Peptide inhibitors of interleukin-23 receptor

Abstract

The present invention relates to compounds that are peptide inhibitors of interleukin-23 receptor (IL-23R) and to their use in the treatment or prevention of a variety of diseases, conditions or disorders, including inflammatory diseases, such as inflammatory bowel disease such as Crohn's disease or ulcerative colitis, psoriasis and psoriatic arthritis. The compounds have good physical and chemical stability in the gastrointestinal tract.

Description

TRANSLATION OF ABSTRACT AND TITLE Request to Record Designated Patent Application No. EP24731273.9 (Publication No. EP4720086) in Hong Kong Our Ref.: P4777HK00 54) Title: Interleukin-23 Receptor Peptide Inhibitors 57) Abstract: This invention relates to a class of interleukin-23 receptor (IL-23R) peptide inhibitors and their use in the treatment or prevention of various diseases, conditions, or disorders, including inflammatory diseases such as inflammatory bowel diseases like Crohn's disease, ulcerative colitis, and psoriasis. These compounds exhibit good physical and chemical stability in the gastrointestinal tract. Abstract

Claims

CLAIMS1. A compound of the formula:Z-R2whereinR2is NHR3or C(=O)R3, wherein R3is hydrogen or C1-4 alkyl optionally substituted with a pyridyl ring; andZ is an amino acid sequence of formula I:X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14 (I) whereinX1 is absent or is selected from 3-(3-Pyridyl)-Ala or 3-aminopropanoyl;X2 is selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D- beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys,Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta- homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr,Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta- homo-Dab, N-Me-Dab, N-Me-homo-Dab,Orn, D-Orn, iso-Orn, D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta- homo-Orn, N-Me-Orn, N-Me-homo-Orn,Lys(Gly),Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta- homo-Asp, N-Me-Asp, N-Me-homo-Asp,Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo- Glu, N-Me-Glu, N-Me-homo-Glu, and2-amino-6-carboxyhexanoyl;X3 is selected from any amino acid or co-hydroxy-C2-6 alkanoic acid;X4 is selected from Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D- homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu,Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta- homo-Asp, N-Me-Asp, N-Me-homo-Asp,Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo- Lys, N-Me-Lys, N-Me-homo-Lys,Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta- homo-Dab, N-Me-Dab, N-Me-homo-Dab,Orn, D-Orn, iso-Orn, D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta- homo-Orn, N-Me-Orn, N-Me-homo-Orn,Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta- homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr,Cys, D-Cys, beta-Cys, D-beta-Cys, homo-Cys, D-homo-Cys, beta-homo-Cys, N-Me-Cys and N-Me-homo-Cys;X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, and an optionally substituted betahomotryptophan residue;X6 is selected from the group consisting of an optionally substituted Gin residue, an optionally substituted Lys residue, an optionally substituted Arg residue, an optionally substituted Dab residue, an optionally substituted Orn residue, an optionally substituted Phe residue, Ala, D-Ala, beta-Ala, D-beta-Ala, homo-Ala, D-homo-Ala, beta-homo-Ala, N- Me-Ala, N-Me-homo-Ala, Cit, D-Cit, beta-Cit, D-beta-Cit, homo-Cit, D-homo-Cit, beta- homo-Cit, N-Me-Cit, N-Me-homo-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Vai, D- Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo- Val or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His and N-Me-homo-His;X7 is selected from Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D- homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu,Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta- homo-Asp, N-Me-Asp, N-Me-homo-Asp,Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo- Lys, N-Me-Lys, N-Me-homo-Lys,Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta- homo-Dab, N-Me-Dab, N-Me-homo-Dab,Orn, D-Orn, iso-Orn, D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta- homo-Orn, N-Me-Orn, N-Me-homo-Orn,Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta- homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr,Cys, D-Cys, beta-Cys, D-beta-Cys, homo-Cys, D-homo-Cys, beta-homo-Cys, N-Me-Cys, and N-Me-homo-Cys;X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted betahomotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted by an optionally substituted carbocylic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted;X9 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted betahomotryptophan residue, an optionally substituted alanine residue, an optionally substituted phenylalanine and an optionally substituted tyrosine residue;X10 is selected from the group consisting of Vai, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly,Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta- homo-Dab, N-Me-Dab, N-Me-homo-Dab,Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo- Lys, N-Me-Lys, N-Me-homo-Lys, 2-Me-Lys,Aib, D-Aib, beta-Aib, D-beta-Aib, homo-Aib, D-homo-Aib, beta-homo-Aib, N-Me-Aib, N- Me-homo-Aib,Ala, D-Ala, beta-Ala, D-beta-Ala, homo-Ala, D-homo-Ala, beta-homo-Ala, N-Me-Ala, N- Me-homo-Ala,Leu, D-Leu, beta-Leu, D-beta-Leu, homo-Leu, D-homo-Leu, beta-homo-Leu, N-Me-Leu, N-Me-homo-Leu, 2-Me-Leu, lie, D-lle, beta-lie, D-beta-lle, homo-lie, D-homo-lle, beta-homo-lle, N-Me-lle, N-Me-homo- lle, and a carbocyclic or heterocyclic ring having an amino substituent and a carbonyl substituent;X11 is selected from the group consisting ofDpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta- homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr,Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta- homo-Dab, N-Me-Dab, N-Me-homo-Dab,Orn, D-Orn, iso-Orn, D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta- homo-Orn, N-Me-Orn, N-Me-homo-Orn,Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo- Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me),Lys(Gly),Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta- homo-Asp, N-Me-Asp, N-Me-homo-Asp,Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo- Glu, N-Me-Glu, N-Me-homo-Glu, and2-amino-6-carboxyhexanoyl;X12 is selected from the group consisting of an optionally substituted Phe residue, an optionally substituted Tyr residue, an optionally substituted His residue, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo- Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, beta-Gly, homo-Gly, beta-homo- Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-CF3, Nle, Gin, D-GIn, iso-GIn, D-iso-GIn, beta-GIn, D-beta-GIn, homo-GIn, D-homo-GIn, beta-homo-GIn, N-Me- Gln, N-Me-homo-GIn, THP, Ser, D-Ser, beta-Ser, D-beta-Ser, homo-Ser, D-homo-Ser, beta-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(OMe), 3- aminotetrahydrofuran-3-carbonyl, THP, Arg, D-Arg, beta-Arg, D-beta-Arg, homo-Arg, D- homo-Arg, beta-homo-Arg, N-Me-Arg, N-Me-homo-Arg, Thr, D-Thr, beta-Thr, D-beta-Thr, homo-Thr, D-homo-Thr, beta-homo-Thr, N-Me-Thr, N-Me-homo-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N- Me-homo-Glu, Asn, D-Asn, beta-Asn, D-beta-Asn, homo-Asn, D-homo-Asn, beta-homo- Asn, N-Me-Asn, N-Me-homo-Asn, GABA, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys wherein the side chain -NH2of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F;X13 is selected from the group consisting of an optionally substituted His residue, an optionally substituted Phe residue, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, Asn, D-Asn, beta-Asn, D- beta-Asn, homo-Asn, D-homo-Asn, beta-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, and Dab, Orn or Lys wherein the side chain -NH2is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, or is absent; andX14 is absent or is selected from the group consisting of Sar, an optionally substituted His residue, Leu, D-Leu, beta-Leu, D-beta-Leu, homo-Leu, D-homo-Leu, beta-homo-Leu, N- Me-Leu, N-Me-homo-Leu, 2-Me-Leu, and an alanine residue substituted by a carbocyclicgroup or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted; wherein(i) the amino acid residue at X11 forms a lactam bridge with the amino acid residue at X1 or at X2 when X1 is absent; and(ii) X4 and X7 are amino acid residues who together form a lactam bridge or a dithioether bridge; or a pharmaceutically acceptable salt or solvate thereof; wherein the compound is not:and pharmaceutically acceptable salts and solvates thereof; wherein:* denotes that the (1c), (2a) and (2c) bridges use the peptide backbone amine or carboxylic acid at the / V- or C-terminus, not the side chain amine or carboxylic acid, (1c) denotes the [2,11] lactam bridge; (2a) denotes the [4,7] 1 ,3-dithio-propan-2-one bridge; (2c) denotes the [4,7] lactam bridge.

