# US 12,178,791 B2 · Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof

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- Number: US 12,178,791 B2
- Document ID: US12178791B2
- Status: Granted
- Kind: B2
- Application number: 17/265,402
- Filed: 2019-08-02
- Published: 2021-11-18
- Granted: 2024-12-31
- Earliest claimed: 2018-08-03
- Assignees: Syntara Limited
- Applicants: Syntara Limited
- Inventors: Alison Dorothy Findlay; Craig Ivan Turner; Mandar Deodhar; Jonathan Stuart Foot; Wolfgang Jarolimek; Wenbin Zhou; Alberto Buson; Angelique Elsa Greco
- Web page: https://patentgrep.com/patent/US12178791B2

## CPC

- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K 31/145: having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) (isothiourea A61K31/155)
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/47: Quinolines; Isoquinolines
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07C 311/29: having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 317/28: with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 317/32: with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/10: with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D 213/71: to which a second hetero atom is attached
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C 2601/16: the ring being unsaturated
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- C07C 2603/74: Adamantanes
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and/or angiogenesis in human subjects as well as in pets and livestock. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.

## Claims

### Claim 1

A Z-isomer compound of Formula I:
or a pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:
A is selected from the group consisting of:
each R1 is independently selected from the group consisting of X—R2, halogen, deuterium, C1-6alkyl, O—C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —CN, —C(O) OR3, —C(O) NR4R5, —S(O)2NR4R5, —S(O)2R6, —NR8C(O)R9, and —NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO2CH3, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3 and —O—CF3;
X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;
R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;
R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO2CH3, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3 and —O—CF3;
R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO2CH3, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3 and —O—CF3; or
R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;
R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3, and —O—CF3;
R7 is selected from the group consisting of halogen, —OH, C1-6alkyl, O—C1-6alkyl C3-7cycloalkyl, —C(O) OR3, —C(O) NR4R5, —NR4C(O)R6, —S(O)2NR4R5, —NR4S(O)2R6 and —S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and —OH;
R8 is hydrogen or C1-6alkyl;
R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3, and —O—CF3; or
R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;
and
n is 0, 1, 2, 3, 4, 5 or 6.

### Claim 2 (depends on 1)

The Z-isomer compound according to claim 1, wherein
A is selected from the group consisting of
R1 is methyl or isopropyl; and
n is 0 or 1.

### Claim 3 (depends on 1)

The Z-isomer compound according to claim 1,
wherein A is
and n is 0.

### Claim 4 (depends on 1)

The Z-isomer compound according to claim 1, of Formula Ia:
or a pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:
each R1 is independently selected from the group consisting of X—R2, halogen, C1-6alkyl, O—C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —CN, —C(O) OR3, —C(O) NR4R5, —S(O)2NR4R5, —S(O)2R6, —NR8C(O)R9, and —NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO2CH3, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3 and —O—CF3;
X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;
R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;
R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or
R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;
R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;
R7 is selected from the group consisting of halogen, —OH, C1-6alkyl, O—C1-6alkyl, C3-7cycloalkyl, —C(O) OR3, —C(O) NR4R5, —NR4C(O)R6, —S(O)2NR4R5, —NR4S(O)2R6 and —S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and —OH;
R8 is hydrogen or C1-6alkyl;
R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C1-4alkyl, —O—C1-4alkyl, —CF3, —CH2CF3, and —O—CF3; or
R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;
and
n is 0, 1, 2 or 3.

### Claim 5 (depends on 4)

The Z-isomer compound according to claim 4,
wherein n is 0.

### Claim 6 (depends on 4)

The Z-isomer compound according to claim 4,
wherein
each R1 is independently selected from the group consisting of halogen, C1-6alkyl,
O—C1-6alkyl, aryl, and —S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more halogen;
R6 is C1-6alkyl;
and
n is 1 or 2.

