# US 12,759,985 B2 · Compounds having 5-(2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide as inhibitors of protein kinase phosphatase enzymes

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- Number: US 12,759,985 B2
- Document ID: US12759985B2
- Status: Granted
- Kind: B2
- Application number: 18/534,527
- Filed: 2023-12-08
- Published: 2024-08-08
- Granted: 2026-10-13
- Earliest claimed: 2023-12-08
- Assignees: Mondego Bio, LDA
- Applicants: Ness Therapeutics, Inc.
- Inventors: Volodymyr Kysil; Vladislav Zenonovich Parchinsky; Alexei Pushechnikov; Alexandre Vasilievich Ivachtchenko; Nikolay Savchuk
- Web page: https://patentgrep.com/patent/US12759985B2

## CPC

- C07D 285/10: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
- A61K 31/433: Thidiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## 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):

## Claims

### Claim 1

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.

### Claim 2

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.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, further comprising an additional pharmaceutically active agent.

### Claim 5 (depends on 1, 3)

A method of inhibiting a protein tyrosine phosphatase enzyme, comprising administering to a subject in need of a treatment for cancer a compound of claim 1 or a pharmaceutical composition of claim 3.

### Claim 6 (depends on 1, 3)

A method of treating a disease or disorder associated with the inhibition of protein tyrosine phosphatase enzyme, the method comprising administering to a subject in need of a treatment for cancer a compound of claim 1 or a pharmaceutical composition of claim 3.

### Claim 7 (depends on 1, 3)

A method of treating cancer, comprising administering to a subject in need of a treatment for cancer a compound of claim 1 or a pharmaceutical composition of claim 3.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

### Claim 9 (depends on 7)

The method of claim 7, wherein the cancer is melanoma.

### Claim 10 (depends on 1, 3)

A method of treating a metabolic disease, comprising administering to a subject in need of a treatment for metabolic disease a compound of claim 1 or a pharmaceutical composition of claim 3.

### Claim 11 (depends on 10)

The method of claim 10, wherein the metabolic disease is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

### Claim 12 (depends on 11)

The method of claim 11, wherein the diabetes is Type I diabetes.

### Claim 13 (depends on 11)

The method of claim 11, wherein the diabetes is Type II diabetes.

### Claim 14 (depends on 11)

The method of claim 11, wherein the diabetes is gestational diabetes.

### Claim 15 (depends on 5)

The method of claim 5, wherein the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase non-receptor type 1 (PTPN1), or protein tyrosine phosphatase non-receptor type 2 (PTPN2).