Example 1 ((65.7 mg, 11.6% yield). Table 2 - HRMS and LCMS properties of purified peptides represented by Examples 1-81 ~ HRMS LCMS / HPLC Example | (Analytical Method D) (Analytical Methoc (Analytical Method B) (Analytical Method D) HRMS (HESI / FT) m / z: [M+3H]"" Calcd for 4 HRMS (HESI / FT) m / z: [M+3H["" Calcd for oo i 1 C175H267N46048 377.9631; Found 1259.6610 | M2 1259.9 IM¥3HI™, Ry = 12.66 min 2 ND miz 1264.7 [M+3H[", Rr = 12.64 min HRMS (HESIFT) miz: [M+3H[" Calcd for = ; 8 C165H251N42042 3489.8562; Found 1164.2059 | M / Z 8734 [M#4HI™, Rr = 12.54 min HRMS (HESI / FT) miz: [M+3H[™" Calcd for rll i 4 C178H273N44049 3807.9988; Found 12703432 | M / Z 953.1 [M#4HI™, Ry = 10.95 min HRMS (HESIFT) mlz: [M+3H” Calcd for regi i $ C165H252N39044 3480.8445; Found 161.2013 | M / Z 871.4 [M#4HI™, Ry = 11.41 min HRMS (HESIFT) m / z: [M+3H” Calcd for a } 6 C182H27ONAB044 38100774; Found 12710360 | ™2 12712 IM+3HI", Ry = 12.61 min | HRMS (HESI / FT) miz: [M+4H]™ Calcd for me } C183H281N45043 3793.0872; Found 949.5311 | M2 949.7 [M#4HI™, Ry = 11.55 min —£183+281145043 3703.0872; Found 949.5311 | — 8 | _ HRMS (HESIFT) m / z: [M+3H]" Calcd for | occ @maiatn® R= 1289 min HRMS (HESI / FT) m / z: [M+3H]™ Calcd for PR ; 8 C178H271N46048 3817.9944; Found 1273.6759 | M / Z 9556 M+4HI™, Rr = 12.99 min HRMS (HESI / FT) m / z: [M+4H|™ Calcd for me } 9 C211H329N49060 4505.3887; Found 127.3612 | M / Z 1127.6 [M+4HI™, Rr = 9.04 min HRMS (HESIFFT) m / z: [M+4H]" Calcd for a } 10 C213H334N50050 4537 436; Found 11361217 | M2 11344 M+4HI", Ry = 14.68 min | 44 | _ HRMS (HESIFT) m / z: [M+3H]™ Calcd for | aco 0 tmeali®™ R. = 12.88 min 13 14 15 18 17 18 19 20 21 22 23 24 25 28 27 28 1 | C17711260N46048 3805.9788; Found 1269.0047 | M / Z 9520 IM+HI", Rr = 12.88 min 12 a Iu Rr apes | 29522 [MHI Re = 13.30 min 13 ce a Four too aga | 29729 [M+4H[*, Rr = 15.46 min 18 | C1771 1260NAOAS 9803.0788: Fauns 960.0040 | M2 8521 IM+4HI®, Rr = 12.84 min 5 | crn. I Taragrag | mz 9600 [M+4HI", Rr = 13.02 min 18 | Co7atiorINdBO4E 9617 9044. Fauna 1275.6750 | M2 9654 MHHI", Rr = 14.16 min 17 | C16611259N42043 9516.8067. Found 1 174.080 | M2 8812 M+4HI", Rr = 12.15 min 18 Ge SD lo113 | M2 1281.2 M+3HI™, Rr = 11.48 min | Bo ai Tagssess | M2 12858 MAHI", Rr = 11.48 min 20 I ae rit] oo es peoa | Miz 11402 M+4HI", Rr = 13.89 min | 21 | CanliooiNG9045 10.8652, Fauna 1171 3046 | M2 11718 MAHI", Rr = 7.67 min 2 | rr ronaron Son Oe Fo taraarg | M2953 MHI", Rr = 11.98 min BD | raison STs ther Four 1aea aaa? | M2 989.7 M+4HI®, Rr = 10.03 min 2 | Craprenaron aes Onn Foun 1aam ote | M2 9823 MHI", Rr = 12:34 min B | curr. a Taga asag | 29643 [M4 Re =4285, my Bo = Sasosa1o | mz 608 BH Rw Rain 21 | CigrirorninOs 578M Fauna 11756413 | M2 11780 MAHI, Rr = 11.86 min | | OH Calo 5 | ™2 1176.3 MY3HI™, Ry = 12.22 min | HRMS (HESI / FT) m / z: [M+3H]" Calcd for TIEN Weg \TTAADIfE" TJ VIE LIVIVIET]. Nd TG AAJ C165H249N38045 3479.813; Found 1160.9532 | miz 1161.3 [M+3H]*, R; = 14.38 min | HRMS (HESI / FT) m / z: [M+3H]" Calcd for ND C171H261N40046 3607.908; Found 1203.6500 | miz 1204.0 [M+3HI™, Rr = 11.61 min | “ND miz 1182.3 [M+3H[", Ry = 8.67 min C1GBL25TFNE0AS 3055.8766, Found 1186303 | M2 11872 M+3HIY, Rr = 8.11 min ND miz 1177.3 IM+3H]", R; = 9.80 min bu I iors: | mz 1061.8 [M#3HI™, Ry = 8.16 min CI nT. AFBI: Fours Teo0a4s0 | M2 10659 Ms3HI®, Rr = 7.76 min C1B7MISTN30AS 3524 8708. Foun B82 2315 | M2 1176.4 IM+3H. Rr = 11.88 min | Ce Jose Top Fru arta 18 miz 1180.4 [M+3HI™, Rr = 11.14 min | CATBI270NASO47 756.0085: Foun 1283.3406 | ™2 $48.0 IM+HI", Rr = 14.16 min C18D11780NA3048 3835-00517 Founa 1276 8057 | ™2 969.6 IM+HI', Rr = 1275 min C1801275N46046 38140356, Found 1272.3564 | M2 9546 M+4HI, Rr = 12.96 min C1621279N46046 3842 0671 Found 1281-6054 | M2 961.7 M+4HI", Rr = 10.45 min C1B1H277N46046 38280515, Found 127.0282 | M2958: M+4HI", Rr = 1279 min C18341280F 148044 3643 0835, Found 1361 7068 | 2 9623 Presta Ry 1088 win C181HDTNHE04E SBaE 005; Four 1362.6891 | M2 9692 [M#4HI", Rr = 13.16 min i rn Fons 19017036 | M2 12800 M+3HI™, Rr = 12.02 min C18 1202NA3040 885.0665. Foun 128.6907 | "2 965. 0 M+3HT", Rr =8.38 min C1BIH276N43048 3616.04; Found 274.0220 | ™2 956.8 IMs3HI™, Rr =8.34 min "HRMS (HESIFT) m / z: [MBH Calcd for | 1. cam + or ae oan 1801272 NéZ050 837.9785, Found 12803376 | M2 960.4 [M+4HI®", Ry = 12.97 min CE i i Saso0z17 | 2960.4 MaHI", Rr = 13.48 min MatGigy ul miz 863.6 [M+4H]", Rr = 13.76 min I i pars Ee Bsa By =~ 148 WA ad Li) I Ei ia IESERE sail Bem 11,02 LO GAER CT tT. I araneso | M2 12798 M43", Rr = 14.11 min | C1878 N4BOAD 46.047, Found 1983.0783 | 2 12834 IMHSHF", Rr = 14.31 min ND es nan Fese7aq | M2 1145.1 M+4HI*, Rr = 14.45 min HRMS (HESI / FT) m / z: [M+4H]" Calcd for 680 ND 61 62 es a. 63 ND 64 67 70 71 72 73 74 75 76 77 78 79 80 ARNO (FE | | 4, [(Mrdi] udil TUF C178H273N46048 3820.01; Found 1274.3477 BE |p J hg roast | mz 11393 [M+4HI", Rr = 14.32 min | B | cians. a a [M+3H, Rr = 8.80 min Tw ND 1 | opiates I ature | M2 1139.7 MHI“, Rr = 927 min 02 |, SEAT a aganzor | M2 11427 [M+4H, Rr = 0.18 min _63 ND miz 1293.3 [M+3H]"", Ry = 9.34 min B | Crater tn So oe oie a aggp | V2 12895 BAST Rem B80 Bourn, RE aoe ag6a | M2 1204.9 MH3HI", Rr = 10.68 min 8 Es rds oca | mz 11800 [M+4HI", Ry = 13.74 min | 7 dela dine in Tioapeta | mz 1154. [MH Ry = 12.37 min | 68 | C1a31i201N42049 d648.052, Found 1763.6960 | M2 12638 IM+3HI", Rr = 10.43 min | 89 | ciouabanioots sent nas. Fone 1agaza | M2 1288.4 IMSIHE, Rr = 10.58 min | | crane. A Ta00.0380 | 2974.8 [M+aH", Rr-=8.08 min T1 | 1842001 45047 3304086, Found 1307 3744 | M2 1303.1 IMFIHI™, Rr = 10.68 min | | oa Til io roagosg | M2 11562 [M+4#1, Rr = 13.88 min 73 | Coronbianisoss damn bos. Fara Tay Bote | Me 11482 MH Rr = 1357 min | 78 | Cramnbenisot Se chee pour toss baa | Me 989.3 M+4HI", Rr = 13.57 min TS | CipomNeaOn OTE Ng Fr To 7112 | 2988.2 MHI". Rr = 10.03 min 78 | C17Bi7aN43080 810.0685. Found 1271-3434 | ™2 9540 M+4HI®, Ry = 1231 min 7 i ie fos Ol iz 12713 MBH", Rr = 11.84 min | 78 CIA OABOAT J883 OB, Fond tha oaza._| ™ / 2 871.6 IMsaHI", Rr = 11.27 min Bg ae es: re tsa 3150 | M12 971.5 [MH4HI', Rr = 14.48 min BD oETaNA048 070.0% Found 127asa7r | M2880 MHI", Rr = 13.70 min oa HRMS (HESIFT) miz. [M+3HT Calcd fo | 1 oes 0 (asd i® B. — 0 £9 min HRMS (HESI / FT) m / z: [M+3H]™" Calcd for 4 oo i 81 | C179H278N47046 381.0625, Found 1274.0306 | M2 955.9 [M+4HI™, Rr = 9.57 min ND —= Not Determined Synthesis of Examples 82-117 Standard Fmoc solid phase peptide synthesis (SPPS) was used to synthesize the peptides which were then cleaved from the resin and purified. General method for Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry. Method a — Exemplified by the Synthesis of Example 82 Peptide Synthesis 1) Add DCM to the vessel containing Rink Amide MBHA Resin (sub: 0.35 mmol / g, 0.2 mmol, 0.57 g) and swell for 2 hours. 