2. The compound of claim 1 , wherein X2 is selected from the group consisting of 4- aminomethyl-phenylacetyl, 3-(3-Pyridyl)-Ala, and 3-aminopropanoyl.

3. The compound of any one of claims 1 or 2, wherein X3 is selected from the group consisting of Ser, Ala, N-Me-Ala, Phe, and N-Me-Ser.

4. The compound of any one of claims 1 to 3, wherein X4 is Glu or Cys.

5. The compound of any one of claims 1 to 4, wherein X5 is Trp or 7-Me-Trp.

6. The compound of any one of claims 1 to 5, wherein X6 is selected from the group consisting of Gin, Q(Me), Q(2Me), Q(pyrrolidin), Ala, Phe, Lys(Ac), Lys(NMePEG3), Dab(Ac), Cit, and Orn.

7. The compound of any one of claims 1 to 6, wherein X7 is selected from Dab or Cys.

8. The compound of any one of claims 1 to 7, wherein X8 is selected from the group consisting of Y(2-ami noethoxy), homo-Phe, F(4-morpholine), 3-quinolinylalanine, Y(2-aminoethoxy)(N(Me)2, Y(nPentylamine)(N+(Me)3), Y(2-trimethyl-PEG2), Y(2- aminoethoxy)(N(Me)2), 7-AzaTrp, beta-homo-Trp, and 7-F-Trp.

9. The compound of any one of claims 1 to 8, wherein X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, 3-quinolinylalanine and cyclopropyl-Ala.

10. The compound of any one of claims 1 to 9, wherein X10 is 2-Me-Leu or Aib.

11. The compound of any one of claims 1 to 10, wherein X11 is Glu.

12. The compound of any one of claims 1 to 11, wherein X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gin, His, THP, Ser, D- Ser, 2-Me-Ser, Ser(OMe), and homo-Ser.

