Search

EP-4735442-A1 - IMIDAZO[1,2-alpha]PYRIDINE COMPOUNDS FOR USE IN TREATING CANCER AND INFLAMMATORY DISEASES AND METHODS TO PREPARE SAID COMPOUNDS

EP4735442A1EP 4735442 A1EP4735442 A1EP 4735442A1EP-4735442-A1

Abstract

The present invention relates to ALDH1 A inhibitor compound isoforms according to Formula (I) and pharmaceutical compositions comprising said compounds. Medical compounds for the inhibition of the activity of subtype 1 A aldehyde dehydrogenase proteins are provided, including 2,6,8-trisubstituted imidazo[1,2-α]pyridines. Pathologies and diseases resulting from an upregulation of one or more ALDH1A isoforms may be prevented or treated thereby.

Inventors

  • LA MOTTA, Concettina
  • MARCATO, PAOLA
  • FERNANDO, Wasundara
  • MACLEAN, Maya
  • DEAN, CHERYL
  • PETRAROLO, Giovanni
  • BERNARDONI, Bianca Laura
  • D'AGOSTINO, Ilaria

Assignees

  • Theranib Inc.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof: where A, X, and Z are each independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups; Ri is selected from hydrogen, amino, fluoro, chloro, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2- C6alkenyloxy, C2-C6alkynyloxy, C3-C7cycloalkyl, C3-C7heterocycloalkyl, hydroxyCl-C6alkyl, hydroxyCl-C6alkoxy, hydroxyCl-C6alkylamino, Cl-C6alkoxyCl-C6alkyl, Cl-C6alkoxyCl- C6alkylamino, aminoCl-C6alkyl, aminoCl-C6alkoxy, Cl-C6alkylamino, di-Cl-C6alkylamino, Cl- C6-alkyldiamino, Cl-C6alkoxycarbonyl, Cl-C6alkoxyaminocarbonyl, Cl-C6alkylthio, phosphateCl-C6alkylthio, sulfateCl-C6alkylthio, thioCl-C6alkyl, thioCl-C6alkoxy, thioCl- C6alkylamino, heterocycloCl-C6alkyl, heterocycloCl-C6alkoxy, heterocycloCl-C6alkylamino, phosphateCl-C6alkylamino, sulfateCl-C6alkylamino, Cl-C6a Ikylsu Ifinyl, Cl-C6alkylsulfonyl, Cl- C6alkylthiocarboxamide, Cl-C6alkylcarboxamide, C1-C6 alkylthiou reyl, Cl-C6alkylureyl, Cl- C6dialkylamino, Cl-C6alkoxycarbonyl, Cl-C6dialkylcarboxamide, C1-C6 dialkylsulfonamide, Cl- C6dialkylthiocarboxamido, Cl-C6haloalkyl, Cl-C6haloalkoxy, Cl-C6guanidinealkyl, Cl- C6cyanoalkyl, arylCl-C6alkoxy, heteroarylCl-C6alkoxy, cyclicCl-C6alkoxy, phosphateCl- C6alkoxy, sulfateCl-C6alkoxy, arylCl-C6alkylamino, heteroarylCl-C6alkylamino, cyclicCl- C6alkylamino, (((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, aryl, heteroaryl, heterocyclic, and cyclic groups; and R 2 and R 3 are each independently selected from hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amido, acetyl, sulfonamido, acryl, acrylaldehyde, but-3-en-2-one, methyl acrylate, N,N-dimethylacrylate, 2- (methylsulfonyl)vinyl, ethane-l-sulfonate, ethane-l-sulfonamido, acrylonitrile, nitrovinyl, pent- 2-ene-l, 4-dione, 4-oxobut-2-enoate, N,N-dimethyl-4-oxobut-2-enoate, ethan-l-one, and oxiran- 2-yl-ethan-l-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6alkenyloxy, C2-C6alkynyloxy, C3- C7cycloalkyl, C3-C7heterocycloalkyl, hydroxyCl-C6alkyl, hydroxyCl-C6alkoxy, hydroxyCl- C6alkylamino, Cl-C6alkoxyCl-C6alkyl, Cl-C6alkoxyCl-C6alkylamino, aminoCl-C6alkyl, aminoCl- C6alkoxy, Cl-C6alkylamino, di-Cl-C6alkylamino, Cl-C6-alkyldiamino, Cl-C6alkoxycarbonyl, Cl- C6alkoxyaminocarbonyl, Cl-C6alkylthio, phosphateCl-C6alkylthio, sulfateCl-C6alkylthio, thioCl- C6a Ikyl, thioCl-C6alkoxy, thioCl-C6alkylamino, heterocycloCl-C6alkyl, heterocycloCl-C6alkoxy, heterocycloCl-C6alkylamino, phosphateCl-C6alkylamino, sulfateCl-C6alkylamino, Cl- C6a Ikylsulfinyl, Cl-C6alkylsulfonyl, Cl-C6alkylthiocarboxamide, Cl-C6alkylcarboxamide, C1-C6 alkylthioureyl, Cl-C6alkylureyl, Cl-C6dialkylamino, Cl-C6alkoxycarbonyl, Cl- C6dialkylcarboxamide, C1-C6 dialkylsulfonamide, Cl-C6dialkylthiocarboxamido, Cl-C6haloalkyl, Cl-C6haloalkoxy, Cl-C6guanidinealkyl, Cl-C6cyanoalkyl, arylCl-C6alkoxy, heteroarylCl- C6alkoxy, cyclicCl-C6alkoxy, phosphateCl-C6alkoxy, sulfateCl-C6alkoxy, arylCl-C6alkylamino, heteroarylCl-C6alkylamino, cyclicCl-C6alkylamino, (((3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl, aryl, heteroaryl, heterocyclic, and cyclic groups; and in which extant aryl, heteroaryl, heterocyclic, and cyclic groups are further functionalized with zero or more substituents selected from hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amido, acetyl, sulfonamido, acryl, acrylaldehyde, but-3-en-2-one, methyl acrylate, N,N-dimethylacrylate, 2- (methylsulfonyl)vinyl, ethane-l-sulfonate, ethane-l-sulfonamido, acrylonitrile, nitrovinyl, pent- 2-ene-l, 4-dione, 4-oxobut-2-enoate, N,N-dimethyl-4-oxobut-2-enoate, ethan-l-one, and oxiran- 2-yl-ethan-l-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, acrylonitrile, dichloroacetamide, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-Cl-C6 alkylamino, amino C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, Cl- C6 alkylaminocarbonyl, C1-C6 dialkyl aminocarbonyl, C1-C6 alkylsulfonyl aminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl and C3-C7 cycloalkylaminocarbonyl.
  2. 2. The compound of claim 1 in which A, X, and Z are each phenyl; Ri is selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, thiol, amino, amido, acetyl, sulfonamido, acryl, acrylaldehyde, but-3-en-2-one, methyl acrylate, N,N- dimethylacrylate, 2-(methylsulfonyl)vinyl, ethane-l-sulfonate, ethane-l-sulfonamido, acrylonitrile, nitrovinyl, pent-2-ene-l, 4-dione, 4-oxobut-2-enoate, N,N-dimethyl-4-oxobut-2- enoate, ethan-l-one, and oxiran-2-yl-ethan-l-one; and R 2 and R 3 are each independently selected from hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amido, acetyl, sulfonamido, acryl, acrylaldehyde, but-3- en-2-one, methyl acrylate, N,N-dimethylacrylate, 2-(methylsulfonyl)vinyl, ethane-l-sulfonate, ethane-l-sulfonamido, acrylonitrile, nitrovinyl, pent-2-ene-l, 4-dione, 4-oxobut-2-enoate, N,N- dimethyl-4-oxobut-2-enoate, ethan-l-one, and oxiran-2-yl-ethan-l-one.
  3. 3. The compound of claim 1 in which A, X, and Z are each phenyl; Ri is selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in either direction), methyl ether, fluoro, chloro, alkoxy, methoxy, and cyano; and R 2 and R 3 are each independently selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano.
  4. 4. The compound of claim 3 in which extant aryl, heteroaryl, heterocyclic, and cyclic groups are further functionalized with up to two additional substituents selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano.
