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EP-3833664-B1 - SMAD3 INHIBITORS

EP3833664B1EP 3833664 B1EP3833664 B1EP 3833664B1EP-3833664-B1

Inventors

  • LO, HO YIN

Dates

Publication Date
20260513
Application Date
20190806

Claims (14)

  1. A compound of Formula 1a(i), or a pharmaceutically acceptable salt thereof: wherein: the moiety -C(=O)NR 1 R 2 is selected from R 14 and R 15 are each selected from hydrogen, CN, NO 2 , OC(O)R 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OR 9 , OS(O) 2 R 9 , NR 9 R 10 , SR 9 , and R 9 ; R 9 and R 10 are each independently selected from hydrogen, C 1-10 alkyl, arylC 1-10 alkyl, hetarylC 1-10 alkyl, and heterocyclic; the C 1-10 alkyl moiety of any one of these groups is optionally interrupted with one or more heteroatoms independently selected from O, N and S; and the C 1-10 alkyl, arylC 1-10 alkyl, hetarylC 1-10 alkyl, and heterocyclic groups are each optionally substituted with 1 to 3 substituents independently selected from halo, CN, NO 2 , OC(O)R 11 , C(O)R 11 , C(O)NR 11 R 12 , C(O)OR 11 , OR 11 , OS(O) 2 R 11 , NR 11 R 12 , and SR 11 ; and R 11 and R 12 are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 alkylhalo; R 4 , R 5 , R 6 , and R 7 , are each independently selected from hydrogen, halo, CN, NO 2 , OC(O)R 11 , C(O)R 11 , C(O)NR 11 R 12 , C(O)OR 11 , OR 11 , OS(O) 2 R 11 , NR 11 R 12 , SR 11 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, monocyclic or bicyclic heterocyclic, and monocyclic or bicyclic aryl; wherein the C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl groups are each optionally interrupted with one or more heteroatoms selected from O, N and S, and wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, heterocyclic, and aryl groups, are each optionally substituted with one or more substituents independently selected from halo, CN, NO 2 , OC(O)R 11 , C(O)R 11 , C(O)NR 11 R 12 , C(O)OR 11 , OR 11 , OS(O) 2 R 11 , NR 11 R 12 , SR 11 , and R 11 ; wherein R 11 and R 12 are each independently selected from hydrogen, C 1-6 alkyl, and C 1-6 alkylhalo; and R 3 is selected from CN, NO 2 , OC(O)R 11 , C(O)R 11 , C(O)NR 11 R 12 , C(O)OR 11 , OR 11 , OS(O) 2 R 11 , NR 11 R 12 , SR 11 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, monocyclic or bicyclic heterocyclic, and monocyclic or bicyclic aryl; wherein the C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl groups are each optionally interrupted with one or more heteroatoms selected from O, N and S, and wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, heterocyclic, and aryl groups, are each optionally substituted with one or more substituents independently selected from halo, CN, NO 2 , OC(O)R 11 , C(O)R 11 , C(O)NR 11 R 12 , C(O)OR 11 , OR 11 , OS(O) 2 R 11 , NR 11 R 12 , SR 11 , and R 11 ; wherein R 11 is selected from hydrogen, ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo and R 12 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  2. The compound of claim 1, wherein R 14 and R 15 are each independently selected from hydrogen, C(O)NR 9 R 10 , OR 9 , and NR 9 R 10 ; and R 9 and R 10 are each independently selected from hydrogen, C 1-6 alkyl, monocyclic arylC 1-6 alkyl, monocyclic hetarylC 1-6 alkyl, and monocyclic heterocyclic, wherein the C 1-6 alkyl moiety of any one of these groups is optionally interrupted with one or more heteroatoms independently selected from O, N and S, and the C 1-6 alkyl, monocyclic arylC 1-6 alkyl, monocyclic hetarylC 1-6 alkyl, and monocyclic heterocyclic, may be optionally substituted with 1 to 3 substituents independently selected from halo, CN, NH 2 , OH, and OC 1-6 alkyl.
  3. The compound according to claim 1 or claim 2, wherein: R 4 , R 5 , R 6 , and R 7 , are each independently selected from hydrogen, halo, OH, CN, NO 2 , NH 2 , C 1-10 alkyl, monocyclic heterocyclic, and monocyclic aryl; wherein the C 1-10 alkyl is optionally interrupted with one or more heteroatoms selected from O, N and S, and wherein the C 1-10 alkyl, heterocyclic, and aryl groups, are each optionally substituted with one or more substituents independently selected from halo, OH, CN, NO 2 , NH 2 , C 1-6 alkyl, and C 1-6 alkylhalo, and R 3 is selected from OH, CN, NO 2 , NH 2 , C 1-10 alkyl, monocyclic heterocyclic, and monocyclic aryl; wherein the C 1-10 alkyl is optionally interrupted with one or more heteroatoms selected from O, N and S, and wherein the C 1-10 alkyl, heterocyclic, and aryl groups, are each optionally substituted with one or more substituents independently selected from halo, OH, CN, NO 2 , NH 2 , ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  4. The compound of any one of claims 1 to 3, wherein R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 alkylhalo.
