Search

KR-102963816-B1 - Isoxazole carboxylic acid as an LPA antagonist

KR102963816B1KR 102963816 B1KR102963816 B1KR 102963816B1KR-102963816-B1

Abstract

The present invention provides a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, and All variable groups herein are as defined herein. These compounds are selective LPA receptor inhibitors.

Inventors

  • 쳉, 피터 타이 와
  • 장, 하오
  • 칼텐바흐, 3세, 로버트 에프.
  • 리, 준
  • 워커, 스티븐 제이.
  • 시, 얀

Assignees

  • 브리스톨-마이어스 스큅 컴퍼니

Dates

Publication Date
20260511
Application Date
20200616
Priority Date
20190618

Claims (16)

  1. Compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. Here X1 , X2 , X3 , and X4 are each independently CR5 or N; provided that at least two of X1 , X2 , X3 , or X4 are N; L is independently a covalent bond or a C 1-4 alkylene; Y is independently Selected from , R 6 , -NR 3 R 6 , and -OR 7 ; R1 is independently Selected from; m is independently 0, 1, or 2 and; n is independently 0, 1, or 2 and; R2 is independently selected from H, C1-4 alkyl, (fully or partially deuterated) C1-4 deuterated alkyl, and C1-4 haloalkyl; R3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C1-6 hydroxyalkyl; the alkyl group is optionally substituted with deuterium, either itself or as part of another moiety, partially or completely; R4 is independently selected from C1-10 alkyl, (fully or partially deuterated) C1-10 deuterated alkyl, C1-10 haloalkyl, C1-10 alkenyl, -( C0-4 alkylene)-( C3-8 cycloalkyl), -(C0-4 alkylene)-phenyl, -( C0-4 alkylene)-(3 to 8-membered heterocyclyl), and -(C0-4 alkylene )-(5 to 6-membered heteroaryl); wherein each alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl is independently substituted with 0 to 3 R8s , either as itself or as part of another moiety; R5 is independently selected from H, halo, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 alkoxyalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; R6 and R7 are independently selected from C1-10 alkyl, (fully or partially deuterated) C1-10 deuterated alkyl, C1-10 haloalkyl, C1-10 alkenyl, -( C0-4 alkylene)-( C3-8 cycloalkyl), -(C0-4 alkylene) -phenyl , -( C0-4 alkylene)-(3 to 8-membered heterocyclyl), and -( C0-4 alkylene)-(5 to 6-membered heteroaryl); wherein each alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl is independently substituted with 0 to 3 R8s , either as itself or as part of another moiety; R8 is each independently selected from deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, (fully or partially deuterinated) C1-6 deuteride alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylamino, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 alkoxyalkyl, C1-6 haloalkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenoxy, -O-( C3-6 cycloalkyl), -( C0-4 alkylene)-( C3-8 cycloalkyl), -( C0-4 alkylene)-phenyl , and -(C0-4 alkylene )-(5 to 6-one heteroaryl); R9 is independently selected from C1-6 alkyl, C1-6 haloalkyl, -( C0-4 alkylene)-( C3-8 cycloalkyl), -( C0-4 alkylene)-phenyl, -( C0-4 alkylene)-(3 to 8-membered heterocyclyl), and -( C0-4 alkylene)-(5 to 6-membered heteroaryl); wherein each C1-6 alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl is independently substituted with 0 to 3 R10 , either as itself or as part of another moiety; R 10 is each independently selected from deuterium, halo, hydroxyl, amino, cyano, C 1-6 alkyl, (fully or partially deuterinated) C 1-6 deuteride alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxyalkyl, C 1-6 haloalkoxyalkyl , C 1-6 alkoxy, and C 1-6 haloalkoxy.
  2. In claim 1, the compound represented by chemical formula (II) or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. Here X 3 is independently CH or N; R1 is independently Selected from; R2 is independently a C1-4 alkyl; R3 is independently selected from H, C1-4 alkyl, and (fully or partially deuterinated) C1-4 deuterinated alkyl; R4 is independently selected from C1-6 alkyl, -( CH2 ) 0-2- ( C3-6 cycloalkyl), and -CH( CH3 )-( C3-6 cycloalkyl); R 5 is independently H or C 1-4 alkyl.
  3. In paragraph 2, X 3 is independently CH or N and; R 1 independently Selected from; R2 is CH3 and; R3 is independently CH3 or CD3 and; R 4 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and -CH(CH 3 )-(C 3-6 cycloalkyl); R 5 is H Compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.
  4. In paragraph 2, X 3 is CH and; R 1 independently And; R2 is CH3 and; R3 is CH3 and; R 4 is independently a C 1-6 alkyl or a C 3-6 cycloalkyl; R 5 is H Compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.
  5. In paragraph 2, X 3 is independently CH or N and; R 1 independently And; R2 is CH3 and; R3 is CH3 and; R 4 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and -CH(CH 3 )-(C 3-6 cycloalkyl); R 5 is H Compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.
  6. In paragraph 1, (±)-trans-5-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-3-carboxylic acid (Example 1), (±)-cis-5-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methyl-isoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-3-carboxylic acid (Example 2), (±)-trans-5-(4-(4-(((isopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-3-carboxylic acid (Example 3), (±)-cis-5-(4-(4-(((isopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-3-carboxylic acid (Example 4), (±)-trans-4-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid (Example 5), (±)-cis-4-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid (Example 6), (±)-cis-4-(4-(4-(((isopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid (Example 7), (±)-trans-4-(4-(4-(((isopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid (Example 8), (2S,4R)-4-(4-(4-(((isopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid (Example 9), (±)-(1S,3R,5S,6S)-5-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methyl-isoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-3-carboxylic acid (Example 10), (±)-(1S,3R,5R,6S)-5-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-3-carboxylic acid (Example 11), (±)-(1R,3R,5R,6R)-5-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-3-carboxylic acid (Example 12), (±)-(1S,3R,5R,6S)-5-((6-(4-(((butyl(methyl)carbamoyl)oxy)methyl)-3-methyl-isoxazole-5-yl)pyridine-3-yl)oxy)bicyclo[4.1.0]heptane-3-carboxylic acid (Example 13), (±)-2-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 14), (±)-3-(4-(4-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-3-methyl-isoxazole-5-yl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 15), 3-(4-(4-(((butyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 16), (±)-2-(4-(4-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-7-carboxylic acid (Example 17), (±)-2-(4-(4-(((butyl(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-7-carboxylic acid (Example 18), (±)-2-(4-(4-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-7-carboxylic acid (Example 19), (±)-2-(4-(4-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-3-methylisoxazole-5-yl)phenoxy)bicyclo[4.1.0]heptane-7-carboxylic acid (Example 20) A compound selected from or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.
  7. For use in the treatment of pathological fibrosis, transplant rejection, cancer, osteoporosis, psoriasis, nephropathy, or pneumonia, One or more compounds according to any one of claims 1 to 6 or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; and Pharmaceutically permissible carriers or diluents A pharmaceutical composition comprising
  8. A pharmaceutical composition according to claim 7, wherein the pathological fibrosis is lung, liver, kidney, heart, skin, eye, or pancreatic fibrosis.
  9. For use in the treatment of idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis, One or more compounds according to any one of claims 1 to 6 or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; and Pharmaceutically permissible carriers or diluents A pharmaceutical composition comprising
  10. A pharmaceutical composition according to claim 7, wherein the cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.
  11. For use in the treatment of fibrosis in mammals requiring treatment of fibrosis, One or more compounds according to any one of claims 1 to 6 or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; and Pharmaceutically permissible carriers or diluents A pharmaceutical composition comprising
  12. For use in the treatment of the above diseases in mammals requiring treatment for pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute renal injury, chronic renal disease, hepatic fibrosis, non-alcoholic steatohepatitis, cutaneous fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, organ transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuropathic pain, One or more compounds according to any one of claims 1 to 6 or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; and Pharmaceutically permissible carriers or diluents A pharmaceutical composition comprising
  13. delete
  14. delete
  15. delete
  16. delete

