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CN-116323601-B - 2- (3-Pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl) -acetamide derivatives as transforming growth factor-beta receptor I/ALK5 inhibitors

CN116323601BCN 116323601 BCN116323601 BCN 116323601BCN-116323601-B

Abstract

The present invention relates to novel 2- (3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl) -acetamide derivatives that are potent inhibitors of transforming growth factor-beta receptor I (also known as activin receptor-like kinase 5) (tgfp RI)/ALK 5. It is a further object of the present invention to provide methods for preparing these compounds, pharmaceutical compositions comprising an effective amount of these compounds, the use of the compounds in the manufacture of a medicament for the treatment of pathological conditions or diseases ameliorated by the inhibition of transforming growth factor-beta receptor I (TGF-beta RI)/ALK 5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD, and lung cancer and skin and eye fibrosis conditions.

Inventors

  • R. Bauser Alta
  • B. Panping Kasar
  • J Kasiteluopaluo Mino laryea

Assignees

  • 阿戈麦布西班牙股份有限公司

Dates

Publication Date
20260512
Application Date
20210929
Priority Date
20200930

Claims (20)

  1. 1. A compound of formula (I): Wherein: -R 1 represents a group selected from: a) Phenyl ring which is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms, 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 and hydroxy, B) A 5-or 6-membered heteroaryl ring which is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms, 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 and hydroxy, -R 2 is a group selected from: a) The hydrogen atom is contained in the mixture, B) A linear or branched C 1 -C 3 alkyl group optionally substituted with 1,2 or 3 halogen atoms, -R 3 represents a group selected from: a) The hydrogen atom is contained in the mixture, B) A linear or branched C 1 -C 3 alkyl group optionally substituted with 1,2 or 3 halogen atoms, C) A halogen atom is used as a halogen atom, -R 4 and R 5 represent groups independently selected from: a) The hydrogen atom is contained in the mixture, B) A linear or branched C 1 -C 3 alkyl group optionally substituted with 1,2 or 3 halogen atoms, C) A halogen atom is used as a halogen atom, N is an integer from 0 to 3, -R 6 represents a group selected from: a) -N (R 7 )(R 8 ) wherein R 7 and R 8 independently represent a linear or branched C 1 -C 6 alkyl group or a hydrogen atom, and B) A saturated 4-to 10-membered mono-or bicyclic nitrogen containing heterocyclyl optionally containing another heteroatom selected from oxygen and nitrogen, said heterocyclyl optionally being substituted with a group selected from C 1 -C 3 alkyl, Or a pharmaceutically acceptable salt thereof.
  2. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 4 and R 5 represent a hydrogen atom.
  3. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 represents methyl.
  4. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 represents a benzene ring substituted with 1 or 2 halogen atoms.
  5. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein N is an integer from 1 to 2 and R 6 represents the-N (R 7 )(R 8 ) group.
  6. 6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 independently represent a group selected from linear C 1 -C 3 alkyl and a hydrogen atom.
  7. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 represents a saturated 6-membered heterocyclyl containing 1 or 2 nitrogen atoms, optionally substituted with methyl.
  8. 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 6 represents a group selected from piperazinyl and piperidinyl.
  9. 9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 4 and R 5 represent a hydrogen atom, R 3 represents a linear C 1 -C 3 alkyl group, R 1 represents a benzene ring substituted with 1 or 2 halogen atoms, n is an integer from 0 to 2, and R 6 represents a group selected from: a) N (R 7 )(R 8 ) wherein R 7 and R 8 are selected from the group consisting of linear C 1 -C 3 alkyl groups and hydrogen atoms, B) Saturated 6-membered heterocyclic group containing 1 or 2 nitrogen atoms, which is optionally substituted with methyl, and C) 1-aza-bicyclo [2.2.2] octanyl.
  10. 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: 2- (dimethylamino) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (dimethylamino) ethyl 5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-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) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (dimethylamino) ethyl 5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) picolinate; 2- (4-methylpiperazin-1-yl) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (diethylamino) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 1-methylpiperidin-4-yl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 1-methylpiperidin-4-yl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoic acid methyl ester; quinuclidin-3-yl (R) -3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; quinuclidin-3-yl (S) -3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; quinuclidin-4-yl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (azetidin-1-yl) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (aziridin-1-yl) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (methylamino) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2-aminoethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (ethylamino) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (isopropylamino) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; 2- (piperazin-1-yl) ethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; Piperidin-4-ylmethyl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate, and Piperidin-4-yl 3-fluoro-5- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-pyrazol-1-yl) acetamido) benzoate; or a pharmaceutically acceptable salt of any of these.
  11. 11. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or pathological condition selected from respiratory diseases, fibrotic skin diseases and fibrotic eye diseases.
  12. 12. The use of a compound according to claim 11, or a pharmaceutically acceptable salt thereof, 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.
  13. 13. The use of a compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the fibrotic skin disease is selected from scleroderma, nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerotic myxoedema and eosinophilic fasciitis.
  14. 14. The use of a compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the fibrotic ocular disease is selected from dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.
  15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  16. 16. The pharmaceutical composition according to claim 15, further comprising a therapeutically effective amount of a therapeutic agent for the treatment of a disease or pathological condition selected from the group consisting of respiratory diseases, fibrotic skin diseases and fibrotic eye diseases.
  17. 17. A combination comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent for the treatment of a disease or pathological condition selected from respiratory diseases, fibrotic skin diseases and fibrotic eye diseases.
  18. 18. 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 10.
  19. 19. A compound according to claim 18, or a salt thereof, selected from: 3- (2- (3- (6-methylpyridin-2-yl) -4- (quinolin-4-yl) -1H-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 of any of these.
  20. 20. A process for preparing a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II): with a compound of formula (III): OH-(CH 2 ) n -R 6 (III) 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 10.