  5. The compound of any one of claims 1 to 4, wherein R 4 , R 5 , R 6 , and R 7 are each hydrogen.
  6. The compound of any one of claims 1 to 4, wherein R 3 is selected from C 1-6 alkyl, C 1-6 alkylhalo, monocyclic heterocyclic, monocyclic aryl and heteroaryl.
  7. The compound of any one of claims 1 to 4, wherein R 3 is selected from C 1-6 alkyl, C 1-6 alkylhalo, and monocyclic heterocyclic, and monocyclic aryl or hetaryl, wherein the aryl and hetaryl groups may be optionally substituted with one or more substituents independently selected from halo, OH, CN, NO 2 , NH 2 , ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  8. The compound of any one of claims 1 to 4 or claim 7, wherein R 3 is monocyclic aryl and heteroaryl, wherein the aryl and hetaryl groups may be optionally substituted with one or more substituents independently selected from halo, OH, CN, NO, NH 2 , ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  9. The compound of any one of claims 1 to 4, 7 or 8, wherein R 3 is monocyclic aryl, wherein the aryl group may be optionally substituted with one or more substituents independently selected from halo, OH, CN, NO 2 , NH 2 , ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  10. The compound of any one of claims 1 to 4 or 7 to 9, wherein R 3 is phenyl, which may be optionally substituted with one or more substituents independently selected from halo, OH, CN, NO 2 , NH 2 , ethyl, n-propyl, iso-propyl, butyl, pentyl, hexyl, and C 1-6 alkylhalo.
  11. The compound of claim 1, selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof: Compound No. Compound Structure Compound Name 7 (E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 8 (E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 9 (E)-1-(isoindolin-2-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 10 (E)-1-(5,6-dimethoxyisoindolin-2-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 11 (E)-1-(5,6-dimethoxyisoindolin-2-yl)-3-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 12 (E)-3-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-1-(5,6-dimethoxyisoindolin-2-yl)prop-2-en-1-one 13 (E)-1-(5,6-dimethoxyisoindolin-2-yl)-3-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 14 (E)-1-(5,6-dimethoxyisoindolin-2-yl)-3-(2-(pyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 15 (E)-1-(5,6-dimethoxyisoindolin-2-yl)-3-(2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 16 (E)-1-(5-aminoisoindolin-2-yl)-3-(2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 17 (E)-1-(isoindolin-2-yl)-3-(6-methyl-2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 18 (E)-1-(isoindolin-2-yl)-3-(6-methoxy-2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 19 (E)-3-(7-hydroxy-2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-1-(isoindolin-2-yl)prop-2-en-1-one 20 (E)-1-(isoindolin-2-yl)-3-(6-phenyl-2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 21 (E)-3-(2,7-di(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-1-(isoindolin-2-yl)prop-2-en-1-one 22 (E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 23 (E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 24 (E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-(4-fluorophenyl)-5-methylimidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one 25 (E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-phenyl-5-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one
  12. A pharmaceutical composition comprising: (i) a compound of Formula 1a(i) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11, and (ii) a pharmaceutically acceptable excipient.
  13. A compound of Formula 1a(i) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11, for use in treating or preventing cancer in a patient in need thereof.
  14. The compound for use according to claim 13, wherein the cancer is a solid tumor selected from the group consisting of: lung cancer, colorectal cancer, gastric cancer, melanoma, pancreatic cancer, breast cancer, liver cancer and prostate cancer.