2) Drain and then wash with DMF (5 times, drain between each wash). 3) A solution of 20% piperidine in DMF was added agitate with N2 bubbling for 30 min. 4) Drain and wash with DMF (5 times, drain between each wash). 5) Add Fmoc-amino acid solution (3.0 equivalents in DMF) and mix for 30 seconds, then add activation buffer (HBTU (2.85 equivalents) and DIEA (6 equivalents) in DMF), agitate with N; bubbling for 1 hour. 6) The coupling reaction was monitored by ninhydrin test 7) If required repeat steps 4 to 6 for same amino acid coupling if inefficient coupling occurs 8) Repeat steps 2 to 6 for next amino acid coupling. Note: for the acids in the table below different protecting groups and / or coupling agents were used 22 26 Step Materials Coupling reagents 22 Fmoc-Asp(OAIl)-OH (2.0 eq HATU (1.9 eq) and DIEA (4.0 eq 26 Fmoc-Lys(Alloc)-OH (3.0 eq HBTU (2.85 eq) and DIEA (6.0 eq a4 Intarrviacd sata DIO N an} MIC ON an dOGBT ION and 3 Intermediate 2 (2.0 eq) DIC (2.0 eq) HOBT (2.0 eq) 32 Intermediate 1(1.5 eq) DIC (1.5 eq) HOBT (1.5eq) Peptide sidechain deprotection cyclisation: 1) Add DCM to the resin and agitate with N; bubbling, then add PhSiH; (10 eq), Pd(PPhj)s (0.2 eq) agitate with N for 15 mins for 3 times. 2) The resin was washed with DCM three times and then DMF three times. 3) The resin was washed with 0.5% Sodium diethyldithiocarbamate trihydrate DMF and 0.5% DIEA in DMF for ten times. 4) HATU (2 eq) and DIEA (4 eq) were added to the resin in DMF and agitate with N, bubbling for 1 hour. 5) The resin was washed with MeOH three times and dried in vacuo. Peptide Cleavage and Purification: 1) Add cleavage buffer (92.5%TFA / 2.5%EDT / 2.5%TI1S / 2.5%H,0) to the flask containing the side chain protected peptide on resin at room temperature and stir for 3 hours. 2) Filter and collect the peptide solution. 3) The peptide is precipitated with cold tert-butyl methyl ether and centrifuged (3 min at 3000 rpm). 4) Residue washed with tert-butyl methyl ether (2 times). 5) Crude peptide dried under vacuum for 2 hours. 6) The crude peptide was purified by prep-HPLC. Prep-HPLC Conditions: Instrument: Gilson 281. Solvent: A- 0.1% TFA in H20, B- acetonitrile, Column: Luna C18 (200x25 mm; 10 um) and Gemini C18 (150*30 mm; 5 um) in series. Gradient [time (min) / solvent B (%)]:0.0 / 25, 60.0 / 55, 60.1 / 90, 70 / 90, 70.1 / 10, at 20 mL / min with UV detection (wave length = 215 / 254 nm) and then lyophilized to give Example 1 (10.3 mg, 1.34% yield). Method b — Exemplified by the Synthesis of Example 105 Peptide Synthesis 9) Add DCM to the vessel containing Rink Amide MBHA Resin (sub: 0.35 mmol / g, 0.15 mmol, 0.42 g) and swell for 2 hours. 10) Drain and then wash with DMF (5 times, drain between each wash). 11) A solution of 20% piperidine in DMF was added agitate with N, bubbling for 30 min. 12) Drain and wash with DMF (5 times, drain between each wash). 13) Add Fmoc-amino acid solution (3.0 equivalents in DMF) and mix for 30 seconds, then add activation buffer (HBTU (2.85 equivalents) and DIEA (6 equivalents) in DMF), agitate with N; bubbling for 1 hour. 14) The coupling reaction was monitored by ninhydrin test 15) If required repeat steps 4 to 6 for same amino acid coupling if inefficient coupling occurs 16) Repeat steps 2 to 6 for next amino acid coupling. Note: for the acids in the table below different protecting groups and / or coupling agents were used. Step Materials Coupling reagents 1 Intermediate 5 (2.0 eq) DIC (2.0 eq) and HOBT (2.0 eq) 16 Intermediate 8 (2.0 eq) DIC (2.0 eq) and HOBT (2.0 eq) 25 Intermediate 2 (2.0 eq) DIC (2.0 eq) HOBT (2.0 eq) 26 Intermediate 1(1.5 eq) DIC (1.5 eq) HOBT (1.5 eq) 10) The resin was washed with DMF five times and MeOH three times and dried in vacuo. Peptide Cleavage and Purification: 7) Add cleavage buffer (92.5%TFA / 2.5%EDT / 2.5%T1S / 2.5%H,0) to the flask containing the side chain protected peptide on resin at room temperature and stir for 3 hours. 8) Filter and collect the peptide solution. 9) The peptide is precipitated with cold tert-butyl methyl ether and centrifuged (3 min at 3000 rpm). 10) Residue washed with tert-butyl methyl ether (2 times). 11) Crude peptide dried under vacuum for 2 hours. 12) The crude peptide was purified by prep-HPLC. Prep-HPLC Conditions: Instrument: Gilson 281. Solvent: A- 0.1% TFA in H20, B- acetonitrile, Column: Luna C18 (200x25 mm; 10 ym) and Gemini C18 (15030 mm; 5 um) in series. Gradient [time (min) / solvent B (%)]:0.0 / 25, 60.0 / 55, 60.1 / 90, 70 / 90, 70.1 / 10, at 20 mL / min with UV detection (wave length = 215 / 254 nm) and then lyophilized to give Example 24 (109.8 mg, 19.3% yield). Table 2a - HRMS and LCMS properties of purified peptides represented by Examples 82- 117 HRMS LCMS / HPLC Method 958.0243 Example | Synthetic HRMS LCMS / HPLC P Method Analytical Method D; (Analytical Method C) HRMS (HESI / FT) miz: IM+4H]™ Calcd for 82 a C181H278N46046 3828.0515; Found miz 958.2 [M+4H]**, Rr = 10.69 min 958.0243 83 a | C175H270N45049 3782.9785: Found JOUER YY HRMS (HESI / FT) m / z: [M+3H]"" Calcd for 83 a C175H270N45049 3782.9785; Found miz 946.8 [M+4H]**, Rr = 12.19 min 1262.0046 HRMS (HESI / FT) m / z: [M+4H["" Calcd for 84 a C178H279N43051 3831.0247; Found m / z 959.0 [M+4HT**. Ry = 11.33 min 1606 VVRD HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 84 a C178H279N43051 3831.0247; Found m / z 959.0 [M+4H]*, Rr = 11.33 min 958.7668 HRMS (HESI / FT) m / z: [M+4H]" Calcd for 85 a C176H275N43050 3786.9985; Found m / z 947.9 [M+4HT** Ry = 11.65 min Swi, CY HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 85 a C176H275N43050 3786.8985; Found m / z 947.9 [M+4H]*, Rr = 11.65 min 947.7603 HRMS (HESI / FT) m / z: [M+4H]" Calcd for 86 a C171H273N43051 3740.9778; Found miz 1248.4 [M+3H]>, Rr = 10.54 min pot. Wy HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 86 a C171H273N43051 3740.9778; Found | m / z 1248.4 [M+3H]*, Rr = 10.54 min | 936.2551 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 87 a C175H271N43052 3802,957; Found m / z 952.1 [M+4HI*". R; = 12.91 min | bhi HRMS (HESI / FT) miz: [M+4H]" Calcd for 87 a C175H271N43052 3802.957; Found | m / z 952.1 [M+4H]**, Ry = 12.91 min 951.7492 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 88 a C174H269N43052 3788.9414: Found | m / z 948.5 [M+4H]*". Ry = 9.69 min ovl.r35%s HRMS (HESI / FT) m / z: [M+4H["" Calcd for 88 a C174H269N43052 3788.9414; Found miz 948.5 [M+4H]*, Ry = 9.69 min 948.2462 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 89 a C173H266N42053 3775.9097; Found m / z 945.2 [M+4H]**, R; = 10.60 min oto. HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 89 a C173H266N42053 3775.8097; Found miz 945.2 [M+4H]*, Rr = 10.60 min 944.9882 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 90 a C175H272N42051 3775.9097; Found m / z 944.5 [M+4H]** R; = 14.42 min Cimimdlisasisd HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 90 a C175H272N42051 3775.8097; Found m / z 944.5 [M+4H]*, Rr = 14.42 min 944.5023 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 91 a C179H272N46048 3829.9944: Found m / z 1278.0 [M+3H]**. R; = 12.20 min lew HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 91 a C179H272N46048 3829.9944; Found m / z 1278.0 [M+3H]™, Ry = 12.20 min | 958.5097 HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 92 a C172H264N42053 3761.894; Found m / z 941.8 [M+4H]**, R; = 11.15 min | MYO.JVI TT HRMS (HESI / FT) miz: [M+4H]" Calcd for 92 a C172H264N42053 3761.884; Found | m / z 941.8 [M+4H]**, Ry = 11.15 min 941.4835 HRMS (HESI / FT) m / z: [M+4HT Calcd for 93 a C177H277N43050 3801.0142: Found | m / z 951.7 [M+4HI** R; = 10.72 min a HRMS (HESI / FT) m / z: [M+4H["" Calcd for 93 a C177H277N43050 3801.0142; Found m / z 951.7 [M+4H]**, Ry = 10.72 min 951.2633 HRMS (HESI / FT) m / z: [M+4H["" Calcd for 94 a C173H275N43052 3782.9883; Found m / z 1262.4 [M+3H]*, Rr = 10.33 min Mu lel HRMS (HESI / FT) m / z: [M+4H]"" Calcd for 94 a C173H275N43052 3782.9883; Found | m / z 1262.4 [M+3H]*, R; = 10.33 min | 946.7572 HRMS (HESI / FT) m / z: [M+3H["" Calcd for 95 a C177H266N45049 3802.947: Found m / z 1269.5 [M+3H]** R; = 13.26 min | Fal. / Jl HRMS (HESI / FT) m / z: [M+3H]" Calcd for C177H266N45049 3802.947; Found miz 1269.5 [M+3H]**, Rr = 13.26 min | 1980 CEND 1268.6602 C178H268N45049 3816.9629: Found HRMS (HESI / FT) m / z: [M+3H]"" Calcd for C178H268N45049 3816.9620; Found | m / z 1273.7 [M+3H]*, R; = 10.38 min | wijavanis 1273.3316 C174H269N43052 3788.9414: Found Je ln IY HRMS (HESI / FT) m / z: [M+4H]"" Caled for C174H269N43052 3788.9414; Found | m / z 1264.3 [M+3H]*, Ry = 12.93 min | QAR DARQ 948.2459 C173H264N41053 3760.8989: Found Ny i HRMS (HESI / FT) m / z: [M+3H]"" Calcd for C173H264N41053 3760.8989; Found | m / z 1254.8 [M+3H]*, Ry = 11.56 min | 1984 RRAND 1254.6640 C176H275N41051 3774.9873; Found 1&9%.00"YV HRMS (HESI / FT) miz: [M+4H]"" Calcd for C176H275N41051 3774.9873; Found | m / z 1259.6 [M+3H]*, Ry = 14.37 min | QAd 7RAeR 944.7565 C175H273N41051 3760.9717; Found gat. rIvJ HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C175H273N41051 3760.9717; Found miz 1254.9 [M+3H]>, Ry = 11.68 min | QA1 PERN 941.2530 C175H272N42051 3773.9668: Found C172H263N42053 3761.894: Found Neds HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C175H272N42051 3773.9668; Found | m / z 1259.2 [M+3H]*, Ry = 13.27 min | 944.5030 ND HRMS (HESI / FT) miz: [M+3H]"" Calcd for C172H263N42053 3761.894; Found | m / z 1256.3 [M+3H]*, Ry = 14.15 min | porptpiadyl 1253.9754 C180H281N43050 3841.0454: Found Jon dive HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C180H281N43050 3841.0454; Found | m / z 961.7 [M+4H]**, Ry = 12.18 min aed 79719 961.2712 C175H267N46049 3793.958: Found le HRMS (HESI / FT) m / z: [M+3H]"" Calcd for C175H267N46049 3793958; Found | m / z 1266.1 [M+3H]*, R; = 13,55 min | 1985 RREN 1265.6650 C173H262N45050 3766.9106; Found Je UJ AI. HRMS (HESI / FT) m / z: [M+3H]"" Calcd for C173H262N45050 3766.9106; Found | m / z 1256.8 [M+3H]*, Ry = 12.15 min | 19RR RAN 1256.6490 C174H264N45050 3780.9265; Found 1690.0" IV HRMS (HESI / FT) miz: [M+3H]"" Calcd for C174H264N45050 3780.9265; Found | m / z 1261.7 [M+3H]*, R; = 15.55 min | 19R41 A9N2 1261.3203 C175H268N45047 3748.9729: Found 1€V 1.uelVo HRMS (HESI / FT) miz: [M+3H]"" Calcd for C175H268N45047 3748.9729; Found | m / z 1251.2 [M+3H]*, Ry = 13.59 min | 1960 R7ND 1250.8702 C173H262N45049 3750.9158: Found ev ie HRMS (HESI / FT) m / z: [M+3H]"" Calcd for C173H262N45049 3750.9158; Found | m / z 1251.6 [M+3H]*, Ry = 12.562 min | 19841 A120 1251.3169 C177H273N43052 3828.9727: Found 1€v 1.9 1VT HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C177H273N43052 3828.9727; Found | m / z 1277.8 [M+3H]*, R; = 8.06 min aQ&sA dR21 958.2533 C174H275N43051 3778.9934: Found OVO. LVJY HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C174H275N43051 3778.9934; Found | m / z 1261.0 [M+3H]*, Ry = 10.42 min | QAR 78201 945.7591 C174H278N44049 3764.03; Found av. Ivd | HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C174H278N44048 3764.03; Found m / z 1256.2 [M+3H]*, Ry; = 13.70 min | Qiao N1 / 89 942.0182 C176H271N43051 3798.9622: Found