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EP-3856736-B1 - NOVEL COMPOUNDS AS NADPH OXIDASE INHIBITORS

EP3856736B1EP 3856736 B1EP3856736 B1EP 3856736B1EP-3856736-B1

Inventors

  • MACHIN, PETER
  • CHAMBERS, MARK
  • HODGES, ALASTAIR
  • SHARPE, ANDREW
  • WISHART, GRANT
  • PERRY, BENJAMIN
  • CELANIRE, SYLVAIN
  • HEITZ, Freddy

Dates

Publication Date
20260506
Application Date
20190927

Claims (15)

  1. A compound according to Formula (I): wherein A 1 , and A 2 groups are independently selected from hydrogen, halogen, CN, CF 3 , CHF 2 , an optionally substituted radical selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, amino, carboxy, alkoxycarbonyl; A 3 is selected from hydrogen and halogen; R i is selected from the group of hydrogen, halogen, CN, CF 3 , CHF 2 , an optionally substituted radical selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroalkyl, heterocycloalkyl, carboxy; R ii is hydrogen or an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo C 1 -C 6 alkyl, an optionally substituted halo C 3 -C 8 cycloalkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted hydroxy C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted alkoxycarbonyl C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted halo C 3 -C 8 cycloalkyl; Ar 1 is selected from: R 1 and R 4 are independently hydrogen, halogen, CN, CF 3 , CHF 2 , NH 2 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, alkoxy, amino, an optionally substituted heterocycloalkyl, carboxy, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted amino heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl; R 2 is selected from hydrogen, halogen, CF 3 , CHF 2 , NH 2 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted alkoxy, amino, an optionally substituted heterocycloalkyl, carboxy, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted amino heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl; R 3 is selected from hydrogen, halogen, CF 3 , CHF 2 , NH 2 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted alkoxy, amino, an optionally substituted heterocycloalkyl, carboxy, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted amino heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl; R 5 is selected from hydrogen, halogen, CF 3 , CHF 2 , NH 2 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted alkoxy, amino, an optionally substituted heterocycloalkyl, carboxy, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted amino heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 carboxy cycloalkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl; wherein when one from R 1 , R 2 , R 3 and R 4 is not H, the other from this group are H or any of R 1 , R 2 , R 3 , R 4 and R 5 can be linked together to form an optionally substituted bicyclic heteroaryl; Ar 1 is also selected from an optionally substituted bicyclic heteroaryl, in particular from the group consisting of: wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, halogen, hydroxy, CN, CF 3 , CHF 2 , NH 2 , alkoxy, amino, carboxy, aminocarbonyl, alkoxy carbonyl, or an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl, acylamino, ureido, sulfonyl, sulfonylamino; Ar 2 is selected from the following group: or from the following group: or from the following group: wherein R 15 , R 16 and R 19 are independently selected from hydrogen, halogen, hydroxy, CN, CF 3 , CHF 2 , NH 2 , alkoxy, amino, carboxy, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted alkenyl, alkynyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl, acylamino, ureido and sulfonyl, or selected from the groups listed below: Wherein y, w, z and t are independently an integer ranging from 1 to 3; h is an integer ranging from 0 to 3; n is an integer ranging from 0 to 4; G is selected from N-R 23 , O, S and SO 2 ; J is selected from C( B )n and N-R 23 ; L is C-(B)n, N-R 23 , O, S, SO 2 ; R 23 is selected from hydrogen, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl and aminosulfonyl; B is selected from hydrogen, halogen, hydroxy, CN, CF 3 , CHF 2 , NH 2 , alkoxy, amino, carboxy, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl, acylamino, ureido, sulfonyl and sulfonylamino; R 17 and R 18 are independently selected from hydrogen, halogen, CN, CF 3 , CHF 2 , alkoxy, amino, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, acylamino, ureido, sulfonyl, aminosulfonyl and sulfonylamino; R 20 and R 22 are independently selected from hydrogen, halogen, CN, CF 3 , CHF 2 , alkoxy, amino, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl and an optionally substituted amino C 3 -C 8 cycloalkyl; R 21 is selected from hydrogen, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl and an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl; R 15 and R 16 can be linked together to form an optionally substituted bicyclic heteroaryl of formula wherein X, Y and Z are each independently C(R 24 R 25 ), CH 2 C(R 24 R 25 ), C(=O), O and N-R 26 ; or R 15 and R 16 can be linked together to form an optionally substituted bicyclic heteroaryl of formula which is 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, wherein the nitrogen in the Z position is N-R 26 ; R 24 and R 25 are each independently selected from