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EP-4222149-B1 - 2-(3-PYRIDIN-2-YL-4-QUINOLIN-4-YL-PYRAZOL-1-YL)-ACETAMIDE DERIVATIVES AS INHIBITORS OF TRANSFORMING GROWTH FACTOR-BETA RECEPTOR I/ALK5

EP4222149B1EP 4222149 B1EP4222149 B1EP 4222149B1EP-4222149-B1

Inventors

  • BOSSER ARTAL, Ramón
  • PAMPÍN CASAL, Begoña
  • CASTRO PALOMINO LARIA, JULIO

Dates

Publication Date
20260506
Application Date
20210929

Claims (15)

  1. A compound of formula (I): wherein: - R 1 represents a group selected from: a) phenyl ring unsubstituted or substituted by 1 or 2 groups selected from halogen atom, linear or branched C 1 -C 3 haloalkyl, linear or branched C 1 -C 3 alkyl, linear or branched C 1 -C 3 alkoxy, cyano group and hydroxy group, b) 5- or 6-membered heteroaryl ring unsubstituted or substituted by 1 or 2 groups selected from halogen atom, linear or branched C 1 -C 3 haloalkyl, linear or branched C 1 -C 3 alkyl, linear or branched C 1 -C 3 alkoxy, cyano group and hydroxy group, - R 2 is a group selected from: a) hydrogen atom, b) linear or branched C 1 -C 3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, - R 3 represents a group selected from: a) hydrogen atom, b) linear or branched C 1 -C 3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) halogen atom, - R 4 and R 5 represent independently a group selected from: a) hydrogen atom, b) linear or branched C 1 -C 3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) halogen atom, - n is an integer from 0 to 3, - R 6 represents a group selected from the group consisting of: a) -N(R 7 )(R 8 ), wherein R 7 and R 8 represent independently a linear or branched C 1 -C 6 alkyl group or a hydrogen atom, and b) saturated 4- to 10-membered, monocyclic or bicyclic, nitrogen-containing heterocyclyl optionally comprising another heteroatom selected from the group consisting of oxygen and nitrogen, said heterocyclyl being optionally substituted by a group selected from C 1 -C 3 alkyl group, or a pharmaceutically acceptable salt thereof.
  2. A compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 2 , R 4 and R 5 represent hydrogen atom.
  3. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 wherein R 3 represents methyl group.
  4. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 wherein R 1 represents a phenyl ring substituted by 1 or 2 halogen atoms.
  5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 wherein n is an integer from 1 to 2.
  6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 wherein R 6 represents a saturated 6-membered heterocyclic group containing 1 or 2 nitrogen atoms, optionally substituted by a methyl group.
  7. A compound or a pharmaceutically acceptable salt thereof according to claim 6 wherein R 6 represents a group selected from piperazinyl and piperidinyl group.
  8. A compound or a pharmaceutically acceptable salt thereof according to claim 1 which is selected from the group consisting of: 2-(dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)nicotinate; 2-(dimethylamino)ethyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H- pyrazol-1-yl)acetamido)nicotinate; 2-morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)benzoate; 2-(dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)picolinate; 2-(4-methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(diethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 1-methylpiperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; (1-methylpiperidin-4-yl)methyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; ( R )-quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; ( S )-quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; quinuclidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)benzoate; 2-(azetidin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)benzoate; 2-(ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; 2-(piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; piperidin-4-ylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazol-1-yl)acetamido)benzoate; and piperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H- pyrazol-1-yl)acetamido)benzoate; or a pharmaceutically acceptable salt thereof.
  9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for use as a medicament.
  10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for use in the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI)/ALK5, wherein the disease or pathological condition is selected from the group consisting of respiratory diseases; fibrotic skin diseases; and fibrotic eye diseases.
  11. The compound or a pharmaceutically acceptable salt thereof for use according to claim 10 wherein the respiratory disease is selected from the group consisting of: pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary arterial hypertension and lung cancer; the fibrotic skin disease is selected from the group consisting of: scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, and eosinophilic fasciitis; and the fibrotic eye disease is selected from the group consisting of: dry eyes, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.
  12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable diluent or carrier.
  13. A compound of formula (II): or a salt thereof; wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in any one of claims 1 to 8.
  14. The compound according to claim 13 selected from the group consisting of: 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid; 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinic acid; and 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylic acid; or a salt thereof.
  15. A process for the preparation of the compound of formula (I) or pharmaceutically acceptable salts thereof according to any one of claims 1 to 8 which comprises reacting a compound of formula (II): or a salt thereof; with a compound of formula (III): OH-(CH 2 ) n -R 6 (III) or a salt thereof; wherein n, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in any one of claims 1 to 8.