ie. 10s HRMS (HESI / FT) m / z: [M+4H]"" Calcd for C176H271N43051 3798.9622; Found m / z 1267.6 [M+3H]*, Ry = 14.43 min | aQen ENG 950.7509 C179H269N46047 3811.9839; Found Mr WL HRMS (HESI / FT) miz: [M+3H]" Calcd for C179H269N46047 3811.9839; Found | m / z 1272.2 [M+3H]*, Ry = 10.81 min | 4974 R720 1271.8720 C180H271N46047 3825.9995: Found lef VF eV HRMS (HESI / FT) m / z: [M+3H]"" Caled for C180H271N46047 3825.9995; Found | m / z 1277.1 [M+3H]™, Ry = 10.95 min | 1276.3429 HRMS (HESI / FT) m / z: [M+3H[" Calcd for C182H275N44048 3842.0195: Found 1281.6846 117 b | C163H248N41044 3480.8193: Found So aS HRMS (HESI / FT) m / z: [M+3H]"" Calcd for 117 b C163H248N41044 3480.8193; Found miz 1161.3 [M+3H]*, Rr = 12.13 min | 1161.2830 ND = Not determined Biological Activity The following examples are provided to illustrate preferred aspects of the invention and are not intended to limit the scope of the invention. Example A. In vitro pharmacological characterization of peptides - Functional agonism of human GLP2 or GLP1 receptors, cAMP accumulation assay cAMP production upon agonist stimulation of human GLP2 or GLP1 receptor was assessed utilizing HiRange cAMP kit (Cisbio). In brief, HEK cells were infected with either human GLP2 or GLP1 receptor BacMam virus for 24 hours and frozen for later use in the assay. On the day, various concentrations of compounds were dispensed using ECHO-555 (LabCyte) to a total volume of 100 nl into a low volume 384-well Proxi plates (Perkin Elmer) followed by addition of 10pl of cell suspension delivering 800k cells per well. Cells were prepared in the assay buffer (HBSS (Lonza) supplemented with 0.5 mM IBMX (Tocris). After 45 min incubation at 37°C, the reaction was stopped by addition of the HTRF detection reagents in the lysis buffer provided in the kit. Following 1-hour incubation at RT, plates were read on Pherastar FS (BMG Labtech, Inc.) Dotmatics Studies software was used for calculation of PECs, values by fitting data to a four parameter dose response curve. Exendin-4 and liraglutide were used as reference compounds for GLP-1 receptor activation whilst Teduglutide and FE-203799 were used as reference compounds for GLP-2 receptor activation. Example Human GLP-1 R agonist cAMP Human GLP-2R agonist cAMP pPECso Emax PECs mh pPECso Emax PECs, Emax Teduglutide 6.5 60.3 11.8 100.6 FE-203799 6.8 61.4 10.8 100.8 Exendin4 12.4 99.7 <8.1 1.6 liraglutide 11.5 97 <6.1 1 1 91 901 94 103.1 2 94 925 10.5 103.2 3 97 947 92 a54 4 93 947 11.0 103.4 5 97 925 ag 103.7 6 7.1 913 a3 102.7 7.8 72.7 94 103.3 8 93 90.8 99 102.9 9 82 62.5 10.0 104.0 85 60.4 10.2 105.1 96 953 10.1 105.0 96 945 10.3 105.3 96 925 105 104.1 94 930 10.5 103.8 10.1 98 2 10.8 103.5 92 941 96 103.8 98 96.3 104 103.8 10.0 978 10.8 104.2 96 954 11.0 103.4 88 841 10.3 104.2 103 96.6 10.8 104.1 94 927 11.14 103.7 a1 943 10.6 102.2 97 96.8 11.4 102.6 10.5 97.6 10.6 103.0 a8 97.1 10.8 102.9 a8 971 10.2 9913 10.1 96.0 a5 996 10.3 96.2 10.5 103.1 103 96.7 10.6 103.7 10.8 98.3 10.4 103.4 10.6 97.8 91 913 10.86 98.1 10.5 102.5 89 B80 97 101.7 91 945 97 102.8 105 971 10.5 103.7 104 97.0 10.6 103.4 93 B88 10.9 104.9 94 926 q7 105.2 93 889 11.2 105.3 96 953 91 976 9.7 94.1 94 96.4 92 952 94 104.8 97 96.1 92 103.5 9.7 96.5 10.3 103.6 99 97.8 10.6 104.8 95 938 98 104 .4 10.8 98.7 11.1 101.3 10.9 989 10.9 102.1 10.0 98 3 10.6 102.3 g9 978 10.9 102.9 118 08.8 11.0 101.5 13 995 10.7 101.6 92 B88 10.5 101.4 103 979 11.0 103.1 10.2 973 10.9 102.6 89 916 105 102.4 83 62.8 10.2 101.8 97 952 10.7 103.1 98 96.5 10.8 102.4 85 69.1 105 101.4 84 71.5 104 102.6 a0 96.9 10.0 997 10.8 98.0 104 103.6 104 979 10.4 102.1 88 B8.1 96 101.0 91 951 98 103.0 a5 94 0 10.1 103.1 82 837 93 950 104 98 2 94 974 10.8 98.2 10.6 102.6 95 957 95 100.9 87 87.2 913 100.0 92 909 10.8 101.6 Q2 950 104 102.3 a0 949 10.9 102.0 93 97.1 10.2 102.1 96 95.5 10.6 103.0 96 973 10.5 102.9 84 64.1 qQ7 999 85 56.1 Q2 916 79 945 10.1 104.5 92 98.1 96 103.4 80 87.3 10.3 103.2 79 952 105 103.0 76 935 10.6 102.8 86 98.7 11.6 102.0 89 99.2 11.5 102.3 85 996 11.6 102.5 81 100.2 10.6 102.1 96 988 11.0 103.9 80 96.5 11.7 9913 84 953 113 98 6 83 926 11.0 103.1 84 97.0 11.4 102.1 93 96.4 11.2 100.6 95 06.6 115 101.0 1.7 96.0 11.2 101.3 86 97.1 11.3 101.4 91 96.0 13 100.0 79 96.7 10.5 100.8 17 993 11.9 100.9 87 97.0 11.8 100.4 84 B83 913 102.4 108 YR 10.6 100.9 a5 972 a3 102.1 10.7 969 10.7 101.4 84 921 93 104.1 1086 970 11.1 102.5 84 88.1 10.8 103.0 a1 932 Q92 104 2 80 926 98 102.1 87 97.0 11.5 101.0 85 B91 10.7 102.1 93 92.0 10.7 104.4 116 95 94 4 11.4 102.8 17 99 94.7 11.5 103.4 Example B. In vitro pharmacological characterization of peptides -- Functional agonism of mouse GLP2 or GLP1 receptors, cAMP accumulation assay: cAMP production upon agonist stimulation of mouse GLP2 or GLP1 receptors was assessed utilizing HiRange cAMP kit (Cisbio). In brief, HEK cells were transiently transfected for 24 hours with cDNA using GeneJuice Transfection reagent (EMD Millipore) and frozen at -80°C for later use in the assay. On the day, various concentrations of compounds were dispensed using ECHO-555 (LabCyte) to a total volume of 100 nl into a low volume 384-well Proxi plate (Perkin Elmer) followed by addition of 10ul of cell suspension delivering 8000 cells per well. Cells were prepared in the assay buffer (HBSS (Lonza) supplemented with 0.5 mM IBMX (Tocris)). After 45 min incubation at 37°C, the reaction was stopped by addition of the HTRF detection reagents in the lysis buffer provided in the kit. Following 1-hour incubation at RT, plates were read on Pherastar FS (BMG Labtech, Inc.) using standard HTRF settings. Dotmatics Studies software was used for calculation of pEC50 values by fitting data to a four-parameter concentration response curve. Liraglutide was used as reference compound for GLP-1 receptor activation whilst Teduglutide and FE-203799 were used as reference compounds for GLP-2 receptor activation. Example Mouse GLP-1R agonist cAMP Mouse GLP-2R agonist cAMP PECso Emax PECso Emax