  5. 5. The compound of claim 1 where the compound is selected from 2,6,8-triphenylimidazo[l,2- a] pyridine, 2-(4-chlorophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(3-chlorophenyl)-6,8- diphenylimidazo[l,2-a] pyridine, 2-(2-chlorophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(3- bromophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(2-bromophenyl)-6,8-diphenylimidazo[l,2- a] pyridine, 2-(4-iodophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(3-iodophenyl)-6,8- diphenylimidazo[l,2-a] pyridine, 2-(2-iodophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(4- nitrophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(3-nitrophenyl)-6,8-diphenylimidazo[l,2- a] pyridine, 2-(2-nitrophenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 6,8-diphenyl-2-(p- tolyl)imidazo[l,2-a] pyridine, 6,8-diphenyl-2-(m-tolyl)imidazo[l,2-a] pyridine, 6,8-diphenyl-2-(o- tolyl)imidazo[l,2-a] pyridine, 2-(4-methoxyphenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(3- methoxyphenyl)-6,8-diphenylimidazo[l,2-a] pyridine, 2-(2-methoxyphenyl)-6,8- diphenylimidazo[l,2-a] pyridine, 4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzonitrile, 3-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl) benzonitrile, 2-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)benzonitrile, 4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzaldehyde, 3-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl) benzaldehyde, 2-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)benzaldehyde, 4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)phenol, 3-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)phenol, 2-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)phenol, 4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl) benzenethiol, 3-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)benzenethiol, 2-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzenethiol, 4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl)aniline, 3-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)aniline, 2- (6,8-diphenylimidazo[l,2-a]pyridin-2-yl)aniline, 4-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)benzamide, 3-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzamide, 2-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)benzamide, 4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzenesulfonamide, 3- (6,8-diphenylimidazo[l,2-a]pyridin-2-yl)benzenesulfonamide, 2-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)benzenesulfonamide, 3-(4-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)phenyl)acryla Idehyde, 4-(4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)but-3-en-2-one, methyl 3-(4-(6,8-diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)acrylate, 3-(4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)-N,N-dimethylacrylamide, 2-(4-(2- (methylsulfonyl)vinyl)phenyl)-6,8-diphenylimidazo[l,2-a] pyridine methyl, 2-(4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)ethene-l-sulfonate, 2-(4-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)phenyl)ethene-l-sulfonamide, 3-(4-(6,8-diphenylimidazo[l,2-a]pyridin-2- yl)phenyl)acrylonitrile, 2-(4-(2-nitrovinyl)phenyl)-6,8-diphenylimidazo[l,2-a] pyridine, l-(4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)pent-2-ene-l, 4-dione, methyl 4-(4-(6,8- diphenylimidazo[l,2-a]pyridin-2-yl)phenyl)-4-oxobut-2-enoate, 4-(4-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)phenyl)-N,N-dimethyl-4-oxobut-2-enamide, l-(3-(4-(6,8-diphenylimidazo[l,2- a]pyridin-2-yl)benzoyl)oxirane-2-yl)ethan-l-one, 6-(4-chlorophenyl)-2,8-diphenylimidazo[l,2- a] pyridine, 6-(3-chlorophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(2-chlorophenyl)-2,8- diphenylimidazo[l,2-a] pyridine, 6-(4-bromophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(3- bromophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(2-bromophenyl)-2,8-diphenylimidazo[l,2- a] pyridine, 6-(4-iodophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(3-iodophenyl)-2,8- diphenylimidazo[l,2-a] pyridine, 6-(2-iodophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(4- nitrophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(3-nitrophenyl)-2,8-diphenylimidazo[l,2- a] pyridine, 6-(2-nitrophenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 2,8-diphenyl-6-(p- tolyl)imidazo[l,2-a] pyridine, 2,8-diphenyl-6-(m-tolyl)imidazo[l,2-a] pyridine, 