# US 2021/0276952 A1 · Novel compounds > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2021/0276952 A1 - Document ID: US20210276952A1 - Status: Published application - Kind: A1 - Application number: 17/254,854 - Filed: 2019-06-21 - Published: 2021-09-09 - Earliest claimed: 2018-06-22 - Applicants: Ucl Business Ltd - Inventors: Kate SMITH; Alexis DENIS; Nerina DODIC; John LIDDLE; David LOMAS - Web page: https://patentgrep.com/patent/US20210276952A1 ## CPC - A61K 31/404: Indoles, e.g. pindolol - C07D 209/34: in position 2 - A61P 11/16: Central respiratory analeptics - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as modulators of alpha I antitrypsin and treating diseases associated with alpha antitrypsin, particularly liver diseases. ## Claims ### Claim 1 A compound having a molecular weight of 1000 Daltons or less that is capable of inhibiting α1-antitrypsin polymerisation; or a pharmaceutically acceptable solvate, complex, tautomer, isotopically labelled derivative or prodrug thereof. ### Claim at position 2 2-33. (canceled) ### Claim 34 (depends on 1) The compound of claim 1, wherein the compound is capable of binding to α1-antitrypsin by inducing formation of a cryptic binding site within the α1-antitrypsin protein structure, said α1-antitrypsin comprising the sequence of SEQ ID NO: 1. ### Claim 35 (depends on 1) The compound of claim 1, wherein the binding site is located between β-sheet-A and β-sheet-B of said α1-antitrypsin, wherein: a) said β-sheet-A comprises the amino acids corresponding to residues 140-144, 111-121, 181-191, 330-340 and 292-299 of SEQ ID NO: 1; and said β-sheet-B comprises the amino acids corresponding to residues 228-231, 236-244, 248-256, 369-376, 381-389, and 49-53 of SEQ ID NO: 1 or b) wherein the binding site is located between amino acid strands corresponding to each of: (a) residues 191-194 of SEQ ID NO: 1; (b) residues 288-293 of SEQ ID NO: 1; (c) residues 371-374 of SEQ ID NO: 1; (d) residues 249-253 of SEQ ID NO: 1; and (e) residues 240-243 of SEQ ID NO: 1; and optionally also (f) residues 338-341 of SEQ ID NO: 1. ### Claim 36 (depends on 35) The compound of claim 35, wherein the binding site comprises one or more of W194, Y244, L291, P289, F252, K290, I293, L338, I340, F372 and M374 of SEQ ID NO: 1. ### Claim 37 (depends on 34) The compound of claim 34, wherein: the KD of the compound to M-α1-antitrypsin is less than about 250 nM, said M-α1-antitrypsin comprising the sequence of SEQ ID NO: 2; or wherein the KD of the compound to Z-α1-antitrypsin is less than about 25 nM, said Z-α1-antitrypsin comprising the sequence of SEQ ID NO: 3; or wherein the KD of the compound to Z-α1-antitrypsin is at least ten times lower than the KD of the compound to M-α1-antitrypsin, said M-α1-antitrypsin comprising the sequence of SEQ ID NO: 2 and said Z-α1-antitrypsin comprising the sequence of SEQ ID NO: 3. ### Claim 38 (depends on 1) The compound of claim 1, wherein the compound comprises a tetravalent moiety of formula (IA) wherein the compound is capable of binding to α1-antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1. ### Claim 39 (depends on 1) The compound of claim 1, wherein the compound comprises a divalent moiety of formula (IB) wherein: the compound is capable of binding to α1-antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; R4 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy; and R5 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy. ### Claim 40 (depends on 39) The compound of claim 39, wherein R5 is hydrogen; and/or R4 is C2-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C1-3 alkoxy; and/or R4 is n-propyl. ### Claim 41 (depends on 1) The compound of claim 1, wherein the compound comprises a monovalent moiety of formula (IC) wherein: the compound is capable of binding to α1-antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; R4 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy; and R5 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy; and R6 is a substituted or unsubstituted aryl or heteroaryl group capable of stacking with the side