Teduglutide <6.1 1 11.1 100.1 FE-203799 <7.3 53.4 10.5 98.1 liraglutide 11.4 97.9 <6.1 1.6 99 915 8.0 97.7 a 10.4 94.3 9.0 91.6 19 ND ND 91 100.6 22 ND ND B.8 945 26 ND ND 8.5 86.4 29 ND ND 8.3 100.0 30 ND ND 89 101.3 31 ND ND a8 101.9 38 ND ND 85 99.0 40 ND ND 89 99 6 46 ND ND 8.0 100.8 48 ND ND 10.2 102.9 49 ND ND [-X] 101.74 50 ND ND 8.1 81.0 51 ND ND 8.4 87.8 52 ND ND 97 103.1 53 ND ND a2 103.1 55 ND ND a5 100.6 56 ND ND 92 08.6 59 ND ND a3 102.7 60 ND ND 91 102.5 64 ND ND 8.7 997 B65 ND ND 8.2 86.3 71 ND ND 8.7 89.71 74 ND ND B.8 936 75 ND ND 8.2 819 76 ND ND 89 102.5 177 ND ND 8.5 1022 78 ND ND 8.7 83.1 79 ND ND 8.5 74 2 87 92 914 112 99.2 88 10.0 96.4 11.2 08.7 89 9.1 94.5 11.2 08.4 92 80 94 8 10.9 98.9 93 86 955 af 98.5 95 83 94.7 11.1 102.1 96 91 96.1 91 100.7 102 ND ND 10.7 99.0 4142 ND ND 8.2 997 113 88 96.3 a7 0992 116 97 955 95 999 117 10.1 96.9 9.8 99.3 ND - Not determined Example C: In vitro pharmacological characterization of peptides —Evaluation of the stability of peptides in Fasted state Simulated Intestinal fluid: Stability of peptides was tested in Fasted-State Simulated Intestinal Fluid (FaSSIF) prepared according to manufacturer's protocol (Biorelevant, art.no. FFF01, pH 6.5). FaSSIF composition: 3 mM sodium taurocholate, 0.75 mM lecithin, 105.9 mM NaCl, 28.4 mM NazHPO4, 8.7 mM NaOH, and 10 mg / ml pancreatin (Sigma). FaSSIF was pre-incubated for 15 min at 37°C and spiked with test and reference item working solutions. Experiments were conducted in duplicate in a non-serial manner. The total incubation volume per replicate was 150 pl. Sampling time points for test items were 0, 0.5, 2, 5, 10, 15 and 30 min. All samples and calibration standards (prepared in FaSSIF) were precipitated by addition of 300 pl precipitant (ACN / 2% acetic acid / 0.2% HFBA, (precipitation reagent, PR)) containing internal standard (ISTD) to 150 pl sample. After incubation for 1 h at room temperature all samples were centrifuged for 10 min at 2,200 x g (room temperature). Prior to subjection to LC-MS, the samples were diluted 1:1 in PBS buffer in order to reduce the organic solvent content in the samples to 33%. The % of compound remaining at t=30mins is summarised below. Neurotensin was included as a reference agent. FASSIF ining (at ASS % remaining (a t=30) 0-27 17 Example [ Neurotensin | Teduglutide 5 2 1 4 43 10 38 1 223 12 10.7 13 38 14 17.1 15 15.8 17 68.7 18 173 19 135 20 86 21 51.7 22 6.8 30 51.1 38 61.3 39 100 40 68.7 45 953 46 95.3 48 80.2 59 61.9 B60 62.5 The % of compound remaining at t=15mins is summarised below. Neurotensin was included as a reference agent. % remaining at % remaining at +=15 mins Example = id nile (FassIF) Neurotensin 49 Teduglutide 1.2 86 51 87 17 88 05 89 10.5 a0 22 a1 88 a3 13.5 105 186 106 a6 107 7.4 109 4.6 110 5 111 26.9 112 40.7 113 34 Example D: In vitro pharmacological characterization of peptides —Evaluation of the stability of peptides in Fasted state Simulated Gastric fluid: Stability of peptides was tested in Fasted-State Simulated gastric Fluid (FaSSGF) prepared according to manufacturer's protocol (Biorelevant, art. no. FFF01). FaSSGF composition: 0.08 mM sodium taurocholate, 0.02 mM lecithin, 34.2 mM NaCl, 25.1 mM HCL, and 0.1 mg / ml pepsin (Sigma). pH was adjusted to 1.6. FaSSGF was pre-incubated for 15 min at 37°C and spiked with test and reference item working solutions. Experiments were conducted in duplicate in a non-serial manner. The total incubation volume per replicate was 150 ul. Sampling time points for test items and reference item neurotensin were 0, 0.5, 2, 5, 10, 15 and 30 min. All samples and calibration standards (prepared in FaSSGF) were precipitated by addition of 300 ul precipitant (ACN / 2% acetic acid / 0.2% HFBA, (precipitation regent, PR)) containing internal standards (ISTD) to 150 ul sample. After incubation for 1 h at room temperature all samples were centrifuged for 10 min at 2,200 x g (room temperature). Prior to subjection to LCMS, the samples were diluted 1:1 in PBS buffer in order to reduce the organic solvent content in the samples to 33%. The % of compound remaining at t=30mins is summarised below. Neurotensin was included as a reference agent. Example | FASSGF % remaining | fmb $="10Y (at t=30) Neurotensin ay Teduglutide 9.2 9 34 30 100 38 100 39 100 40 84.9 45 100 46 100 48 100 59 100 60 100 Example E: In vitro pharmacological characterization of peptides —~Evaluation of the stability of peptides in rat intestinal fluid: Peptides were tested for in vitro stability in native intestinal fluid obtained from the rat small intestine. Rat Sprague Dawley Small Intestinal Fluid (ratlF) (from Biotrend art. no. RSD-SIF- MI-30ML, undiluted) was preincubated for 15 min at 37°C and spiked with test and reference item working solutions. Experiments were conducted in duplicate in a non-serial manner. The total incubation volume per replicate was 150 pl. Sampling time points for test items and reference item neurotensin were 0, 0.5, 2, 5, 10, 15 and 30 min. All samples and calibration standards (prepared in ratlF) were precipitated by addition of 300 pl precipitant (ACN / 2% acetic acid / 0.2% HFBA, (precipitation regent, PR)) containing internal standards (ISTD) to 150 ul sample. After incubation for 1 h at room temperature all samples were centrifuged for 10 min at 2,200 x g (room temperature). The resulting samples were transferred to auto sampler vials and subsequently subjected to LC-MS analysis to subjection to LC-MS. The % of compound remaining at t=30mins is summarised below. Neurotensin was included as a reference agent. Rat IF% remaining (at Example t=30) 0.4 13 | Neurotensin | Teduglutide 9 t 225 27 11 29 413 31 24.8 36 233 37 26.8 a8 334 Ki] 19.7 40 14.7 45 6824 48 100 51 66.9 55 684.9 14 799 59 63.6 680 89.6 4 738 72 828 74 71.2 The % of compound remaining at t=15mins is summarised below. Neurotensin was included as a reference agent. Example % remaining at | t=15 mins (ratlF) Neurotensin 0.5 Teduglutide 5.7 112 24.5

