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EP-4739671-A1 - NEW COMPOUNDS

EP4739671A1EP 4739671 A1EP4739671 A1EP 4739671A1EP-4739671-A1

Abstract

The invention relates to a compound of formula I, I wherein R1, R2, R3, R4, R5, R6, R7a, R7b, Q, A, E and L are as defined in the specification, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, said compound is useful in the treatment of a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase.

Inventors

  • GRIFFIN, MARTIN
  • RATHBONE, Daniel L
  • RATCLIFFE, ANDREW JAMES
  • WANG, ZHUO
  • AQIL, REHAN

Assignees

  • Aston University

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. Claims 1. A compound of formula I, wherein: Q is selected from the group consisting of O and NH; A is N; the -E-L- linker represents: R 1 represents a 9-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups; each X is independently selected from the group consisting of halogen, -N(R 8a )R 8b , -OR 9 , -C(O)OR 10 , -C(O)N(R 11a )R 11b , a C1-4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and/or halogen atoms; R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen and C1-3 alkyl, which C1-3 alkyl group is optionally substituted by one or more halogen atoms; or R 2 and R 3 together with the carbon atoms to which they are bound form a 5- or 6-membered heterocycloalkyl group; or R 2 and R 4 together with the carbon atoms to which they are bound form a 5- or 6-membered heterocycloalkyl group; R 5 is selected from the group consisting of hydrogen, C1-3 alkyl, C3-6 cycloalkyl, which C1-3 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of deuterium atoms and halogen atoms; R 6 is selected from the group consisting of hydrogen, halogen, deuterium, and C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more halogen atoms, -CH 2 N(R 12 )Ph and -CH 2 OCH 2 Ph; R 7a and R 7b are each independently selected from the group consisting of hydrogen, halogen, methyl, and deuterium; R 8a , R 8b , R 9 , R 10 , R 11a and R 11b , are each independently selected from the group consisting of hydrogen, C1-3 alkyl, and C3-6 cycloalkyl, which C1-3 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and/or halogen atoms; or or R 8a and R 8b and/or R 11a and R 11b , together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group; R 12 is selected from the group consisting of hydrogen and C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more halogen atoms; and Ph is phenyl optionally substituted by one or more halogen atoms or C1-3 alkyl groups, which C1-3 alkyl groups are optionally substituted by one or more halogen atoms, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. 2. The compound according to Claim 1, wherein Q is O. 3. The compound according to Claim 1 or Claim 2, wherein the 9-membered, bicyclic heteroaryl group: (a) contains 1, 2, 3 or 4 ring heteroatoms each independently selected from the group consisting of N and S; and (b) is substituted by 0, 1,
  2. 2,
  3. 3, 4 or 5 X groups.
  4. 4. The compound according to any one of Claims 1 to 3, wherein R 1 is selected from the group consisting of: wherein Z 1 is selected from the group consisting of C and N; Z 2 is selected from the group consisting of S, NR 13 and CR 14 ; Z 3 , Z 4 and Z 5 are each independently selected from the group consisting of CR 15 or N; X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , R 14 and R 15 are each independently selected from the group consisting of hydrogen, halogen, -OR 9 , a C1-4 alkyl group, and a C 3-6 cycloalkyl group, which C 1-4 alkyl and C 3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and/or halogen atoms; X 4 and R 13 are each independently selected from the group consisting of hydrogen, a C 1-4 alkyl group, and a C 3-6 cycloalkyl group, which C 1-4 alkyl and C 3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and/or halogen atoms; and R 9 is as defined in Claim 1.
  5. 5. The compound according to any one of Claims 1 to 4, wherein R 1 is selected from the group consisting of: wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 13 , R 14 and R 15 are as defined in Claim 4.
  6. 6. The compound according to any one of Claims 1 to 5, wherein R 1 is selected from the group consisting of: wherein X 1 , X 2 , X 4 , R 13 , R 14 and R 15 are as defined in Claim 4 or Claim 5.
