NEW SELECTIVE LYSOL OXIDASE INHIBITORS

Claims

1. Compound of formula I: Formula I or a pharmaceutically acceptable salt thereof; where: A is aryl; each R 1 independently selected from the group consisting of XR 4 , halogen, deuterium, C 1-6 alkyl, OC 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -C(O)OR 5 , -C(O)NR 6 R 7 , -S(O)2NR 6 R 7 , -S(O)2R 8 , -NR 9 C(O)R 10 and -NR 9 S(O)2R 10 ; and each C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH and -C 1-4 alkyl; R 2 represents H or F; R 3 represents H or F; provided that one and only one of R 2 or R 3represents F; X is selected from the group consisting of O, CH2, and S(O)2; R 4 selected from the group consisting of aryl and heterocycloalkyl; each aryl being optionally substituted with -S(O)2R 8 ; and wherein each heterocycloalkyl is optionally substituted with =O; R 5 selected from the group consisting of hydrogen and C 1-6 alkyl; R 6 and R 7 independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 8 represents C 1-6 alkyl; R 9 represents hydrogen or C 1-6 alkyl; R 10 represents C 1-6 alkyl; a n is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, in which R 2 represents F, and R 3 represents H.

3. A compound according to claim 1 or 2, wherein A is selected from the group consisting of phenyl, naphthyl and 1,4-benzodioxanyl.

4. A compound according to any one of paragraphs 1-3, in which each R 1 independently selected from the group consisting of XR 4 , halogen, deuterium, C 1-6 alkyl, OC 1-6 alkyl, heteroaryl, -CN, -NO2, -C(O)OR 5 , -C(O)NR 6 R 7 and -S(O)2R 8 ; and each C 1-6 alkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen and -C 1-4 alkyl.

5. The compound according to claim 1 of formula Ib Formula 1b or a pharmaceutically acceptable salt thereof; where: each R 1a independently selected from the group consisting of XR 4 , halogen, deuterium, C 1-4 alkyl and -CN; each R 1b independently selected from the group consisting of XR 4 , halogen, deuterium, -C 1-4 alkyl, -OC 1-4 alkyl, heteroaryl, -CN, -NO2, -C(O)OR 5, -C(O)NR 6 R 7 , -S(O)2R 8 , and each -C 1-4 alkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen and -C 1-4 alkyl; R 1c selected from the group consisting of deuterium, -C 1-4 alkyl, -CN, -C(O)OR 5 and -S(O)2R 8 ; X is selected from the group consisting of O, CH2, and S(O)2; R 4 selected from the group consisting of aryl and heterocycloalkyl; each aryl being optionally substituted with -S(O)2R 8 ; and wherein each heterocycloalkyl is optionally substituted with =O; R 5 selected from the group consisting of hydrogen and C 1-4 alkyl; R 6 and R 7 independently selected from the group consisting of hydrogen and C 1-4 alkyl; and R 8 represents C 1-4 alkyl.

6. The compound according to item 5, in which each R 1aindependently selected from the group consisting of XR 4 , chlorine, deuterium, methyl and -CN; each R 1b independently selected from the group consisting of XR 4 , halogen, deuterium, -C 1-4 alkyl, -OCH3, heteroaryl, -CN, -NO2, -C(O)OH, -C(O)NH2, -S(O)2CH3, each -C 1-4 alkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro and -C 1-4 alkyl; R 1c selected from the group consisting of deuterium, methyl, -CN, -C(O)OH and -S(O)2CH3; X is selected from the group consisting of O, CH2, and S(O)2; and R 4 selected from the group consisting of phenyl and ; wherein each phenyl is optionally substituted with -S(O)2CH3.

7. The compound according to item 5 or 6, in which each R 1b independently selected from the group consisting of XR 4, F, Cl, Br, deuterium, -methyl, -CF3, isopropyl, -OCH3, thiazolyl, pyrazolyl, -CN, -NO2, -C(O)OH, -C(O)NH2, -S(O)2CH3, wherein each thiazolyl or pyrazolyl is optionally substituted with methyl.

8. The compound according to claim 1, selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.

9. The compound according to paragraph 1 of the formula: or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, which is a hydrochloride salt:

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 and at least one pharmaceutically acceptable excipient, carrier or diluent.

12. A method for inhibiting the amine oxidase activity of any of lysyl oxidase (LOX), lysyl oxidase-like protein-1 (LOXL1), LOXL2, LOXL3 or LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11.

13. A method for treating a pathological condition by inhibiting the activity of any of the proteins LOX, LOXL1, LOXL2, LOXL3 or LOXL4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11.

14. The method of claim 13, wherein the pathological condition is selected from the group consisting of fibrosis, cancer, and malignant myeloid neoplasm.

15. The method of claim 14, wherein when the pathological 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, scleroderma / systemic sclerosis, arthrofibrosis, Dupuytren's contracture, adhesive capsulitis, pancreatic fibrosis, intestinal fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, fibrostenosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, Peyronie's disease and scleroderma or is associated with a respiratory disease, atypical wound healing and repair, scarring, hypertrophic scarring, postoperative scars, cardiac arrest and all conditions in which excessive or aberrant deposition of fibrous material is associated with disease, injury, implants or surgery;preferably the fibrosis is selected from the group consisting of keloid, scarring, hypertrophic scarring, scleroderma and Dupuytren's contracture; wherein when the pathological 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; uterine carcinoma; glioma, glioblastoma, medulloblastoma and other brain tumors; myelofibrosis, kidney cancer; head and neck cancer; stomach cancer; multiple myeloma; testicular cancer; embryonal cell tumor; neuroendocrine tumor; cervical cancer; oral cancer, gastrointestinal carcinoids, breast and other organs; signet ring cell carcinoma;mesenchymal tumors, including sarcomas, fibrosarcomas, hemangiomas, angiomatosis, hemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumor, lipoma, angiolipoma, granular cell tumor, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma, or leiomyosarcoma; and; wherein in the case where the pathological condition is a malignant myeloid formation, the malignant myeloid formation is selected from the group consisting of myelodysplastic syndromes (MDS), myelodysplastic neoplasm (MPN), mixed MDS / MPS syndromes and acute myeloid leukemia (AML), including acute promyelocytic leukemia (APL).

16. The method according to claim 13, wherein the pathological condition is scarring.

17. A method for treating or preventing keloid diseases or scars, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11.

18. The method of claim 17, wherein the keloid diseases or scars are keloids, hypertrophic scars, post-operative scars, burn scars, post-traumatic scars, Dupuytren's contracture or are caused by external injuries or surgical procedures, or are the result of damage to the skin caused by acne, burns, chickenpox, infection, puncturing, scratches, surgical incisions, or vaccination.

19. The method of claim 17 or 18, wherein the treatment promotes wound healing and improves skin pliability or skin appearance of the subject.

20. The method according to any one of claims 12-19, wherein the compound or composition is applied topically.

21. The method according to any one of claims 12-19, wherein the compound or composition is administered orally.

22. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 for the preparation of a medicament for the treatment of a pathological condition by inhibiting the activity of any of the proteins LOX, LOXL1, LOXL2, LOXL3 or LOXL4.