### Claim 7 (depends on 1)

The Z-isomer compound according to claim 1 selected from the group consisting of
1
(Z)-3-fluoro-4- (phenylsulfonyl)but-2- en-1-amine
2
(Z)-4-((3,5- bis(trifluoromethyl) phenyl)sulfonyl)-3- fluorobut-2-en-1-amine
3
(Z)-3-fluoro-4-((4- (methylsulfonyl)phenyl) sulfonyl)but-2-en-1-amine
4
N-((1R,3R,5S)-adamantan- 1-yl)-4-(((Z)-4-amino-2- fluorobut-2-en-1- yl)sulfonyl)benzamide
5
(Z)-4-((2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl)-N,N- dimethylbenzene- sulfonamide
6
(Z)-4-(2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy)- N,N- dimethylbenzene- sulfonamide
7
(Z)-4-((2- (benzyloxy)phenyl) sulfonyl)-3-fluorobut-2- en-1-amine
8
(Z)-4-((2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl) benzenesulfonamide
9
(Z)-4-((3-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl)-N,N- dimethylbenzene- sulfonamide
10
(Z)-4-((4-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl)-N,N- dimethylbenzene- sulfonamide
11
(Z)-4-((2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl)-N,N- diisopropylbenzene- sulfonamide
12
N-((1S,3R,5S)-adamantan- 1-yl)-2-(((Z)-4-amino-2- fluorobut-2-en-1- yl)sulfonyl)benzamide
13
N-((1S,3R,5S)-adamantan- 1-yl)-3-(((Z)-4-amino-2 fluorobut-2-en-1- yl)sulfonyl)benzamide
14
(Z)-4-((2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)phenoxy) methyl)-N- isopropylbenzene- sulfonamide
15
(Z)-2-((4-amino-2- fluorobut-2-en-1- yl)sulfonyl)-N-(4-(N,N- diisopropylsulfamoyl) phenyl)benzamide
16
(Z)-4-(3-(4-amino-2- fluorobut-2- enylsulfonyl)phenoxy)- N,N- dimethylbenzene- sulfonamide
17
(Z)-3-(3-(4-amino-2- fluorobut-2- enylsulfonyl)phenoxy)- N,N- dimethylbenzene- sulfonamide
18
(Z)-3-(2-(4-amino-2- fluorobut-2- enylsulfonyl)phenoxy)- N,N- dimethylbenzene- sulfonamide
19
(Z)-4-(2- chlorophenylsulfonyl)-3- fluorobut-2-en-1-amine
20
(Z)-4-(biphenyl-2- ylsulfonyl)-3-fluorobut- 2-en-1-amine
21
(Z)-3-fluoro-4-(2- isopropylphenylsulfonyl) but-2-en-1-amine
22
(Z)-3-fluoro-4-(2- methoxyphenylsulfonyl) but-2-en-1-amine
23
(Z)-3-fluoro-4- (naphthalen-1- ylsulfonyl)but-2-en-1- amine
24
(Z)-3-fluoro-4- (naphthalen-2- ylsulfonyl)but-2-en-1- amine
25
(Z)-4-(2,4- dichlorophenylsulfonyl)- 3-fluorobut-2-en-1-amine
26
(Z)-4-(3- chlorophenylsulfonyl)-3- fluorobut-2-en-1-amine
27
(Z)-4-(4- chlorophenylsulfonyl)-3- fluorobut-2-en-1-amine
28
(Z)-4-(3,5- dichlorophenylsulfonyl)- 3-fluorobut-2-en-1-amine
29
(Z)-3-fluoro-4-(pyridin- 4-ylsulfonyl)but-2-en-1- amine
30
(Z)-3-fluoro-4-(pyridin- 2-ylsulfonyl)but-2-en-1- amine
31
(Z)-3-fluoro-4-(pyridin- 3-ylsulfonyl)but-2-en-1- amine
32
(Z)-3-fluoro-4- (quinolin-2- ylsulfonyl)but-2-en-1- amine
33
(Z)-3-fluoro-4- (quinolin-8- ylsulfonyl)but-2-en-1- amine
34
(Z)-3-fluoro-4-(5- isopropylpyridin-2- ylsulfonyl)but-2-en-1- amine
35
(Z)-3-fluoro-4-(5- methylpyridin-2- ylsulfonyl)but-2-en-1- amine
36
(Z)-3-fluoro-4-(6- methylpyridin-2- ylsulfonyl)but-2-en-1- amine
37
(Z)-3-fluoro-4-(2- fluorophenylsulfonyl)but- 2-en-1-amine
38
(Z)-3-fluoro-4-(3- fluorophenylsulfonyl)but- 2-en-1-amine
39
(Z)-3-fluoro-4-(4- fluorophenylsulfonyl)but- 2-en-1-amine
40
(Z)-3-fluoro-4-(o- tolylsulfonyl)but-2-en- 1-amine
41
(Z)-3-fluoro-4-(m- tolylsulfonyl)but-2-en- 1-amine
42
(Z)-3-fluoro-4-tosylbut- 2-en-1-amine
43
(Z)-3-fluoro-4-(3- methylpyridin-2- ylsulfonyl)but-2-en-1- amine
44
(Z)-3-fluoro-4-(2- methylpyridin-4- ylsulfonyl)but-2-en-1- amine
45
(Z)-3-fluoro-4-(2- isopropylpyridin-3- ylsulfonyl)but-2-en-1- amine
46
(Z)-3-fluoro-4-(6- methylpyridin-3- ylsulfonyl)but-2-en-1- amine
47
(Z)-3-fluoro-4-(2- methylpyridin-3- ylsulfonyl)but-2-en-1- amine
48
(Z)-3-fluoro-4-(4- methylpyridin-3- ylsulfonyl)but-2-en-1- amine
49
(Z)-3-fluoro-4-(6- isopropylpyridin-3- ylsulfonyl)but-2-en-1- amine
50
(Z)-3-fluoro-4-((2- methylbenzo[d]thiazol-4- yl)sulfonyl)but-2-en-1- amine
51
(Z)-3-fluoro-4-((3- fluoroquinolin-8- yl)sulfonyl)but-2-en-1- amine
52
(Z)-4-((2,3-dimethyl-1H- indol-7-yl)sulfonyl)-3- fluorobut-2-en-1-amine; and
53
(Z)-3-fluoro-4- ((quinolin-8-yl- d6)sulfonyl)but-2-en-1- amine
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 8 (depends on 1)