2,8-diphenyl-6-(o- tolyl)imidazo[l,2-a] pyridine, 6-(4-methoxyphenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(3- methoxyphenyl)-2,8-diphenylimidazo[l,2-a] pyridine, 6-(2-methoxyphenyl)-2,8- diphenylimidazo[l,2-a] pyridine, 4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benzonitrile, 3-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl) benzonitrile, 2-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)benzonitrile, 4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benza Idehyde, 3-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl) benzaldehyde, 2-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)benza Idehyde, 4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)phenol, 3-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)phenol, 2-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)phenol, 4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl) benzenethiol, 3-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)benzenethiol, 2-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benzenethiol, 4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl)aniline, 3-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)aniline, 2- (2,8-diphenylimidazo[l,2-a]pyridin-6-yl)aniline, 4-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)benzamide, 3-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benzamide, 2-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)benzamide, 4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benzenesulfonamide, 3- (2,8-diphenylimidazo[l,2-a]pyridin-6-yl)benzenesulfonamide, 2-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)benzenesulfonamide, 3-(4-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)phenyl)acrylaldehyde, 4-(4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)but-3-en-2-one, methyl 3-(4-(2,8-diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)acrylate, 3-(4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)-N,N-dimethylacrylamide, 6-(4-(2- (methylsulfonyl)vinyl)phenyl)-2,8-diphenylimidazo[l,2-a] pyridine, methyl 2-(4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)ethene-l-sulfonate, 2-(4-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)phenyl)ethene-l-sulfonamide, 3-(4-(2,8-diphenylimidazo[l,2-a]pyridin-6- yl)phenyl)acrylonitrile, 6-(4-(2-nitrovinyl)phenyl)-2,8-diphenylimidazo[l,2-a] pyridine, l-(4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)pent-2-ene-l, 4-dione, methyl 4-(4-(2,8- diphenylimidazo[l,2-a]pyridin-6-yl)phenyl)-4-oxobut-2-enoate, 4-(4-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)phenyl)-N,N-dimethyl-4-oxobut-2-enamide, l-(3-(4-(2,8-diphenylimidazo[l,2- a]pyridin-6-yl)benzoyl)oxirane-2-yl)ethan-l-one, 8-(4-chlorophenyl)-2,6-diphenylimidazo[l,2- a] pyridine, 8-(3-chlorophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(2-chlorophenyl)-2,6- diphenylimidazo[l,2-a] pyridine, 8-(4-bromophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(3- bromophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(2-bromophenyl)-2,6-diphenylimidazo[l,2- a] pyridine, 8-(4-iodophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(3-iodophenyl)-2,6- diphenylimidazo[l,2-a] pyridine, 8-(2-iodophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(4- nitrophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(3-nitrophenyl)-2,6-diphenylimidazo[l,2- a] pyridine, 8-(2-nitrophenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 2,6-diphenyl-8-(p- tolyl)imidazo[l,2-a] pyridine, 2,6-diphenyl-8-(m-tolyl)imidazo[l,2-a] pyridine, 2,6-diphenyl-8-(o- tolyl)imidazo[l,2-a] pyridine, 8-(4-methoxyphenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(3- methoxyphenyl)-2,6-diphenylimidazo[l,2-a] pyridine, 8-(2-methoxyphenyl)-2,6- diphenylimidazo[l,2-a] pyridine, 4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzonitrile, 3-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl) benzonitrile, 2-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)benzonitrile, 4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzaldehyde, 3-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl) benzaldehyde, 2-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)benzaldehyde, 4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)phenol, 3-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)phenol, 2-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)phenol, 