Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof

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 R 1 is independently selected from the group consisting of X—R 2 , halogen, deuterium, C 1-6 alkyl, O—C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —CN, —C(O) OR 3 , —C(O) NR 4 R 5 , —S(O) 2 NR 4 R 5 , —S(O) 2 R 6 , —NR 8 C(O)R 9 , and —NR 8 S(O) 2 R 9 ; wherein each C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO 2 CH 3 , —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 and —O—CF 3 ;

X is selected from the group consisting of O, CH 2 , OCH 2 , CH 2 O, CH 2 S(O) 2 , CONH and NHCO;

R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R 2 is optionally substituted by one or more R 7 ;

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO 2 CH 3 , —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 and —O—CF 3 ;

R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO 2 CH 3 , —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 and —O—CF 3 ; or

R 4 and R 5 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;

R 6 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;

R 7 is selected from the group consisting of halogen, —OH, C 1-6 alkyl, O—C 1-6 alkyl C 3-7 cycloalkyl, —C(O) OR 3 , —C(O) NR 4 R 5 , —NR 4 C(O)R 6 , —S(O) 2 NR 4 R 5 , —NR 4 S(O) 2 R 6 and —S(O) 2 R 6 ; wherein each C 1-6 alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and —OH;

R 8 is hydrogen or C 1-6 alkyl;

R 9 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or

R 8 and R 9 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.

2. 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.

3. The Z-isomer compound according to claim 1 ,

wherein A is

 and n is 0.

4. 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 R 1 is independently selected from the group consisting of X—R 2 , halogen, C 1-6 alkyl, O—C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —CN, —C(O) OR 3 , —C(O) NR 4 R 5 , —S(O) 2 NR 4 R 5 , —S(O) 2 R 6 , —NR 8 C(O)R 9 , and —NR 8 S(O) 2 R 9 ; wherein each C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SO 2 CH 3 , —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 and —O—CF 3 ;

X is selected from the group consisting of O, CH 2 , OCH 2 , CH 2 O, CH 2 S(O) 2 , CONH and NHCO;

R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R 2 is optionally substituted by one or more R 7 ;

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; or

R 4 and R 5 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;

R 6 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl;

R 7 is selected from the group consisting of halogen, —OH, C 1-6 alkyl, O—C 1-6 alkyl, C 3-7 cycloalkyl, —C(O) OR 3 , —C(O) NR 4 R 5 , —NR 4 C(O)R 6 , —S(O) 2 NR 4 R 5 , —NR 4 S(O) 2 R 6 and —S(O) 2 R 6 ; wherein each C 1-6 alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and —OH;

R 8 is hydrogen or C 1-6 alkyl;

R 9 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-4 alkyl, —O—C 1-4 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or

R 8 and R 9 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.

5. The Z-isomer compound according to claim 4 ,

wherein n is 0.

6. The Z-isomer compound according to claim 4 ,

wherein

each R 1 is independently selected from the group consisting of halogen, C 1-6 alkyl,

O—C 1-6 alkyl, aryl, and —S(O) 2 R 6 ; wherein each C 1-6 alkyl is optionally substituted by one or more halogen;

R 6 is C 1-6 alkyl;

and

n is 1 or 2.

7. 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- d 6 )sulfonyl)but-2-en-1- amine

or a pharmaceutically acceptable salt or solvate thereof.

8. The Z-isomer compound according to claim 1 selected from the group consisting of

 or a pharmaceutically acceptable salt or solvate thereof.

9. The Z-isomer compound according to claim 1 selected from the group consisting of

 or a pharmaceutically acceptable salt or solvate thereof.

10. 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.

11. 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 .

12. 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.

13. 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.

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

15. 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.

16. 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.

17. 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.

18. 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.