US 12,759,985 B2Granted

Compounds having 5-(2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide as inhibitors of protein kinase phosphatase enzymes

AssigneeMondego Bio, LDA

InventorsVolodymyr Kysil, Vladislav Zenonovich Parchinsky, Alexei Pushechnikov, Alexandre Vasilievich Ivachtchenko, Nikolay Savchuk

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Abstract

The present invention is generally directed to inhibitors of protein tyrosine phosphatase enzymes useful in the treatment of diseases and disorders modulated by said enzymes and having the Formula (I):

Claims15

Dependent claims

A compound of Formula (I-A-2-A):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein:
RL is hydrogen;
R1 is hydrogen;
each R2 is hydrogen;
each R3 is hydrogen;
each R5 is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R6;
or two R5, together with the nitrogen atom to which they are attached, come together to form 3- to 10-membered heterocyclyl or heteroaryl, optionally substituted with one or more R6;
each R6 is independently selected from —C(O)R7, —C(O)NRNR7, —C(O)OR7, —NRNR7, —NRNC(O)R7, —OC(O)R7, —S(O)2R7, halo, —CN, —NO2, —OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R7;
each R7 is independently selected from —C(O)OR8, halo, —OH, —CN, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R8;
each R8 is independently selected from —S(O)R9, halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R9;
each R9 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R10;
each R10 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R11;
each R11 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;
each RN is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

11 more elements

A compound selected from:

Example No.
Name
35
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-phenylurea;
36
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(4-methylphenyl)urea;
37
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(4-methoxyphenyl)urea;
38
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea;
39
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(2-methylphenyl)urea;
40
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(2-methoxyphenyl)urea;
41
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(trifluoromethyl)phenyl]urea;
42
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(3-methylphenyl)urea;
43
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(3-methoxyphenyl)urea;
44
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-pyridin-4-ylurea;
45
1-{1-[(2-chlorobenzyl)sulfonyl]piperidin-4-yl}-3-[4-(1,1-dioxido-4-oxo-
1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl]urea;
46
1-(3-chlorophenyl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-
fluoro-5-hydroxyphenyl]urea;
47
1-(4-chlorophenyl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-
fluoro-5-hydroxyphenyl]urea;
48
1-(2-chlorophenyl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-
fluoro-5-hydroxyphenyl]urea;
49
1-(1H-benzimidazol-5-yl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-
yl)-3-fluoro-5-hydroxyphenyl]urea;
50
1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-
thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl]urea;
51
1-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}-3-[4-(1,1-dioxido-4-oxo-
1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl]urea;
52
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-pyridin-3-ylurea;
53
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(4-fluorophenyl)urea;
54
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(3-fluorophenyl)urea;
55
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[2-(trifluoromethyl)phenyl]urea;
56
1-cyclohexyl-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-
5-hydroxyphenyl]urea;
57
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(tetrahydrofuran-2-ylmethyl)urea;
58
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(3-methoxypropyl)urea;
59
1-(3,4-dimethoxyphenyl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-
yl)-3-fluoro-5-hydroxyphenyl]urea;
60
1-benzyl-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]urea;
61
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-tricyclo[3.3.1.13,7]dec-1-ylurea;
62
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(3-methylbutyl)urea;
63
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(4-methoxybenzyl)urea;
64
1-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]-3-[4-(1,1-dioxido-4-oxo-1,2,5-
thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl]urea;
65
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(morpholin-4-yl)phenyl]urea;
66
tert-butyl 4-[4-({[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-
5-hydroxyphenyl]carbamoyl}amino)phenyl]piperazine-1-carboxylate;
67
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(piperazin-1-yl)phenyl]urea hydrochloride;
68
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-methoxy-3-(trifluoromethyl)phenyl]urea;
69
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(methylsulfonyl)phenyl]urea;
70
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(propan-2-yl)phenyl]urea;
71
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[4-(trifluoromethoxy)phenyl]urea;
72
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(1-methylpiperidin-4-yl)urea;
73
N-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3,4-dihydroquinoline-1(2H)-carboxamide;
74
N-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
75
(3S)-N-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-
carboxamide;
76
3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-1-methyl-1-phenylurea;
77
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)urea;
88
1-cyclopentyl-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-
5-hydroxyphenyl]urea;
89
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(4-methylcyclohexyl)urea;
90
1-(4-tert-butylcyclohexyl)-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-
yl)-3-fluoro-5-hydroxyphenyl]urea;
91
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(trans-4-hydroxycyclohexyl)urea;
92
1-cycloheptyl-3-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-
5-hydroxyphenyl]urea;
93
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-(2-fluorophenyl)urea;
94
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[3-(piperidin-1-yl)propyl]urea;
95
1-[4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-
hydroxyphenyl]-3-[3-(morpholin-4-yl)propyl]urea;
98
tert-butyl 4-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-
yl)phenyl]carbamoyl-amino]piperidine-1-carboxylate;
99
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
(4-piperidyl)urea;
100
1-(2-azaspiro[4.5]decan-4-ylmethyl)-3-[3-fluoro-5-hydroxy-4-(1,1,4-
trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]urea;
101
tert-butyl 4-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-
yl)phenyl]carbamoyl-amino]methyl]-2-azaspiro[4.5]decane-2-carboxylate;
102
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[(2-isopentyl-2-azaspiro[4.5]decan-4-yl)methyl]urea;
103
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[(1S)-2-hydroxy-1-phenylethyl]urea;
104
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
(3-piperidyl)urea;
105
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
(2-hydroxycyclohexyl)urea;
106
tert-butyl 3-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-
yl)phenyl]carbamoylamino]piperidine-1-carboxylate;
107
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[4-(hydroxymethyl)-cyclohexyl]urea;
108
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[(1R,2S)-2-hydroxyindan-1-yl]urea;
109
1-[(1S)-1-benzyl-2-hydroxy-ethyl]-3-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-
1,2,5-thiadiazolidin-2-yl)phenyl]urea;
110
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[(1S)-1-(hydroxymethyl)-3-methyl-butyl]urea;
111
1-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3-
[3-(hydroxymethyl)-1-bicyclo[1.1.1]pentanyl]urea;
112
3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-
yl)phenyl]carbamoylamino]-N-isobutyl-bicyclo[1.1.1]pentane-1-
carboxamide
or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

200 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/534,527Filed 8 Dec 2023
Published: US 2024/0262801 A18 Aug 2024
Granted: 13 Oct 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 285/10
Not condensed with other rings: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Family

US 2024/0262801 A1Pre-grant publication · published 8 Aug 2024
US 12,759,985 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I-A-2-A):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein:
RL is hydrogen;
R1 is hydrogen;
each R2 is hydrogen;
each R3 is hydrogen;
each R5 is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R6;
or two R5, together with the nitrogen atom to which they are attached, come together to form 3- to 10-membered heterocyclyl or heteroaryl, optionally substituted with one or more R6;
each R6 is independently selected from —C(O)R7, —C(O)NRNR7, —C(O)OR7, —NRNR7, —NRNC(O)R7, —OC(O)R7, —S(O)2R7, halo, —CN, —NO2, —OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R7;
each R7 is independently selected from —C(O)OR8, halo, —OH, —CN, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R8;
each R8 is independently selected from —S(O)R9, halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R9;
each R9 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R10;
each R10 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R11;
each R11 is independently selected from halo, —CN, —OH, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;
each RN is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

11 more elements

Facts

Application

18/534,527Filed 8 Dec 2023

Published

US 2024/0262801 A18 Aug 2024

Granted

13 Oct 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 285/10
Not condensed with other rings: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone