US 12,441,755 B2
Galactoside inhibitor of galectins
Fredrik Zetterberg, Askim (SE)
Assigned to GALECTO BIOTECH AB, Copenhagen (DK)
Appl. No. 17/624,730
Filed by GALECTO BIOTECH AB, Copenhagen (DK)
PCT Filed Jul. 3, 2020, PCT No. PCT/EP2020/068834
§ 371(c)(1), (2) Date Jan. 4, 2022,
PCT Pub. No. WO2021/004940, PCT Pub. Date Jan. 14, 2021.
Claims priority of application No. 19184577 (EP), filed on Jul. 5, 2019.
Prior Publication US 2022/0259251 A1, Aug. 18, 2022
Int. Cl. C07H 19/056 (2006.01)
CPC C07H 19/056 (2013.01) 11 Claims
 
1. A D-galactopyranose compound of formula (1)

OG Complex Work Unit Chemistry
wherein
the pyranose ring is β-D-galactopyranose,
A1 is

OG Complex Work Unit Chemistry
wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose;
wherein Het1 is a five or six membered heteroaromatic ring selected from the group consisting of formulas 2 to 10, wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the triazole group in formula A1:

OG Complex Work Unit Chemistry
wherein R2 to R11, R16 to R23, R27, R35 and R36 are independently selected from H; halogen; OH; CN; SH; S—C1-6 alkyl; C1-6 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC1-6 alkyl optionally substituted with a F; and NR24R25, wherein R24 is selected from H and C1-6 alkyl, and R25 is selected from H, C1-3 alkyl, and COR26, wherein R26 is selected from H, and C1-6 alkyl;
wherein B1 is selected from the group consisting of a heteroaryl, an aryl and a heterocycloalkyl, optionally substituted with one or more groups selected from a) C1-6 alkyl optionally substituted with one or more of C1-6 alkyl, amino, CN, halogen, hydroxy, C1-6 alkoxy, carboxy, alkoxycarbonyl, or H2NCO, b) R28—C1-6 alkyl, c) C3-6 cycloalkyl optionally substituted with one or more of C1-6 alkyl, amino, CN, halogen, or hydroxy, d) C1-6 alkenyl, e) C1-6 alkoxy, f) C1-6 alkylthio, g) C1-6 alkylsulfonyl, h) carbonyl substituted with any one of hydroxy, C1-6 alkoxy, C1-6 alkylNH, ((R29)(R30)N)C1-6 alkylNH, or (pyridinyl)C1-6 alkylNH, i) (R31)(R32)N, j) C2-alkynyl, and k) R28;
wherein R28 is selected from any one of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C2-alkynyl, halogen, C1-6 alkyl, halo-C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, halo-C1-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, CONH2, and (R33)(R34)N; or b) (C1-6 alkyl-SO2)phenyl, (C1-6 alkyl SO2) (halo)phenyl, (aminoSO2)phenyl, (di-C1-6 alkylaminoSO2)phenyl, ((C1-6 alkyl-NHSO2)—C1-6 alkyl)phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl) methyl)phenyl, phenoxyphenyl, (benzyloxy)phenyl, ((methyl) thiazolyl)-phenyl, (thiazolyl)-benzenesulfamido, ((methyl) thiadiazolyl) benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl;
wherein
R29 is hydrogen or C1-6 alkyl;
R30 is hydrogen or C1-6 alkyl; or
(R29)(R30)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and hydroxy;
R31 is hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl;
R32 is hydrogen or C1-6 alkyl; or
(R31)(R32)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl;
R33 is hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl;
R34 is hydrogen or C1-6 alkyl; or
(R33)(R34)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl;
R1 is selected from the group consisting of a) H, b) OH, c) OC1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR17, NR18R19, and CONH2, wherein R17 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R20—CONH— wherein R20 is selected from C1-3 alkyl and cyclopropyl, R18 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R21—CONH— wherein R21 is selected from C1-3 alkyl and cyclopropyl, and R19 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R22—CONH— wherein R22 is selected from C1-3 alkyl and cyclopropyl, d) branched OC3-6 alkyl optionally substituted with one or more halogen, CN, OR23, NR24R25, and CONH2, wherein R23 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R26—CONH— wherein R26 is selected from C1-3 alkyl and cyclopropyl, R24 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R27—CONH— wherein R27 is selected from C1-3 alkyl and cyclopropyl, and R25 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R28—CONH— wherein R28 is selected from C1-3 alkyl and cyclopropyl, e) cyclic OC3-6 alkyl optionally substituted with one or more halogen, CN, OR29, NR30R31, and CONH2, wherein R29 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R32—CONH— wherein R32 is selected from C1-3 alkyl and cyclopropyl, R30 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R33—CONH— wherein R33 is selected from C1-3 alkyl and cyclopropyl, and R31 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH3 optionally substituted with a F, OCH2CH3 optionally substituted with a F, OH, and R34—CONH— wherein R34 is selected from C1-3 alkyl and cyclopropyl, and f) a fluorine (F); or a pharmaceutically acceptable salt or solvate thereof.