chain of W194 of SEQ ID NO: 1. ### Claim 42 (depends on 41) The compound of claim 41, wherein: R6 is a substituted or unsubstituted 4-oxindolyl group; or R6 is a group of formula R6′ wherein R1 is selected from the group consisting of H, F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, Cl, Br and I. ### Claim 43 (depends on 42) The compound of claim 42, wherein R1 is selected from the group consisting of H, F, CH3, NH2, OH and Cl; optionally wherein R1 is selected from the group consisting of H and F. ### Claim 44 (depends on 1) The compound of claim 1, wherein the compound has the formula (ID) wherein: the compound is capable of binding to α1-antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; R4 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy; R5 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C1-4 alkoxy; R6 is a group of formula R6′ wherein R1 is selected from the group consisting of H, F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, Cl, Br and I; and R7 is a substituted or unsubstituted aryl or heteroaryl group. ### Claim 45 (depends on 44) The compound of claim 44, wherein R7 is a substituted or unsubstituted phenyl group; optionally wherein R7 is a group of formula R7′ wherein: R2 is selected from the group consisting of CH3, Cl, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, SH, CN, F, Br and I; and R3 is selected from the group consisting of F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, Br, I and SH. ### Claim 46 (depends on 45) The compound of claim 45, wherein R2 is selected from the group consisting of CH3, Cl, NH2, OH, SH, CN and F, optionally wherein R2 is selected from the group consisting of CH3 and Cl; and R3 is selected from the group consisting of F, Cl, CN, CH3, NH2, OH and SH, optionally wherein R3 is selected from the group consisting of F, Cl and CN. ### Claim 47 (depends on 1) The compound of claim 1, wherein the compound has the formula (I) wherein R1 is selected from the group consisting of H, F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, Cl, Br and I; R2 is selected from the group consisting of CH3, Cl, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, SH, CN, F, Br and I; and R3 is selected from the group consisting of F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, OH, Br, I and SH. ### Claim 48 (depends on 47) The compound of claim 47, wherein R1 is selected from the group consisting of H, F, CH3, NH2, OH and Cl, optionally wherein R1 is selected from the group consisting of H and F; R2 is selected from the group consisting of CH3, Cl, NH2, OH, SH, CN and F, optionally wherein R2 is selected from the group consisting of CH3 and Cl; and R3 is selected from the group consisting of F, Cl, CN, CH3, NH2, OH and SH, optionally wherein R3 is selected from the group consisting of F, Cl and CN. ### Claim 49 (depends on 48) The compound of claim 48, wherein R1 is H, R2 is CH3 and R3 is F, or R1 is H, R2 is CH3 and R3 is Cl, or R1 is F, R2 is Cl and R3 is CN, or R1 is F, R2 is Cl and R3 is F. ### Claim 50 (depends on 1) A method for treating of a disease or condition mediated by α1-antitrypsinpolymerisation, comprising administering to a patient in need thereof a compound according to claim 1. ### Claim 51 (depends on 50) The method of claim 50, wherein the disease or condition is mediated by Z-α1-antitrypsin polymerisation and the compound is capable of inhibiting Z-α1-antitrypsin polymerisation. ### Claim 52 (depends on 35) A method for identifying a drug candidate compound, the method comprising: i) contacting the drug candidate compound with α1-antitrypsin comprising the sequence of SEQ ID NO: 1 to form a complex between the drug candidate compound and said α1-antitrypsin; ii) resolving the structure of the complex; and iii) determining whether, in the complex, the drug candidate compound is present in a binding site as defined in claim 35; optionally wherein said contacting the drug candidate compound with said α1-antitrypsin comprises forming a crystal of said α1-antitrypsin and contacting said crystal with said drug candidate.