Claims

Claims 1. A compound comprising the sequence of formula (1a) or formula (1b): Rl R? A a AACAAYAAE 2 AR" oO (1a); or Rr R i AA ANZ AAS ALANS AR% ART AR ARS ARTO ART LAA 2 AR AR A AA ST AN EAR TAA ARS AN AR ARTZ 0 (1b) wherein: R is selected from: oO H AN O arth NH. H 0 NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more RY groups; R" is selected from halogen, hydroxyl, amino or Cig alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis1t03; R' and R? are independently selected from hydrogen or a Cy alkyl group, or together with the carbon to which they are aftached join to form a Cys cycloalkyl or a heterocycly group; S is the sequence -Giu-Nle-; T is the sequence ~Phe-lle-; W is the sequence -Trp-Leu-ile-~; Z is absent or is ~-Pro-; AA! is -NHCHR®CO-; wherein R® is selected from -(CH,),CONH,, ~(CH),COOH or - (CH) tetrazolyl; where y is 1 or 2; AA? is -Gly-, -DAla-, -Lys- optionally joined to AA® via a lactam bridge or -Glu- optionally joined to AA® via a lactam bridge; AA® is -Ser-Phe- or -Ser-2-F-a-Me-Phe-; AA% is -Ser- or -Giu- optionally joined to AA® via a factam bridge; AA® is -Asp- optionally joined to AA? via a lactam bridge or -Lys- optionally joined to AAZ or AA’ via a lactam bridge; AA? is -D-Phe-, -D-a-Me-Phe- or -Lys- optionally joined to AA via a lactam bridge; AA’ is -Asp- optionally joined to AA® via a lactam bridge, -Glu- optionally joined to AA" via a lactam bridge or -Lys- optionally joined to AA" via a lactam bridge; AA8 is -lle or -a-Me-Leu-: AA® is -Leu-Asp- or -Leu-ACPC-; AA" is -Asp- optionally joined to AA” or AA'™ via a lactam bridge, -Glu- optionally joined to AA” or AA™ via a lactam bridge or -Lys- optionally joined to AA’ via a lactam bridge; AA" is -LysR- where LysR is an N-substituted Lysine residue, -Glu- optionally joined to AA" via a lactam bridge or -Lys- optionally joined to AA' via a lactam bridge; AA"? is -Ala- or -AIB-; AA" is -Ala- or -AIB-; AA is -AIB- or is -Lys- optionally joined to AA" or AA" via a lactam bridge; AA is -Asp- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; AA" is -Asn-, -ACPC-, -Lys- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; AA" is -GIn-, -ACPC-, -Lys- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; AA" is -Thr-, -Lys- optionally joined to AA? via a lactam bridge or -Glu- optionally joined to AA? via a lactam bridge; AA" is -Pro-, -PIPALA-, -Lys- or -Glu- optionally joined to AA” via a lactam bridge; AA? is absent or is -lle-, -a-Me-Leu- or -Pro-; AA?! is absent or is -Thr-! AAZ is absent or is -Lys- optionally joined to AA or AA™ via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; S% is the sequence -Ser-Phe-; T® is the sequence -Glu-Nle-; W? is the sequence -Ala-Ala-; X? is the sequence -Asp-Phe-lle-; Y? is the sequence -Trp-Leu-lle-; 2° is absent or is the sequence -lle-Thr-; AA" is -NHCHR’CO-; wherein R® is selected from -(CH,),CONH;, -(CH),COOH or - (CH) tetrazolyl; where y is 1 or 2; AA” is -Gly-, -DAla-, -Lys- optionally joined to AA* via a lactam bridge or -Glu- optionally joined to AA* via a lactam bridge; AA® is -Ser- or is -Glu- optionally joined to AA via a lactam bridge; AA® is -Asp- optionally joined to AA? via a lactam bridge, or -Lys- optionally joined to AAZ or AA® via a lactam bridge; AA® is -DPhe-, -Asp- optionally joined to AA™ via a factam bridge or -Lys- optionally joined to AA¥ via a lactam bridge; AA® is -Thr-, -Asp- optionally joined to AA“ or AA® via a lactam bridge, -Glu- optionally joined to AA®® via a lactam bridge or -Lys- optionally joined to AA® via a lactam bridge; AA" is -lle- or an a-methyl Leucine residue of formula: Hw © H uv sch Ax z= ~~ AA® is -Asp- or is -Lys- optionally joined to AA* via a lactam bridge; AA® js -Leu-, -Lys- optionally joined to AA®® or AA" via a lactam bridge, -Asp- optionally joined to AA® or AA™ via a lactam bridge or -Glu- optionally joined to AA"? via a lactam bridge; AA is -Lys- or is -Glu- optionally joined to AA'™ via a lactam bridge; AA" js -Aib-, -Lys- optionally joined to AA* or AA via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Asp- optionally joined to AA™ via a lactam bridge; AA’? js -Asn-, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA™ via a lactam bridge; AA™ is -Gin-, -Asp- optionally joined to AA'™® via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge; AA" is -Thr- or is -Lys- optionally joined to AA™® via a lactam bridge; AA is .Lys- optionally joined to AA via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; AA is absent or is -Asp-, -Phe-, -Lys- optionally joined to AA? via a lactam bridge or -Glu- optionally joined to AA™ or AA via a lactam bridge; wherein the C-terminus is a carboxy! group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains one, two, three, four or five lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof.

