Search

US-12617801-B2 - Tetrahydrothieno pyridine derivatives as DDRS inhibitors

US12617801B2US 12617801 B2US12617801 B2US 12617801B2US-12617801-B2

Abstract

The present invention relates to compounds of general formula (I) inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms.

Inventors

  • Laura Carzaniga
  • Fabio RANCATI
  • Andrea Rizzi
  • Keith Christopher KNIGHT
  • Anna KARAWAJCZYK
  • Barbara Karolina Wołek
  • Toby Matthew Grover Mullins
  • Ben Paul WHITTAKER

Assignees

  • CHIESI FARMACEUTICI S.P.A.

Dates

Publication Date
20260505
Application Date
20220325
Priority Date
20210326

Claims (15)

  1. 1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: L is selected from the group consisting of —C(O)— and —CH 2 —; Hy is a monocyclic heteroaryl optionally substituted with one or more groups selected from —(C 1 -C 4 )alkyl, a halogen atom, cyano, —(CH 2 ) n NR 4 R 5 , —NH-heterocycloalkyl, —O—(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —C(O)NH—(C 1 -C 6 )alkylene-NR 4 R 5 , —O—(C 1 -C 6 )alkylene-cycloalkyl, —NHC(O)—(C 1 -C 6 )alkyl, —NHC(O)—(C 1 -C 6 )alkylene-NR 4 R 5 , —NHC(O)—(C 1 -C 6 )alkylene-O—(C 1 -C 4 )alkyl, —NH—(C 1 -C 6 )alkylene-O—(C 1 -C 4 )alkyl, —NH—(C 1 -C 6 )alkylene-OH, -heteroaryl optionally substituted by one or more of —(C 1 -C 4 )alkyl and —NH-heteroaryl, wherein the heteroaryl is optionally substituted by one or more —(C 1 -C 4 )alkyl, and heterocycloalkyl optionally substituted by one or more groups selected from oxo and —(C 1 -C 6 )alkyl; R 1 is selected from the group consisting of: Het which is an heteroaryl optionally substituted with one or more groups selected from —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, and aryl, wherein the aryl is optionally substituted with one or more groups selected from —(C 1 -C 4 )alkyl and a halogen atom; and X wherein: R 2 is selected from the group consisting of —O(C 1 -C 4 )haloalkyl, a halogen atom, —O(C 3 -C 7 )cycloalkyl, and —(C 1 -C 4 )haloalkyl; and R 3 is H or is selected from the group consisting of a halogen atom, cyano, —O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, heterocycloalkyl-(C 1 -C 4 )alkylene-, —(C 1 -C 4 )alkylene-heterocycloalkyl-NR 4 R 5 , and heteroaryl optionally substituted with one or more —(C 1 -C 4 )alkyl, and wherein the heterocycloalkyl is optionally substituted with one or more —(C 1 -C 4 )alkyl; n is 0, 1 or 2; R 4 is H or —(C 1 -C 4 )alkyl; and R 5 is H or —(C 1 -C 4 )alkyl.
  2. 2 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by formula (Ia):
  3. 3 . The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein the compound is represented by formula (Iaa):
  4. 4 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrimidin-5-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)-5-fluorophenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-cyanopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-chloropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methoxypyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methylpyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(trifluoromethyl)phenyl)-6-((5-(trifluoromethyl) pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-fluoropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(4-methyl-3-oxopiperazin-1-yl) pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(1,1-dioxidothiomorpholino)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(2-(dimethylamino) acetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-acetamidopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(methylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-methoxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((6-acetamidopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-amino-4-methylpyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((6-(methylamino)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino) pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino) pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-(2-fluoropropan-2-yl)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino) pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-methoxypyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((4-cyclopropoxypyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino) pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino) pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((5-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; and 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.
  5. 5 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by formula (Iaa′):
  6. 6 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by formula (Iaa″)
  7. 7 . The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein the compound is represented by formula (Iab):
  8. 8 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by formula (Ib):
  9. 9 . The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein the compound is represented by formula (Iba):
  10. 10 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 , in admixture with one or more pharmaceutically acceptable carriers or excipients.
  11. 11 . The pharmaceutical composition according to claim 10 formulated for administration by inhalation.
  12. 12 . A method for treating a disease, disorder, or condition associated with dysregulation of Discoidin Domain Receptor, comprising administering the compound or pharmaceutically acceptable salt thereof according to claim 1 to subject in need of such treatment.
  13. 13 . A method for treating at least one selected from fibrosis and a disease, disorder, or condition involving fibrosis comprising administering the compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need of such treatment.
  14. 14 . A method for treating at least one selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis, comprising administering the compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need of such treatment.
  15. 15 . A method for treating idiopathic pulmonary fibrosis (IPF), comprising administering the compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need of such treatment.

Description

FIELD OF THE INVENTION The present invention relates to compounds inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms. BACKGROUND OF THE INVENTION Discoidin Domain Receptors (DDRs) are type I transmembrane receptor tyrosine kinase (RTKs). The DDR family comprises two distinct members, DDR1 and DDR2. DDRs are unique receptors among the other members of the RTK superfamily, in that DDRs are activated by collagen whereas other members of the RTK superfamily are typically activated by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1:25-34). Moreover, DDRs are unusual RTKs also because they form ligand-independent stable dimers that are non-covalently linked (see Noordeen, N. A. (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445). The DDR1 subfamily is composed of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. The five DDR1 isoforms all have in common the extracellular and transmembrane domains but differ in the cytoplasmic region (see Valiathan, R. R. (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323). DDR receptor family has been found involved in a series of fibrotic diseases, such as pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IPF). The first evidence for a protective role of DDR1 deletion in lung fibrosis was generated in 2006 by the research group of Dr. Vogel (see Avivi-Green C, Am J Respir Crit Care Med 2006; 174:420-427). The authors demonstrated that DDR1-null mice were largely protected against bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and cytokines ELISA. These results indicated that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis. DDR2 deficiency or downregulation reduces bleomycin-induced lung fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24:1734-1744). Zhao et al, demonstrated that DDR2 plays a critical role in the induction of fibrosis and angiogenesis in the lung, in particular that DDR2 synergizes with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy against lung fibrosis. In a second publication, Jia et al showed that mice lacking DDR2 are protected from bleomycin-induced lung fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018; 59:295-305. In addition, DDR2-null fibroblasts are significantly more prone to apoptosis than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for progression of fibrosis. Some compounds have been described in the literature as DDR1 or DDR2 antagonists. WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors useful as therapeutic agents for preventing and treating inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scar, atherosclerosis and cancer. Of note, antagonizing the DDR receptors may be useful for the treatment of fibrosis and disease, disorder and conditions that result from fibrosis and even more antagonizing both receptors DDR1 and DDR2 may be particularly efficacious in the treatment of the above-mentioned disease, disorder and conditions. Several efforts have been done in the past years to develop novel DDR1 and DDR2 receptor antagonists useful for the treatment of several disease and some of those compounds have shown efficacy also in humans. Despite the above cited prior art, there remains a potential for developing selective inhibitors of both receptors DDR1 and DDR2 useful for the treatment of diseases or conditions associated with a dysregulation of DDR receptors, in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), to be administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity in the lung, a good lung retention and to a low metabolic stability in order to minimize the systemic exposure and correlated safety issues. In this direction, we have surprisingly found a new series of compounds of general formula (I), as herein below reported, that solves the problem of providing inhibitors for receptors DDR1 and DDR2 for administration by inhalation, that are active as selective inhibitors of DDR1 and DDR2 receptors with respect to other human protein kinases. These compounds show high potency, good inhalatory profile, low metabol