Description

2- (3-Pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl) -acetamide derivatives as transforming growth factor-beta receptor I/ALK5 inhibitors Technical Field The present invention relates to novel 2- (3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl) -acetamide derivatives that are potent inhibitors of transforming growth factor-beta receptor I (also known as activin receptor-like kinase 5) (tgfp RI)/ALK 5. It is a further object of the present invention to provide methods for preparing these compounds, pharmaceutical compositions comprising an effective amount of these compounds, the use of the compounds in the manufacture of a medicament for the treatment of pathological conditions or diseases ameliorated by the inhibition of transforming growth factor-beta receptor I (TGF-beta RI)/ALK 5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD, and lung cancer, as well as skin and eye fibrotic conditions. Prior Art Transforming growth factor-beta (TGF-beta) belongs to the TGF-beta superfamily, which consists of TGF-beta 1, TGF-beta 2, TGF-beta 3, and other proteins. TGF- β is involved in many cellular processes including cell proliferation, cell migration, invasion, epithelial-mesenchymal transformation, extracellular matrix production, and immunosuppression. TGF- β and its receptors are often overexpressed for long periods in a variety of human diseases, including cancer, inflammation, tissue fibrosis, and autoimmunity. Thus, blocking the TGF- β signaling 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-beta signals through two related transmembrane type I and type II serine/threonine kinase receptors. After TGF-beta binds to a constitutively active type II receptor, the type I receptor (also known as activin receptor-like kinase 5 (ALK 5)) is phosphorylated and creates a binding site for Smad2 and Smad3 proteins, the latter being further phosphorylated. Phosphorylated Smad2/Smad3 proteins form heteromeric complexes with Smad4, which translocate into the nucleus, assemble with specific DNA-binding cofactors and cofactors, and bind to promoters of TGF- β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst R J et al, TARGETING THE TGF. Beta. SIGNALLING PATHWAY IN DISEASE, nature/Reviews, 10 th 2012, volume 11). In most cell types, the activin receptor-like kinase 5-ALK5 (also known as tgfp R1) is the predominant tgfp receptor I, which is activated by tgfp through tgfp receptor II. This interaction requires extracellular and intracellular domains for signal transduction. ALK5 and tgfp receptor II proteins may also form active hetero-oligomeric complexes in the absence of ligand. When the two receptors are co-expressed, these complexes are able to transduce the underlying signal because they have an intrinsic affinity for interaction. (Bierie B et al, TGF-. Beta.: the molecular Jekyll and Hyde of Cancer, nature Reviews, cancer, volume 6, month 7 of 2006). Functional tgfbetarii-tgfbetari (ALK 5) heteromeric signaling complex is often associated with human cancers, and it regulates downstream Smad-dependent and Smad-independent pathway activation. Indeed, many studies have identified mutations in components associated with the TGF- β pathway, and are associated with the occurrence and prognosis of cancer in many human tissues. Overexpression of TGF- β1 is associated with breast, colon, esophageal, gastric, hepatocellular, lung and pancreatic cancers. Importantly, overexpression of TGF- β in human cancers is associated with tumor progression, metastasis, angiogenesis, and poor prognosis. Transforming growth factor (TGF- β) cytokines play a critical role in the development and progression of chronic respiratory disease. In the most common chronic respiratory diseases including pulmonary fibrosis, asthma, COPD and lung cancer, TGF- β is overexpressed in chronic inflammation, remodeling, the fibrotic process and susceptibility to viral infection. Idiopathic pulmonary fibrosis Pulmonary fibrosis is a chronic and progressive lung disease in which repeated trauma and repair processes lead to irreversible structural changes and tissue hardening. Pathophysiological steps include alveolar epithelial injury caused by external stimuli, fibroblast activation, and sustained fibrotic response. Differentiation of lung fibroblasts into myofibroblasts is a key step in the development of tissue fibrosis. TGF-beta is the most potent factor inducing myofibroblast differentiation, and increased expression of this factor in the fibrotic lung has been reported. 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-beta induces molecular modulators of small GTPases and promotes pulmonary fibrosis by inhibiting the product