4-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl) benzenethiol, 3-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)benzenethiol, 2-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzenethiol, 4-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl)aniline, 3-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)aniline, 2- (2,6-diphenylimidazo[l,2-a]pyridin-8-yl)aniline, 4-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)benzamide, 3-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzamide, 2-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)benzamide, 4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzenesulfonamide, 3- (2,6-diphenylimidazo[l,2-a]pyridin-8-yl)benzenesulfonamide, 2-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)benzenesulfonamide, 3-(4-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)phenyl)acrylaldehyde, 4-(4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)phenyl)but-3-en-2-one, methyl 3-(4-(2,6-diphenylimidazo[l,2-a]pyridin-8-yl)phenyl)acrylate, 3-(4-(2,6- diphenylim idazo[l,2-a]pyridin-8-yl) phenyl)-N,N-dimethylacrylam ide, 8-(4-(2- (methylsulfonyl)vinyl)phenyl)-2,6-diphenylimidazo[l,2-a] pyridine, methyl 2-(4-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethene-l-sulfonate, 2-(4-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)phenyl)ethene-l-sulfonamide, 3-(4-(2,6-diphenylimidazo[l,2-a]pyridin-8- yl)phenyl)acrylonitrile, 8-(4-(2-nitrovinyl)phenyl)-2,6-diphenylimidazo[l,2-a] pyridine, l-(4-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl)phenyl)pent-2-ene-l, 4-dione, methyl 4-(4-(2,6- diphenylimidazo[l,2-a]pyridin-8-yl)phenyl)-4-oxobut-2-enoate, 4-(4-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)phenyl)-N,N-dimethyl-4-oxobut-2-enamide, l-(3-(4-(2,6-diphenylimidazo[l,2- a]pyridin-8-yl)benzoyl)oxirane-2-yl)ethan-l-one, l,l'-((2-phenylimidazo[l,2-a]pyridine-6,8- diyl)bis(4,l-phenylene))bis(ethan-l-one), 4-(8-(4-acetylphenyl)-2-phenylimidazo[l,2-a]pyridin-6- yl)benzonitrile, 4-(8-(4-acetylphenyl)-2-phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile, l-(4-(6-(4- fluorophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(6-(4-chlorophenyl)- 2-phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(6-(4-bromophenyl)-2- phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(6-(3,5-dimethoxyphenyl)-2- phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, dimethyl 4,4'-(2-phenylimidazo[l,2- a]pyridine-6,8-diyl)dibenzoate, methyl 4-(6-(4-cyanophenyl)-2-phenylimidazo[l,2-a]pyridin-8- yl)benzoate, methyl 4-(6-(3-cyanophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)benzoate, methyl 4-(6-(4-fluorophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)benzoate, methyl 4-(6-(4- chlorophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)benzoate, methyl 4-(6-(4-bromophenyl)-2- phenylimidazo[l,2-a]pyridin-8-yl)benzoate, methyl 4-(6-(3,5-dimethoxyphenyl)-2- phenylimidazo[l,2-a]pyridin-8-yl)benzoate, 6,8-bis(4-chlorophenyl)-2-phenylimidazo[l,2- a] pyridine, 4-(8-(4-chlorophenyl)-2-phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile, 3-(8-(4- chlorophenyl)-2-phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile, 8-(4-chlorophenyl)-6-(4- fluorophenyl)-2-phenylimidazo[l,2-a] pyridine, 6-(4-bromophenyl)-8-(4-chlorophenyl)-2- phenylimidazo[l,2-a] pyridine, 8-(4-chlorophenyl)-6-(3,5-dimethoxyphenyl)-2- phenylimidazo[l,2-a] pyridine, l-(4-(8-(4-chlorophenyl)-2-phenylimidazo[l,2-a]pyridin-6- yl)phenyl)ethan-l-one, 3-(8-(4-acetylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)imidazo[l,2- a]pyridin-6-yl)benzonitrile, l-(4-(2-(4-((2-hydroxyethyl)amino)phenyl)-6-phenylimidazo[l,2- a]pyridin-8-yl)phenyl)ethan-l-one, 3-(8-(4-acetylphenyl)-2-(4-((2- hydroxyethyl)amino)phenyl)imidazo[l,2-a]pyridin-6-yl)benzonitrile, l-(4-(6-(3,5- dimethoxyphenyl)-2-(4-((2-hydroxyethyl)amino)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan- 1-one, 3-(8-(4-acetylphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[l,2-a]pyridin-6- yl)benzonitrile, 3-(8-(4-acetylphenyl)-2-(4-((14-hydroxy-3,6,9,12- tetraoxatetradecyl)amino)phenyl)imidazo[l,2-a]pyridin-6-yl)benzonitrile3-(8-(4-acetylphenyl)-2- (4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)imidazo[l,2-a]pyridin-6-yl)benzonitrile, l-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[l,2-a]pyridin-8- yl)phenyl)ethan-l-one, l-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12- tetraoxatetradecyl)amino)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(6-(3,5- dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)imidazo[l,2- a]pyridin-8-yl)phenyl)ethan-l-one, 