The Z-isomer compound according to claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 9 (depends on 1)

The Z-isomer compound according to claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a Z-isomer compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

### Claim 11 (depends on 1)

A method of inhibiting the amine oxidase activity of any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a Z-isomer compound according to claim 1.

### Claim 12 (depends on 1)

A method of remedying a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of Z-isomer compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the condition is selected from the group consisting of fibrosis, cancer and angiogenesis.

### Claim 13 (depends on 12)

The method of claim 12, wherein in a case that the condition is fibrosis, the fibrosis is selected from the group consisting of mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, systemic sclerosis, arthrofibrosis, Dupuytren's contracture, adhesive capsulitis, fibrosis of the pancreas, fibrosis of the intestine, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, fibrostenosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, Peyronie's disease and scleroderma or is associated with respiratory disease, abnormal wound healing and repair, scarring, hypertrophic scarring/keloids, scarring post surgery, cardiac arrest and all conditions where excess or aberrant deposition of fibrous material is associated with disease, injury, implants or surgery; and
wherein in a case that the condition is cancer, the cancer is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; mesothelioma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma the of uterus; glioma, glioblastoma, medullablastoma, and other tumours of the brain; myelofibrosis, kidney cancer; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumour; neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomysarcoma.

### Claim 14 (depends on 12)

The method according to claim 12, further comprising administering a second therapeutic agent.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the second therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-inflammatory agent, an anti-hypertensive agent, an anti-fibrotic agent, an anti-angiogenic agent, an immunosuppressive agent and a metabolic agent.

### Claim 16 (depends on 8)

A pharmaceutical composition comprising a Z-isomer compound according to claim 8, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

### Claim 17 (depends on 9)

A pharmaceutical composition comprising a Z-isomer compound according to claim 9, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

### Claim 18 (depends on 12)

The method of claim 12, wherein in a case that the condition is fibrosis, the fibrosis is selected from the group consisting of myelofibrosis, systemic sclerosis, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis and radiation induced fibrosis.