  7. 7. The compound according to any one of Claims 4 to 6, wherein: X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , R 14 and R 15 are each independently selected from the group consisting of hydrogen, -OCH 3 , -OCHF 2 , -OCHF[ 18 F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH 2 CH 3 , -CH(CH 3 ) 2 , , -CD 3 , Cl and F; and X 4 and R 13 are each independently selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, , and -CD3.
  8. 8. The compound according to any one of Claim 1 to 7, wherein: X 1 is selected from the group consisting of hydrogen, -OCH 3 , -OCHF 2 , -OCHF[ 18 F], -OCHFCl, -CF 3 , -OCH 2 F, -OCF 2 Cl, and -OH; X 4 is selected from the group consisting of hydrogen -CH3 and -CH2CH3; R 14 is selected from the group consisting of hydrogen, F, Cl and -CH 3 ; X 2 , R 13 and R 14 are each independently selected from the group consisting of hydrogen and -CH3; and X 3 , X 5 , X 6 , X 7 and X 8 are each hydrogen.
  9. 9. The compound according to any one of Claims 1 to 8, wherein: R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, methyl, and ethyl; or R 2 and R 4 together with the carbon atoms to which they are bound form a 5-membered heterocycloalkyl group.
  10. 10. The compound according to any one of Claims 1 to 9, wherein R 5 is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl, and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms.
  11. 11. The compound according to any one of Claims 1 to 10, wherein: R 6 is hydrogen; and R 7a and R 7b are independently selected from the group consisting of hydrogen and deuterium.
  12. 12. The compound according to Claim 1, wherein the compound is selected from the group consisting of: , or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof.
  13. 13. A compound selected from the group consisting of: , or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof.
  14. 14. A pharmaceutical formulation comprising a compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, and a pharmaceutically acceptable excipient.
  15. 15. A compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 14, for use in medicine.
  16. 16. A method of treating or preventing a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase comprising administering a compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in any one of Claim 14, to a subject in need thereof.
  17. 17. The method according to Claim 16, wherein the disease or condition which is responsive to treatment with an inhibitor of a transglutaminase is selected from the group consisting of fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation, pulmonary hypertension, and diseases or conditions associated with pathological angiogenesis.
  18. 18. The method according to Claim 17, wherein the disease or condition is selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, cardiac fibrosis, cystic fibrosis, liver fibrosis, fibrosis of the kidney, scarring, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, multiple sclerosis, coeliac disease, thrombosis, prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, sarcomas, AIDS, psoriasis, chronic inflammatory disease, inflammatory bowel disease, Crohn's disease, diabetic retinopathy, age- related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch and central retinal vein occlusion and retinal trauma.
  19. 19. A method for preventing or treating rejection of a transplanted organ comprising contacting the organ with a compound as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 14, optionally wherein the organ is treated: (a) prior to transplantation; or (b) during and/or after transplantation into a patient, and preferably wherein the organ is a heart, lung, kidney or liver.
  20. 20. A process for preparing a compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, which process comprises: (a) reaction of a compound of formula II, with a compound of formula III, wherein Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , A, E and L are as defined in any one of Claims 1 to 13 and G 1 is a suitable leaving group; (b) compounds of formula I, reaction of a compound of formula V, with a compound of formula XIX, wherein Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b and L are as defined in any one of Claims 1 to 13 and M is a suitable metal atom; or (c) for compounds of formula I where R 7a and R 7b are both deuterium, reaction of a compound of formula XXII, with a suitable source of deuterium, wherein Q, R 1 , R 2 , R 3 , R 4 , R 5 , A, E and L are as defined in any one of Claims 1 to 13 and each R 17 is independently a C1-3 alkyl group.