3-(8-(4-acetylphenyl)-2-(4-(2- morpholinoethoxy)phenyl)imidazo[l,2-a]pyridin-6-yl)benzonitrilel-(4-(6-(3,5-dimethoxyphenyl)- 2-(4-(2-morpholinoethoxy)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(2-(4-(2- (diethylamino)ethoxy)phenyl)-6-(3,5-dimethoxyphenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan- 1-one, 3-(8-(4-acetylphenyl)-2-(4-(2-(diethylamino)ethoxy)phenyl)imidazo[l,2-a]pyridin-6- yl)benzonitrile, l-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-(piperazin-l- yl)ethyl)amino)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, 3-(8-(4-acetylphenyl)-2- (4-((2-(piperazin-l-yl)ethyl)amino)phenyl)imidazo[l,2-a]pyridin-6-yl)benzonitrile, 3-(8-(4- acetylphenyl)-2-(4-(2-(piperazin-l-yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-6-yl) benzonitrile, 3-(8- (4-acetylphenyl)-2-(4-((2-(4-methylpiperazin-l-yl)ethyl)amino)phenyl)imidazo[l,2-a]pyridin-6- yl)benzonitrile, l-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-(piperazin-l- yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l-one, l-(4-(6-(3,5-dimethoxyphenyl)- 2-(4-((2-(4-methylpiperazin-l-yl)ethyl)amino)phenyl)imidazo[l,2-a]pyridin-8-yl)phenyl)ethan-l- one, N-(4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl)imidazo[l,2-a]pyridin-2-yl)phenyl)-2- aminoacetamide, N-(4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[l,2-a]pyridin-2-yl)phenyl)- 2-aminoacetamide, 4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[l,2-a]pyridin-2-yl)phenyl acetate, 4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl)imidazo[l,2-a]pyridin-2-yl)phenyl acetate, l-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[l,2-a]pyridin-8- yl)phenyl)ethan-l-one, 3-(8-(4-acetylphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[l,2-a]pyridin-6- yl)benzonitrile, l,l'-((2-phenylimidazo[l,2-a]pyridine-6,8-diyl)bis(4,l-phenylene))bis(ethan-l- one), 3-(8-(4-acetylphenyl)-2-phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile, l-(4-(6-(4- fluorophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethane-l-one, l-(4-(6-(4- chlorophenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethane-l-one, l-(4-(6-(3,5- dimethoxyphenyl)-2-phenylimidazo[l,2-a]pyridin-8-yl)phenyl)ethane-l-one, 6,8-bis(4- chlorophenyl)-2-phenylimidazo[l,2-a] pyridine, 2-phenyl-6,8-di-p-tolylimidazo[l,2-a] pyridine, 6.8-bis(4-methoxyphenyl)-2-phenylimidazo[l,2-a] pyridine, 4,4'-(2-phenylimidazo[l,2-a]pyridine- 6.8-diyl)dibenzaldehyde, dimethyl 4,4'-(2-phenylimidazo[l,2-a]pyridine-6,8-diyl)dibenzoate, l,l'-((2-(4-hydroxyphenyl)imidazo[l,2-a]pyridine-6,8-diyl)bis(4,l-phenylene))bis(ethan-l-one), and l,l'-((2-(4-methoxyphenyl)imidazo[l,2-a]pyridine-6,8-diyl)bis(4,l-phenylene))bis(ethan-l- one).
  6. 6. The compound of claim 1 in which the compound is l,l'-((2-phenylimidazo[l,2-a]pyridine-6,8- diyl)bis(4,l-phenylene))bis(ethan-l-one).
  7. 7. The compound of claim 1 in which the compound is 4-(8-(4-acetylphenyl)-2-phenylimidazo[l,2- a]pyridin-6-yl)benzonitrile.
  8. 8. A method of manufacture of a 2,6,8-trisubstitued imidazo[l,2-a]pyridine, the method comprising reacting an alpha-aminopyridine directly connected to bromine and to iodine with a beta-carbonyl alkyl halide directly connected to a first functional group to produce an imidazo[l,2-a]pyridine nucleus directly connected to the first functional group, then reacting the product sequentially with a boronic acid directly connected to a second functional group and a boronic acid directly connected to a third functional group, wherein the 2,6,8- trisubstituted imidazo[l,2-a]pyridine results.
  9. 9. The method of manufacture of claim 8 in which the resulting compound is l,l'-((2- phenylimidazo[l,2-a]pyridine-6,8-diyl)bis(4,l-phenylene))bis(ethan-l-one).
  10. 10. The method of manufacture of claim 8 in which the resulting compound is 4-(8-(4-acetylphenyl)- 2-phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile.
  11. 11. A method of treatment of a pathology or disease resulting from abnormal regulation of subtype 1A aldehyde dehydrogenase activity in a subject suffering therefrom, the method comprising administering a therapeutically effective amount of an inhibitor of aldehyde dehydrogenase proteins.