hydrogen, halogen, hydroxy, CN, CF 3 , CHF 2 , NH 2 , alkoxy, amino, carboxy, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, an optionally substituted amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl, an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl, acylamino, ureido, sulfonyl and sulfonylamino; R 24 and R 25 can be linked together to form an optionally substituted C 3 -C 8 cycloalkyl or an optionally substituted heterocycloalkyl; R 26 is selected from hydrogen, aminocarbonyl, alkoxy carbonyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted halo alkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 1 -C 6 alkyl, an optionally substituted aryl C 1 -C 6 alkyl, an optionally substituted heteroaryl C 1 -C 6 alkyl, an optionally substituted alkoxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, an optionally substituted carboxy C 1 -C 6 alkyl, an optionally substituted aminocarbonyl C 1 -C 6 alkyl, an optionally substituted heterocycloalkyl C 3 -C 8 cycloalkyl, an optionally substituted aryl C 3 -C 8 cycloalkyl, an optionally substituted heteroaryl C 3 -C 8 cycloalkyl, an optionally substituted alkoxy C 3 -C 8 cycloalkyl, an optionally substituted amino C 3 -C 8 cycloalkyl, an optionally substituted carboxy C 3 -C 8 cycloalkyl and an optionally substituted aminocarbonyl C 3 -C 8 cycloalkyl, aminosulfonyl; R 15 and R 19 can be linked together to form an optionally substituted bicyclic heteroaryl; R 15 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; R 17 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; R 20 and R 21 can be linked together to form an optionally substituted bicyclic heteroaryl; wherein when A 3 is hydrogen at least one of A 1 and A 2 is not H, as well as tautomers, geometrical isomers, optically active forms, pharmaceutically acceptable salts thereof for use in the treatment or prophylaxis of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney diseases, reproduction disorders, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, cancers, fibrotic disorders, psychotic disorders, infectious diseases, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, angiogenesis and angiogenesis-dependent, wherein the term "alkoxy" refers to the group -O-R where R includes C 1 -C 6 alkyl, aryl, heteroaryl, aryl C 1 -C 6 alkyl or heteroaryl C 1 -C 6 alkyl and the term "aminocarbonyl" refers to the group -C(O)NRR' where R and R' are independently H, C 1 -C 6 alkyl, aryl, heteroaryl, aryl C 1 -C 6 alkyl or heteroaryl C 1 -C 6 alkyl.
  2. A compound for use according to claim 1 wherein the said disease or condition is selected from an inflammatory disorder, a fibrotic disorder, a pain condition, or an angiogenic disorder.
  3. A compound for use according to claim 1 or 2, wherein the said inflammatory disorder is selected from skin inflammation, liver inflammation, and central nervous system inflammation, or wherein the said fibrotic disorder is selected from pulmonary fibrosis (such as idiopathic pulmonary fibrosis), kidney fibrosis, liver fibrosis (such as NASH), corneal fibrosis, skin fibrosis (such as scleroderma), and in cancers with a fibrotic stromal component, or wherein the said cancer is selected from head and neck cancer, breast cancer, colorectal cancer, melanoma, lung cancer and glioblastoma, or wherein the pain disorder is selected from neuropathic pain in particular diabetic neuropathy, spinal or nerve injury related pain, amputation, drug induced pain, multiple sclerosis, multiple myeloma, shingles, Lyme disease, Herpes Zoster infection, cancer retaled pain, HIV-related pain, trigeminal neuralgia and inflammatory pain in particular pelvic pain including endometriosis, fibromyalgia, joint pain associated with inflammatory disorders, burn related pain, trauma-induced pain, or wherein the angiogenic disorder is selected from a cancer with solid tumors or benign and malignant vascular tumors endometriosis and proliferative retinopathies.
  4. A compound according to Formula (I): as well as tautomers, geometrical isomers, optically active forms, and pharmaceutically acceptable salts thereof, wherein A1-A3, Ar1 and Ar2, Ri and Rii are as defined in claim 1.
  5. A compound according to claim 4, wherein R i is H, or wherein R i is halogen, in particular chloro.
  6. A compound according to any one of claims 4 or 5, wherein R ii is H.
  7. A compound according to any one of claims 4 to 6, wherein R ii is optionally substituted C 1 -C 6 alkyl such as optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, C 1 -C 6 alkyl optionally substituted with alkoxy such as methoxy ethyl or with optionally substituted C 2 -C 8 heterocycloalkyl such as oxetan methyl or with optionally substituted C 3 -C 8 cycloalkyl or with optionally substituted aryl C 1 -C 6 alkyl, or with an optionally substituted amide C 1 -C 6 alkyl or with optionally substituted acyl.
  8. A compound according to any one of claims 4 to 6, wherein R ii is optionally substituted C 3 -C 8 cycloalkyl, such as an optionally susbstituted cyclopropyl.
  9. A compound according to any one of claims 4 to 8, wherein A 1 and A 2 groups are independently selected from hydrogen, halogen and optionally substituted C 1 -C 6 alkyl.