Description

FIELD This disclosure relates to Smad3 inhibitor compounds. This disclosure also relates to compositions comprising the Smad3 inhibitor compounds. This disclosure also relates to the Smad3 inhibitor compounds for use in treating or preventing cancer. BACKGROUND Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid proliferation of abnormal cells that grow beyond their usual boundaries. Cancer cells can then invade adjoining parts of the body and spread to other organs in a process known as metastasis. Metastasis is the main cause of death from cancer and can also be promoted by the cells surrounding the cancer called cancer stromal cells or cancer micro-environments. According to the World Health Organization (WHO), cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008. Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year. Despite intense research effort and technological advancement in biomedical sciences, deaths from cancer worldwide are projected to continue rising, with an estimated 13.1 million deaths in 2030. Because of the prevalence of cancer and its significant impact on humanity, there remains an urgent need to develop new and more effective strategies for cancer treatment. The present disclosure addresses this and other related needs in that it provides alternative Smad3 inhibitor compounds that can inhibit cancer cell growth and supportive function of the cancer microenvironment. WO 2014/063659 A1 discloses a method of treating cancer by inhibiting Smad3 signalling, such as through administration of SIS3, an inhibitor of Smad3. JP 2013253065 A discloses a chronic myelogenous leukemia therapeutic agent comprising a selective inhibitory drug for a TGF-β-Smad signal. M. Jinnin et al: "Characterisation of SIS3, a Novel Specific Inhibitor of Smad3, and its Effect on Transforming Growth Factor-beta-1-Induced Extracellular Matrix Expression", Molecular Pharmacology, vol. 69, no. 2, January 2006 (2006-01), pages 597-607 discloses that SIS3 is a potent and selective inhibitor of Smad3 function. Lad Nitin P et al: "Piperlongumine derived cyclic sulfonamides (sultams): Synthesis and in vitro exploration for therapeutic potential against HeLa cancer cell lines, European Journal Of Medicinal Chemistry, Elsevier, Amsterdam, NL, vol. 126, 10 December 2016 (2016-12-10), pages 870-878 discloses a modification of piperlongumine bearing a cyclic sulphonamide (sultam) and its synthesis. WO 02/14313 A2 discloses compounds of the general formula (I) and the use of the compounds as medicaments, especially as medicaments having a beta-amyloid inhibiting effect. EP 0225522 A1 discloses imidazopyridazinealkenecarboxamides of the formula (I) and the use of the compounds for the treatment of illnesses, in particular as antihypertensives, diuretics and saluretics. Li Y et al: "Design, synthesis and antiproliferative actives of novel benzamide derivatives as HDAC inhibitors", European Journal Of Chemistry, vol. 100, 5 June 2015 (2015-06-05), pages 270-276 discloses HDAC inhibitors bearing a bicyclic heterocycle moiety based on compound MS-275. US 2013/317003 A1 discloses compounds of formula (I) for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDAC1, HDAC2, and HDAC3). WO 2005/009947 A2 discloses aryl heteroaromatic products of formula (I) having an anticancer activity, and especially a tubulin polymerization inhibition activity. WO 2016/177658 A1 discloses amido-substituted cyclohexane compounds of general formula (I), and the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms. WO 2012/045729 A1 discloses compounds of formula (I). WO 2013/033116 A1 discloses compounds of formulae (I) and (II) and discloses methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit or c-kit and PDGFR (PDGFRa, PDGFRβ) kinases. WO 2015/078417 A1 discloses a compound as represented by formula I, or pharmaceutically acceptable salt, hydrate or solvate thereof. WO 2014/018888 A1 discloses 4-alkoxy/aralkoxy-5-substituted-pyrrolopyrimidine compounds of Formula (I). WO 2015/083028 A1 discloses pharmaceutically active pyrrolo [2,3-d] pyrimidinyl and pyrrolo [2,3-d] pyridinyl acrylamides and analogues thereof for inhibiting Janus Kinase (JAK). Database Registry, Chemical Abstracts Service, Ohio, US, discloses compounds having the following Database accession numbers 2224435-50-9; 2224343-17-1; 1186404-55-6; 1922659-70-8; 1921814-78-9; 1808371-54-1; 1627398-07-5; 1331593-74-8; 1287385-43-6; 1002697-02-0 and 853593-18-7. SUMMARY The present inventors have identified novel and alternative Smad3 inhibitor compounds, which may be used in the treatment of cancers. The Smad3 inhibitor compounds, at least according to