  12. 12. The method of treatment of claim 11 in which the inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof: where A, X, and Z are each independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups; Ri, R2, R3 are each independently selected from hydrogen, hydroxy, amino, halogen, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6alkenyloxy, C2-C6alkynyloxy, C3-C7cycloalkyl, C3- C7heterocycloalkyl, hydroxyCl-C6alkyl, hydroxyCl-C6alkoxy, hydroxyCl-C6alkylamino, Cl- C6alkoxyCl-C6alkyl, Cl-C6alkoxyCl-C6alkylamino, aminoCl-C6alkyl, aminoCl-C6alkoxy, Cl- C6alkylamino, di-Cl-C6alkylamino, Cl-C6-alkyldiamino, Cl-C6alkoxycarbonyl, Cl- C6alkoxyaminocarbonyl, Cl-C6alkylthio, phosphateCl-C6alkylthio, sulfateCl-C6alkylthio, thioCl- C6a Ikyl, thioCl-C6alkoxy, thioCl-C6alkylamino, heterocycloCl-C6alkyl, heterocycloCl-C6alkoxy, heterocycloCl-C6alkylamino, phosphateCl-C6alkylamino, sulfateCl-C6alkylamino, Cl- C6a Ikylsulfinyl, Cl-C6alkylsulfonyl, Cl-C6alkylthiocarboxamide, Cl-C6alkylcarboxamide, C1-C6 alkylthioureyl, Cl-C6alkylureyl, Cl-C6dialkylamino, Cl-C6alkoxycarbonyl, Cl- C6dialkylcarboxamide, C1-C6 dialkylsulfonamide, Cl-C6dialkylthiocarboxamido, Cl-C6haloalkyl, Cl-C6haloalkoxy, Cl-C6guanidinealkyl, Cl-C6cyanoalkyl, arylCl-C6alkoxy, heteroarylCl- C6alkoxy, cyclicCl-C6alkoxy, phosphateCl-C6alkoxy, sulfateCl-C6alkoxy, arylCl-C6alkylamino, heteroarylCl-C6alkylamino, cyclicCl-C6alkylamino, aryl, heteroaryl, heterocyclic, and cyclic groups; and in which extant aryl, heteroaryl, heterocyclic, and cyclic groups are further functionalized with one or more substituents selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, hydroxy, carboxy, formyl, carbamoyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-Cl-C6 alkylamino, amino C1-C6 alkyl, C3- C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, Cl- C6 alkylaminocarbonyl, C1-C6 dialkyl aminocarbonyl, C1-C6 alkylsulfonyl aminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl and C3-C7 cycloalkylaminocarbonyl.
  13. 13. The method of treatment of claim 12 in which the compound is l,l'-((2-phenylimidazo[l,2- a]pyridine-6,8-diyl)bis(4,l-phenylene))bis(ethan-l-one).
  14. 14. The method of treatment of claim 12 in which the compound is 4-(8-(4-acetylphenyl)-2- phenylimidazo[l,2-a]pyridin-6-yl)benzonitrile.
  15. 15. The method of treatment of claim Il in which the pathology or disease is cancer.
  16. 16. The method of treatment of claim Il in which the pathology or disease is inflammatory disease.
  17. 17. The method of treatment of claim Il in which the pathology or disease is a tumor selected from head and neck, thyroid, lung, pleura, gastrointestinal tract, genitourinary tract, gynecological, breast, bone and soft tissue, skin, central nervous system, neuroblastoma, glioblastoma, retinoblastoma, rhabdomyosarcoma, hepatocellular carcinoma, glioblastoma multiformae, melanoma, squamous cell carcinoma, pancreatic cancer, mesothelioma, and rare pediatric tumor types.
  18. 18. The method of treatment of claim Il in which the pathology or disease is an inflammatory disease exhibited within a body region selected from respiratory tree, lungs, gastrointestinal tract, bile duct, and the gallbladder.
  19. 19. The method of treatment of claim Il in which the pathology or disease is selected from diabetes, psoriasis, rheumatoid arthritis, acute nephropathies, chronic nephropathies, arterial restenosis, auto-immune diseases, acute infections, eye diseases resulting from alteration of the microcirculation, and endometriosis.
  20. 20. A method of prevention of a pathology or disease resulting from abnormal regulation of subtype 1A aldehyde dehydrogenase activity in a subject suffering therefrom, the method comprising administering a prophylactically effective amount of an inhibitor of aldehyde dehydrogenase proteins.