13. The compound of any one of claims 1 to 12, wherein X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 2-Me-3-(3-Pyridyl)-Ala, N-Me-3- (3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, His, D-His, and His(Me), or is absent.

14. The compound of any one of claims 1 to 13, wherein X14 is is absent or is selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-Pyridyl)-Ala.

15. The compound according to any one of claims 1 to 14, wherein the compound is not when X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or N-Me-Ser; X6 is Gin or Q(pyrrolidin); X8 is Y(2-ami noethoxy); X9 is 2-Nal, X10 is 2-Me-Leu; X12 is Dab, D- Arg, or Ser; X13 is 3-(3-Pyridyl)-Ala or absent; X14 is absent; and R2is NH2.

16. The compound according to any one of claims 1 to 15, wherein X1 is absent; optionally wherein X2 is 4-aminomethyl-phenylacetyl; optionally wherein X3 is Ser or Ala, optionally wherein X3 is Ser; optionally wherein X6 is Gin.

17. The compound according to any one of the preceding claims, wherein X8 is Y(2- aminoethoxy); optionally wherein X9 is 2-Nal; optionally wherein X10 is 2-Me-Leu; optionally wherein X12 is Dab.

18. The compound according to any one of the preceding claims, wherein X13 is 3-(3- Pyridyl)-Ala or is absent; optionally wherein X13 is 3-(3-Pyridyl)-Ala; optionally wherein X14 is absent.

19. The compound according to any one of the preceding claims, wherein R2is NHR3wherein R3is hydrogen or C1-4 alkyl; optionally wherein R2is NH2 or NHMe.

20. The compound according to any one of the preceding claims, wherein X4 is Glu, X7 is Dab, and wherein X4 and X7 together form a lactam bridge.

21. The compound according to any one of claims 1-19, wherein X4 and X7 are both Cys, and X4 and X7 together form a dithioether bridge, wherein the dithioether bridge between X4 and X7 is of the formula -S-L-Y-L-S-, wherein: each S is a sulfur atom and is part of the amino acid residue at X4 and X7; each L is independently C1-4 alkylene; andY is either absent or C(=O); optionally wherein each L is independently C1-2 alkylene, optionally wherein each L is methylene; optionally wherein Y is C(=O); optionally wherein the dithioether bridge between X4 and X7 is of the formula - SCH2C(=O)CH2S-, wherein each S is a sulfur atom and is part of the amino acid residue at X4 and X7.

22. The compound according to any one of the preceding claims, wherein:X1 is absent and X2 is 4-aminomethyl-phenylacetyl; orX1 is absent; X2 is 4-aminomethyl-phenylacetyl; X8 is Y(2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; orX1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X8 is Y(2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; orX1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X6 is Gin; X8 is Y(2- aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; orX13 is 3-(3-Pyridyl)-Ala and X14 is absent; orX13 is 3-(3-Pyridyl)-Ala, X14 is absent, and R2is NHMe.

23. The compound according to claim 1 wherein Z is an amino acid sequence selected from the group consisting of:wherein:* denotes that the (1c), (2a), (2c), and (4c) bridges use the peptide backbone amine or carboxylic acid at the / V- or C-terminus, not the side chain amine or carboxylic acid,(1c) denotes the [2,11] lactam bridge; (2a) denotes the [4,7] 1 ,3-dithio-propan-2-one bridge; (2c) denotes the [4,7] lactam bridge; (4c) denotes the [1,11] lactam bridge.

24. A compound according to claim 1 which is selected from:or a pharmaceutically acceptable salt or solvate thereof; wherein:* denotes that the (1c), (2a), (2c), and (4c) bridges use the peptide backbone amine or carboxylic acid at the / V- or C-terminus, not the side chain amine or carboxylic acid,(1c) denotes the [2,11] lactam bridge; (2a) denotes the [4,7] 1 ,3-dithio-propan-2-one bridge; (2c) denotes the [4,7] lactam bridge; (4c) denotes the [1,11] lactam bridge.

25. A pharmaceutical composition comprising a compound according to any one of the preceding claims in combination with a pharmaceutically acceptable carrier, excipient or vehicle.

26. The pharmaceutical composition according to claim 25, wherein said pharmaceutical composition is for oral administration.

27. A method for the synthesis of a compound according to any one of claims 1 to 24, comprising synthesising the analogue by solid-phase or liquid-phase peptide synthesis methodology, optionally isolating and / or purifying the final product, and optionally further comprising the step of forming an amide bond between the amino acid residues at position X1 or at position X2 when X1 is absent and at position X11 , and optionally further comprising the step of forming an amide bond or forming two thioether bonds with a linker between the amino acid residues at positions X4 and X7.

28. A compound according to any one of claims 1 to 24, or a pharmaceutical composition according to any of claims 25-26, for use in a method of medical treatment.

29. A compound according to any one of claims 1 to 24, or a pharmaceutical composition according to any of claims 25-26, for use in a method of prevention or treatment of inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, and combinations thereof.

30. The compound or pharmaceutical composition for use according to claim 29, wherein the IBD is selected from Crohn’s Disease or ulcerative colitis.