  10. A compound according to any one of claims 4 to 9, selected from the following group: 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro [3.3]heptane; 1-(4-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro [3.3]heptane; 1-(4-(6-chloro-5-(2-methylpyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)-6-oxa-1-azaspiro [3.3]heptane; 6-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-2-oxa-6-azaspiro [3.3]heptane; 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-7-oxa-2-azaspiro [3.5]nonane; 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-3-methylazetidin-3-ol; 6-chloro-2-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole; 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxylic acid; 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidine-3-carboxamide; (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)azetidin-3-yl) methanol; 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl)-1H-indole; N-(1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-3-yl) methanesulfonamide; (1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)pyrrolidin-2-yl) methanol; 1-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-5-(hydroxymethyl) pyrrolidin-2-one; 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-3-fluoropyridin-2-yl) morpholine; 6-chloro-5-(5-methoxypyridin-3-yl)-2-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-1H-indole; 6-chloro-2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole; 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide; 6-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole; 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)-1-methylpiperazin-2-one; 3'-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methyl-5'H-spiro[azetidine-3,7'-furo[3,4-b]pyridine]; 7-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazine; (5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)(oxetan-3-yl) methanol; 6-chloro-2-(6-(methoxy(oxetan-3-yl)methyl)pyridin-3-yl)-5-(5-methoxypyridin-3-yl)-1H-indole; 2-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)propan-1-ol; 5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one; 4-(6-chloro-5-(5-methoxypyridin-3-yl)-1 H -indol-2-yl)-1-(cyclopropylmethyl)pyridin-2(1 H )-one; 4-(5-(7-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(4,6-difluoro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(quinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(5-chloropyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole; 6-fluoro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole; 4-chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole; 6-chloro-5-(5-methoxypyridin-3-yl)-2-(2-methylpyridin-4-yl)-1H-indole; 5-(5-methoxypyridin-3-yl)-4-methyl-2-(2-methylpyridin-4-yl)-1H-indole; 5-(5-methoxypyridin-3-yl)-6-methyl-2-(2-methylpyridin-4-yl)-1H-indole; 4-methyl-2,5-di(pyridin-4-yl)-1H-indole; 6-methyl-2,5-di(pyridin-4-yl)-1H-indole; 4-(5-(4-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-chloro-2,5-di(pyridin-4-yl)-1H-indole; 6-chloro-2,5-di(pyridin-4-yl)-1H-indole; 5-(6-chloro-2-(6-morpholinopyridin-3-yl)-1H-indol-5-yl)quinolin-2-ol; 4-(5-(6-chloro-5-(thieno[2,3-c]pyridin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(6-fluoroquinolin-4-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(2-methoxyquinolin-5-yl)-1H-indol-2-yl)pyridin-2-yl)morpholine; 4-(5-(6-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)pyridin-2-yl) morpholine; 7-(4-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine; and 7-(6-chloro-5-(5-methoxypyridin-3-yl)-1-methyl-1H-indol-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.
  11. A compound according to any one of claims 4 to 10 for use as a medicament.
  12. A pharmaceutical composition containing at least one derivative according to any one of claims 4 to 10 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
  13. A compound for use according to any one of claim 1 to 3, wherein the compound of Formula (I) is a compound according to any one of claims 5 to 10.
  14. A compound for use according to any one of claims 1 to 3, wherein said compound is to be administered in combination with a co-agent useful in the treatment of cancer, such as substances used in conventional chemotherapy directed against solid tumors and for control of establishment of metastases or substances used in hormonotherapy or any other molecule that act by triggering programmed cell death, for example a co-agent selected from the category of drugs that stop the synthesis of pre DNA molecule building blocks such as methotrexate (Abitrexate ® ), fluorouracil (Adrucil ® ), hydroxyurea (Hydrea ® ), and mercaptopurine (Purinethol ® ),for example a co-agent selected from the category of drugs that directly damage the DNA in the nucleus of the cell such as cisplatin (Platinol ® ) and antibiotics - daunorubicin (Cerubidine ® ), doxorubicin (Adriamycin ® ), and etoposide (VePesid ® ), for example a co-agent selected from the category of drugs that effect the synthesis or breakdown of the mitotic spindles such as Vinblastine (Velban ® ), Vincristine (Oncovin ® ) and Pacitaxel (Taxol ® ).
  15. A compound for use according to any one of claims 1 to 3, wherein said compound is to be administered in combination with radiation therapy.