Description

NEW COMPOUNDS Field of the Invention The present invention relates to novel compounds, and the use of such compounds in medicine. In particular, the present invention relates to compounds that are useful in treating a disorder or condition which is responsive to treatment with an inhibitor of a transglutaminase. Background of the Invention Transglutaminases (TGs or TGases) are a group of enzymes able to modify proteins by mediating an acyl-transfer reaction between the γ-carboxamide group of peptide-bound glutamine and a primary amine. The result of this reaction is post-translational modification, either through protein crosslinking, if the amine is the ε-amino group of peptide-bound lysine, or modification of the peptide glutamine by crosslinking to a primary amine such as a polyamine. Under certain conditions and in the absence of a suitable primary amine, the deamidation of peptide bound glutamine can also occur. Because of their ability to crosslink proteins into high molecular weight protein aggregates TGs have been termed as “Nature’s Biological glues” (Griffin et al., 2002). TGs are found widely in nature, but in mammals their enzymatic activity is Ca2+-dependent, and other factors including GTP/GDP can also affect the activity of some of the mammalian TGs (Verderio et al., 2004). Not all of the eight active members (TG1-7 and factor XIII) of the mammalian TG family have been fully characterized (Collighan and Griffin, 2009). Another member of this family, band 4.2, is catalytically inactive and is mainly associated with the regulation of the erythrocyte cytoskeleton. TG2 (tissue transglutaminase, TG2M, tTG) is probably the most ubiquitous member of the mammalian TG family which is found both in the intra- and extra-cellular environment. In addition to its transamidating, GTPase and ATPase activity (Nakaoka et al., 1994), further novel activities have recently been reported for TG2 e.g. the protein disulfide isomerase (PDI) (Hasegawa et al., 2003) and protein kinase activities (Mishra and Murphy, 2004), thus further extending the potential physiological and pathological importance of this diverse group of enzymes. Abnormal levels of transglutaminase particularly TG2 and /or activity have been observed in many disease states, like celiac sprue, neurodegenerative diseases (Alzheimer, Parkinson, Huntington disease), fibrosis, cataract, cancer metastasis, and the list is certainly not intended to be exhaustive. Moreover, proof of concept studies using either TG2-/- animal models (Bailey and Johnson, 2005; Mastroberardino et al., 2002) or inhibitor studies (Huang et al., 2009; Johnson et al., 2008) have shown the enzyme to be a potential novel candidate for therapeutic intervention. Due to its implication in a wide variety of biological processes and pathologies, developing chemicals tools to further investigate TG2s multifunctional roles is an active research area. Most of the inhibitors developed so far target the enzyme's catalytic site, but there are also reports of small molecules competing for the TG2 cofactor binding site. Depending on their ability to reach and react with the catalytic cysteine residue (CYS277 in case of hTG2), they can further be divided into reversible and irreversible inhibitors. Peptidic inhibitors bearing various electrophilic moieties (e.g. chloroacetamides (Pardin et al., 2006), α,β-unsaturated amides (Pardin et al., 2006), maleimides (Halim et al., 2007), sulfonium methyl ketones (Griffin et al., 2008), dihydroisoxazoles (Dafik and Khosla, 2011), cinnamoyl derivatives (Pardin et al., 2008a; Pardin et al., 2008b), oxindoles (Klock et al., 2011), sulfonamidopiperazines (Prime et al., 2012) are examples of such derivatives. The resolved TG2 structures co-crystallized either with irreversible inhibitors (Lindemann et al., 2012; Pinkas et al., 2007) or nucleotides (Han et al., 2010; Liu et al., 2002), revealed the huge conformational change of the enzyme when passing from the inactive to the active state, and will certainly enhance the design of more potent inhibitors in the future. It has been shown that small molecule inhibitors of TG2 may be effective treatments of various fibrotic diseases. For instance, Wang et al., 2018 report that cardiac fibrosis can be attenuated by blocking the activity of TG2 using a selective small-molecule inhibitor. Moreover, both Huang et al., 2009 and Johnson et al., 2007 report that TG2 inhibition ameliorates fibrotic kidney disease. Further still, Fell et al., 2021 identified TG2 as a potential therapeutic target for idiopathic pulmonary fibrosis. An example of a TG2 inhibitor is compound 1–155 (i.e. Reference Compound 1), which was first disclosed in WO 2014/057266. As a TG2 inhibitor, compound 1–155 is useful in the treatment or prevention of a disease or condition which is responsive to treatment with an inhibitor of tissue transglutaminase. For example, such compounds may be useful in the treatment of fibrosis, scarring, neurodegen