Description

Field of the Invention The present invention relates to novel 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as potent inhibitors of transforming growth factor-β receptor I, (also named activin receptor-like kinase 5) (TGFβRI)/ALK5. Other objectives of the present invention are to provide a procedure for preparing these compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of the compounds for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by inhibition of transforming growth factor-β receptor I (TGFβRI)/ALK5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD and lung cancer, and dermal and ocular fibrotic conditions. State of the art Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which consists of TGF-β1, TGF-β2, TGF-β3, among other proteins. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production, and immune suppression. TGF-β and its receptors are often chronically over expressed in various human diseases, including cancer, inflammation, tissue fibrosis, and autoimmunity. Therefore, blockade of TGF-β signalling pathway is considered an attractive target for drug development. (Heldin C H, et al, Signalling Receptors for TGF-b Family Members, Cold Spring Harb Perspect Biol, 2016). TGF-β signals via two related transmembrane type I and type II serine/threonine kinase receptors. Following TGF-β binding to the constitutively active type II receptor, the type I receptor (also called activin receptor-like kinase 5 (ALK5)) is phosphorylated and creates a binding site for Smad2 and Smad3 proteins, which are further phosphorylated. Phosphorylated Smad2/Smad3 proteins form a heteromeric complex with Smad4, which translocate into the nucleus, assembles with specific DNA-binding cofactors and co-modulators, and binds to the promoters of TGF-β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst R J, et al, Targeting the TGFβ signalling pathway in disease, Nature/Reviews, October 2012, VOLUME 11). In most cell types, activin receptor-like kinase 5 - ALK5 (also known as TGFβR1) is the predominant TGFβ receptor I that is activated by TGF-β through TGFβ receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGFβ receptor II proteins can also form active heterooligomeric complexes in the absence of ligand. These complexes are able to transduce basal signals when both receptors are co-expressed because of their intrinsic affinity for interaction. (Bierie B et al, TGF-β: the molecular Jekyll and Hyde of cancer, Nature Reviews, Cancer, Volume 6, July 2006). The functional TGFβRII-TGFβRI (ALK5) heteromeric signalling complex is commonly associated with human cancer, and it regulates the activation of downstream Smad-dependent and Smad-independent pathways. In fact, many studies have identified mutations in components that are associated with the TGF-β pathway, and which correlate with cancer occurrence and prognosis in many human tissues. The over expression of TGF-β1 has been associated with breast, colon, oesophageal, gastric, hepatocellular, lung and pancreatic cancer. Importantly, the overexpression of TGF-β in human cancer correlates with tumour progression, metastasis, angiogenesis and poor prognostic outcome. The transforming growth factor (TGF-β) cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodelling, fibrotic process, and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including pulmonary fibrosis, asthma, COPD and lung cancer. Idiopathic pulmonary fibrosis Pulmonary fibrosis is a chronic and progressive lung disease, in which repeated wound and repair processes lead to irreversible structural alterations and tissue stiffening. Pathophysiological steps include alveolar epithelial damage by extrinsic irritants, fibroblast activation and persistent fibrotic reaction. Differentiation of lung fibroblasts into myofibroblasts is a key step in the development of tissue fibrosis. TGF-β is the most potent factor for the induction of myofibroblast differentiation and increased expression of this factor has been reported in fibrotic lungs. The major cellular sources of TGF-β in pulmonary fibrosis have been shown to be alveolar macrophages and metaplastic type II alveolar epithelial cells. TGF-β induces molecules regulators of small GTPases and promotes lung fibrosis by suppressing production of anti-fibrotic molecules such as hepatocyte growth factor and prostaglandin E2. Furthermore, TGF-β inhibits alveolar epithelial cell growth and repair, so it is a key p