Description

Field of the Invention The present invention relates to novel derivatives of Formula (I) as defined in claim 1, pharmaceutical composition thereof and to them for use for the treatment and/or prophylaxis of disorders according to the appended claims, such as fibrotic disorders, cardiovascular diseases, neurodegenerative diseases, inflammatory disorders and cancers. Specifically, the present invention is related to novel derivatives useful for the preparation of a pharmaceutical formulation for the modulation, notably the inhibition of the activity or function of the Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). Background of the Invention NADPH oxidases (NOX) are proteins that transfer electrons across biological membranes. In general, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. The biological function of NOX enzymes is therefore the generation of reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are oxygen-derived small molecules, including oxygen radicals (super-oxide anion [•O2-], hydroxyl [HO•], peroxyl [ROO*], alkoxyl [RO*] and hydroperoxyl [HOO•]) and certain non-radicals that are either oxidizing agents and/or are easily converted into radicals. Nitrogen-containing oxidizing agents, such as nitric oxide are also called reactive nitrogen species (RNS). ROS generation is generally a cascade of reactions that starts with the production of superoxide. Superoxide rapidly dismutates to hydrogen peroxide either spontaneously, particularly at low pH or catalyzed by superoxide dismutase. Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical. ROS avidly interact with a large number of molecules including other small inorganic molecules as well as DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction may generate a second radical, thus multiplying the potential damage. ROS are involved not only in cellular damage and killing of pathogens, but also in a large number of reversible regulatory processes in virtually all cells and tissues. However, despite the importance of ROS in the regulation of fundamental physiological processes, ROS production can also irreversibly destroy or alter the function of the target molecule. Consequently, ROS have been increasingly identified as major contributors to damage in biological organisms, so-called "oxidative stress". During inflammation, NADPH oxidase is one of the most important sources of ROS production in vascular cells under inflammatory conditions (Thabut et al., 2002, J. Biol. Chem., 277:22814-22821). In the lung, tissues are constantly exposed to oxidants that are generated either endogenously by metabolic reactions (e.g. by mitochondrial respiration or activation of recruited inflammatory cells) or exogenously in the air (e.g. cigarette smoke or air pollutants). Further, the lungs, constantly exposed to high oxygen tensions as compared to other tissues, have a considerable surface area and blood supply and are particularly susceptible to injury mediated by ROS (Brigham, 1986, Chest, 89(6): 859-863). NADPH oxidase-dependent ROS generation has been described in pulmonary endothelial cells and smooth muscle cells. NADPH oxidase activation in response to stimuli has been thought to be involved in the development of respiratory disorders such as pulmonary hypertension and enhancement of pulmonary vasoconstriction (Djordjevic et al., 2005, Arterioscler. Thromb. Vasc. Biol., 25, 519-525; Liua et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol., 287: L111-118). Further, pulmonary fibrosis has been characterized by lung inflammation and excessive generation of ROS. Osteoclasts, which are macrophage-like cells that play a crucial role in bone turn-over (e.g. bone resorption), generate ROS through NADPH oxidase-dependent mechanisms (Yang et al., 2002, J. Cell. Chem. 84, 645-654). Diabetes is known to increase oxidative stress (e.g. increased generation of ROS by autooxidation of glucose) both in humans and animals and increased oxidative stress has been said to play an important role in the development of diabetic complications. It has been shown that increased peroxide localization and endothelial cell dysfunction in the central retina of diabetic rats coincides with the areas of NADPH oxidase activity in the retinal endothelial cells (Ellis et al., 2000, Free Rad. Biol. Med., 28:91-101). Further, it has been suggested that controlling oxidative stress (ROS) in mitochondria and/or inflammation may be a beneficial approach for the treatment of diabetes (Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8(5):401-408). ROS are also strongly implicated in the pathogenesis of atherosclerosis, cell proliferation, hyperte