2. The compound according to claim 1 according to formula (1a): 1 2 R| R ry AAAS ARATE AREA A ARE ARAN ANKE AREY AN AA 0 0 (ta) wherein: R is selected from: 7 0 AN oO ath oe A 0 NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more R® groups; RY is selected from halogen, hydroxyl, amino or Cis alkyi having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis1to 3: R' and R? are independently selected from hydrogen or a Cy. alkyl group, or together with the carbon to which they are attached join to form a Cass cycloalkyl or a heterocyclyl group; 8S? is the sequence -Ser-Phe-; T? is the sequence -Glu-Nle-; Weis the sequence -Ala-Ala-; X? is the sequence -Asp-Phe-lle-; Y? is the sequence -Trp-Leu-Hle-; 2% is absent or is the sequence -lie-Thr-; AA" is -NHCHR®CO-; wherein R® is selected from -(CHz),CONH;, ~(CH,),COOH or - (CH,),tetrazolyl; where y is 1 or 2; AAZ is -Gly-, -DAla-, -Lys- optionally joined to AA* via a lactam bridge or -Glu- optionally joined to AA* via a lactam bridge; AA*® is -Ser- or is -Glu- optionally joined to AA% via a lactam bridge; AA* is -Asp- optionally joined to AA? via a lactam bridge, or -Lys- optionally joined to AA® or AA® via a lactam bridge; AA* is -DPhe-, -Asp- optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA¥ via a lactam bridge; AA® is -Thr-, -Asp- optionally joined to AA* or AA® via a lactam bridge, -Glu-~ optionally joined to AA® via a lactam bridge or -Lys- optionally joined to AA® via a lactam bridge; AA" is -lle- or an a-methyl Leucine residue of formula: H © H Oo A ~ AA® is -Asp- or is -Lys- optionally joined to AA® via a lactam bridge; AA® is -Leu-, -Lys- optionally joined to AA® or AA" via a lactam bridge, -Asp- optionally joined to AA® or AA" via a lactam bridge or -Glu- optionally joined to AA"? via a lactam bridge; AA js -Lys- or is -Glu- optionally joined to AA!" via a lactam bridge: AA? is -Aib-, -Lys- optionally joined to AA® or AA'® via a lactam bridge, -Glu- optionally joined to AA® via a lactam bridge or -Asp- optionally joined to AA® via a lactam bridge; AA™2 is _Asn-, -Glu- optionally joined to AA via a lactam bridge or -Lys- optionally joined to AA™® via a lactam bridge; AA js .Gin-, -Asp- optionally joined to AA’? via a lactam bridge or -Lys- optionally joined to AA? via a lactam bridge; AA is -Thr- or is -Lys- optionally joined to AA via a lactam bridge: AA is -Lys- optionally joined to AA'® via a lactam bridge or ~Glu- optionally joined to AA via a lactam bridge: AA'®? is absent or is -Asp-, -Phe-, -Lys- optionally joined to AAS via a lactam bridge or -Glu- optionally joined to AA or AA'® via a lactam bridge; wherein the AA’ or AA™® C-terminus is a carboxyl group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains one or two lactam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or switterion thereof.

3. The compound according to claim 1 of formula (1b) a 2 R{ F . X . a J.AAZ, 3, a, Sa 8, zy 8, 9 antl, 12, BA HAAS EW 7 Ane. 1°, 20 21, 227 0 (1b) wherein: R is selected from: 0 H Bape o athe NTL 0 NH, or Q is phenyl or a monocyclic heteroaryl ring each of which may be optionally substituted with one or more R® groups; R" is selected from halogen, hydroxyl, amino or Cys alkyl having an alkyl chain optionally containing one or more heteroatoms selected from O, N, or S; nis1t03; R' and R? are independently selected from hydrogen or a Cy alkyl group, or together with the carbon to which they are aftached join to form a Cis cycloalkyl or a heterocycly group; S is the sequence -Giu-Nle-; T is the sequence -Phe-ile-; W is the sequence ~Trp-Leu-lle-; Z is absent or is -Pro-; AA" is -NHCHR®CO-; wherein R® is selected from -(CH,),CONH,, ~(CH,),COOH or - (CH,),tetrazolyl; where y is 1 or 2; AA? is -Gly-, -DAla-, -Lys- optionally joined to AA® via a lactam bridge or -Glu- optionally joined to AAS via a lactam bridge; AAZ is -Ser-Phe or -Ser-2-F-a-Me-Phe-: AAY is -Ser- or -Giu- optionally joined to AA® via a factam bridge; AA® is -Asp- optionally joined to AA? via a lactam bridge or -Lys- optionally joined to AAZ or AA’ via a lactam bridge; AA® is -D-Phe-, -D-u-Me-Phe- or -Lys- optionally joined to AA via a lactam bridge; AA’ is -Asp- optionally joined to AA® via a lactam bridge, -Glu- optionally joined to AA via a lactam bridge or -Lys- optionally joined to AA™ via a lactam bridge; AAS is lle or -a-Me-Leu-; AA® is -Leu-Asp- or ~Leu-ACPC-; AA" is -Asp- optionally joined to AA” or AA" via a lactam bridge, -Glu- optionally joined to AA” or AA™ via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge; AA" is -LysR- where LysR is an N-substituted Lysine residue, -Glu- optionally joined to AA™ via a lactam bridge or -Lys- optionally joined to AA via a lactam bridge; AA? is -Ala- or ~AIB-: AA" is -Ala- or -AIB-: AA" is -AIB- or is -Lys- optionally joined to AA or AA! via a lactam bridge: AA’ is -Asp- optionally joined to AA'! via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; AA is -Asn-, -ACPC-, -Lys- optionally joined to AA" via a lactam bridge or -Glu- optionally joined to AA" via a lactam bridge; AA" is -GIn-, -ACPC-, -Lys- optionally joined to AA via a factam bridge or -Glu- optionally joined to AA via a lactam bridge; AA is -Thr-, -Lys- optionally joined to AA? via a lactam bridge or -Glu- optionally joined to AA? via a lactam bridge; AA" is -Pro-, -PIPALA-, -Lys- or -Glu- optionally joined to AA? via a lactam bridge; AAZ is absent or is -lle-, -o-Me-Leu- or -Pro-; AA? is absent or is ~Thr- AA% is absent or is -Lys- optionally joined to AA or AA™ via a lactam bridge or -Glu- optionally joined to AA'® via a lactam bridge; wherein the C-terminus is a carboxy! group or a carboxamide group, or is adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups, and wherein the compound contains three, four or five factam bridges; or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or rwitterion thereof.