Description

IMIDAZ0[1,2-A]PYRIDINE COMPOUNDS FOR USE IN TREATING CANCER AND INFLAMMATORY DISEASES AND METHODS TO PREPARE SAID COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of Italian patent application 10202300013581 entitled "Composto medicale per I'inibizione di aldeide deidrogenasi sottotipo 1A" filed Jun 29, 2023, which is hereby incorporated by reference in its entirety. BACKGROUN D [0002] Aldehyde dehydrogenases are known to be NAD(P)+-dependent enzymes that catalyze the irreversible oxidation of endogenous and exogenous aldehydes to the corresponding carboxylic acids. They are widely expressed in the liver, kidney, heart, skeletal muscle, uterus, and brain, located in diverse cellular compartments including cytosol, mitochondria, endoplasmic reticulum, and nucleus. [0003] The ALDH1A enzyme subfamily, including isoforms 1A1, 1A2, and 1A3 (hereafter collectively "ALDHIAs"), specifically converts retinaldehyde into trans-retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid. These metabolites collectively regulate the transcription of more than 400 target genes associated with metabolism, immunity, organogenesis, and reproduction, thereby allowing ALDH1A enzymes to play a key role in multiple cellular processes. The alteration of the normal functioning of these enzymes therefore determines the onset of numerous pathologies such as cancer, obesity, type II diabetes, pulmonary arterial hypertension, and neointimal hyperplasia. Specifically, overexpression of specific ALDH1A isoforms has been associated with tumor growth and poor prognosis of several types of malignant tumors, both solid and non-solid, such as those of the head and neck, thyroid, lung, pleura, gastrointestinal, genitourinary, gynecological, breast, bone and soft tissue, skin, central nervous system, rare pediatric solids, lymphatic neoplasms, chronic and acute pediatric leukemias. [0004] Furthermore, ALDHIAs overexpression is also both a hallmark and vital element of a subset of cancer cells known as cancer stem cells (CSCs), which are responsible for tumor development and metastasis, as well as radio- and chemo-resistance. Therefore, the inhibition of the ALDH1A enzymes, including the isoforms 1A1, 1A2, and 1A3, represents a promising therapeutic approach for the treatment of cancer along with the selective eradication of CSCs. [0005] ALDHIAs activity is also important for the induction and function of Treg cells, mediated by the production of retinoic acid by multiple cell types such as dendritic cells, macrophages, and eosinophils. Thus, ALDHIAs inhibition may increase the ratio of effector T cells to Treg cells within tumor tissue, leading to increased tumor immunity and tumor rejection. [0006] ALDHIAs promote the proliferation of vascular smooth muscle cells and pulmonary arteries. The resulting neointima formation narrows the luminal space, leading to pathologies such as neointimal hyperplasia, a major cause of restenosis, and pulmonary arterial hypertension. Therefore, ALDHIAs inhibition may reduce intimal hyperplasia and, thus, be useful for the treatment of restenosis, coronary angioplasty, stenting and bypass surgery, and in patients after transplantation. [0007] ALDHIAs overexpression, found in patients with type II diabetes, identifies dedifferentiated pancreatic beta cells, characterized by impaired insulin secretion and mitochondrial function. The inhibition of these enzymes reactivates the differentiation of beta cells, thus representing a therapeutic strategy to reduce glycemia and increase insulin secretion in diabetic subjects. [0008] Finally, since it has been demonstrated in animal models that the lack of the ALDH1A enzymes confers resistance to the development of diet-induced obesity, these isoenzymes also represent a possible target for the development of drugs for the treatment and/or prevention of obesity. [0009] The literature describes numerous heterocyclic derivatives as inhibitors of ALDHIAs. However, compounds described in the prior art show some important drawbacks. In particular, the described compounds show poor pharmacokinetic properties, including the short half-life and the lack of oral bioavailability, which limits their use to intravenous or intraperitoneal administration. Furthermore, they show off-target toxicity and/or lack of in vivo efficacy. To date, there are no selective inhibitors for the ALDH1A enzyme isoforms which have received the market approval as drugs or are under clinical development. [0010] Therefore, there is a clear need for potent and selective ALDHIAs inhibitors with good pharmacokinetic profile, which are suitable for oral dosing and have minimal or no toxicity. SUMMARY [0011] Among other advantages that will be apparent upon review of the description, examples, claims, and Figures herein, compounds described herein and pharmaceutically relevant compositions comprising compounds described herein have the ability to inhibit ALDH1A1, ALD