4. The compound according to any one of claims 1 to 3, wherein Q is:

5. The compound according to any one of claims 1 to 4, wherein nis 1 or 2.

6. The compound as defined in any one of claims 1 to 5, wherein R' and R? are independently selected from hydrogen or a Cy alkyl group.

7. The compound according to claim 8, wherein R' and R? are both methyl.

8. The compound according to any one of claims 1 to 7, wherein R® represents - CHoatetrazolyl or CH,COOH.

9. The compound according to any one of claims 1 to 8, wherein AA? is cyclised to AAS, and either AA is cyclised to one of AA®, AA” or AA™ or AA'' is cyclised to one of AA™ or AA'S and either AA'® is cyclised to AA or AAZ is cyclised to either AA or AA 10. The compound according to any one of claims 1 to 8, wherein AA is cyclised to AA" and AAZ is cyclised to either AA'® or AA'®, 11. The compound according to any one of claims 1 to 8, wherein AA? is -Gly- or -DAla-, AA¥ js -Ser-, AA® is -Asp-, AA™ is -DPhe-, AA® is -Thr-, AA® is -Asp-, AA is -Lys- and AA's -Lys-.

12. The compound according to any one of claims 1 to 11, wherein AA% is -Leu-, -Glu- joined to AA''® via a lactam bridge or -Lys- joined to AA'™ via a lactam bridge.

13. The compound according to any one of claims 1 to 12, wherein AA" is -Lys- optionally joined to AA® via a lactam bridge or -Glu- joined to AA® via a lactam bridge.

14. The compound according to any one of claims 1 to 13, wherein AA’? is -Asn- or is - Glu- joined to AA'*® via a lactam bridge.

15. The compound according to any one of claims 1 to 14, wherein AA™® is -GIn- or is - Lys- joined to AA'?® via a lactam bridge.

16. The compound according to any one of claims 1 to 15, wherein AA" is -Thr- or is - Lys- joined to AA'®® via a lactam bridge.

17. The compound according to any one of claims 1 to 16, wherein AA'® is -Phe- or is - Glu- joined to AA'*® via a lactam bridge.

18. The compound according to any one of claims 1 to 17, wherein Z* and AA™® are absent.

19. The compound according to any one of claims 1 to 18, wherein the C-terminus is a carboxamide group.

20. The compound according to claim 1 which is selected from any one of Examples 1 to 117.

21. The compound according to claim 1 which is selected from the group consisting of: Example 30: Example 31: = : t # lt 7 —- 3 0. — — — Example 46: Example 48: Beagrie rR [PEE Example 52: Example 55: Example 60: Example 74: Example 76: Example 93: Example 96: Example 115: Example 117: or a tautomer, salt or zwitterion thereof.

22. The compound according to any one of claims 1 to 21 having GLP-1 and / or GLP-2 receptor agonist activity.

23. The compound according to claim 22 having higher GLP-2 receptor agonist activity compared to GLP-1 receptor agonist activity.

24. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 23 and a pharmaceutically acceptable excipient.

25. The compound or composition according to any one of claims 1 to 24 for use in the treatment of gastrointestinal and metabolic diseases, promoting intestinal recovery and nutritional status of patients with malabsorption disorders, intestinal failure, intestinal insufficiency, diarrheal diseases, chronic inflammatory bowel disorders, improve mucosal barrier funclion, ameliorate gut inflammation, inflammatory disorders, celiac disease, congenital and acquired digestion and malabsorption syndromes, chronic diarrhoeal diseasas, conditions caused by mucosal damage (e.g. cancer treatment), hyperglycemia during enteral and parenteral nutrition therapy in patients with inlestinal failure, insufficiency or malabsorption disorders, gastrointestinal injury, diarrheal diseases, intestinal insufficiency, intestinal failure, acid-induced intestinal injury, arginine deficiency, obesity, celiac disease, chemotherapy-induced enteritis, diabetes, obesity, fat malabsorption, steatorrhea, autoimmune diseases, food allergies, gastric ulcers, gastrointestinal barrier disorders, Parkinson's disease, sepsis, bacterial peritonitis, inflammatory bowel disease, chemotherapy-associated tissue damage, bowel trauma, bowel ischemia, mesenteric ischemia, short bowel syndrome, malnutrition, necrotizing enterocolitis, necrotizing pancreatitis, neonatal feeding intolerance, NSAID-induced gastrointestinal damage, nutritional insufficiency, total parenteral nutrition damage to gastrointestinal tract, neonatal nutritional insufficiency, radiation-induced enteritis, radiation-induced injury to the intestines, mucositis, pouchitis, ischemia, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resislance, hyperglycemia, insulin resistance, glucose inlolerance, brush border enzyme deficiencies (congenital lactase deficiency, congenital sucrase- isomaltase deficiency, congenital maltase-glucoamylase-deficiency), defects of membrane carriers (glucose-galactose-malabsorption, fructose malabsorption, Fanconi-Bickel syndrome, Acrodermatitis enteropathica, Congenital chloride / sodium diarrhoea, Lysinuric protein intolerance, Primary biliary malabsorption, cystic fibrosis), enzyme deficiencies (hereditary pancreatitis, congenital pancreas lipase deficiency), lipid / lipoprotein metabolism defects (chylomicron retention disease, hypobetalipoproteinemia, abetalipoproteinemia), defects of enterocyte differentiation or cellular polarisation (Microvillous atrophy, Tufting enteropathy, Trichohepatoenteric syndrome, Familiar haemophagocytic lymphohistiocytosis type 5), defects of enteroendocrine cells (Congenital malabsorptive diarrhoea, anendocrinosis, protein- convertase 1 / 3 deficiency), congenital diarrheal diseases.

26. The use according to claim 25, wherein the disorder is Tufting enteropathy.