Description

Isoxazole carboxylic acid as an LPA antagonist Cross-reference regarding related applications This application claims the benefit of priority of U.S. provisional application No. 62/862,930 filed on June 18, 2019; the full text of which is incorporated herein by reference. Field of invention The present invention relates to a novel substituted isoxazole carboxylic acid compound, a composition containing the same, and a method of using the same for the treatment of disorders associated with, for example, one or more lysophosphatidic acid (LPA) receptors. Lysophospholipids are membrane-derived bioactive lipid mediators, the most medically important of which is lysophosphatidic acid (LPA). LPA is not a single molecule but a collection of endogenous structural variants with fatty acids of varying lengths and degrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280, 35038-35050). The structural backbone of LPA is derived from glycerol-based phospholipids, such as phosphatidylcholine (PC) or phosphatidic acid (PA). LPA is a bioactive lipid (signaling lipid) that regulates various cellular signaling pathways by binding to 7-transmembrane-coupled (GPCR) receptors of the same class (Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4 & Zhao, Y. et al., Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Of Lipids, 2013, 1831, 86-92). Currently known LPA receptors are designated as LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 , and LPA 6 (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Kihara, Y., et al, Br. J. Pharmacol., 2014, 171, 3575-3594). Although LPA has long been known as a precursor for phospholipid biosynthesis in both eukaryotic and prokaryotic cells, it has recently emerged as a signaling molecule that affects target cells by being rapidly produced and released by activated cells, particularly platelets, and acting on specific cell-surface receptors (see, e.g., Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc. Trans., 2003, 31, 1209-1212). In addition to being synthesized in the endoplasmic reticulum and processed into more complex phospholipids, LPA can be generated through the hydrolysis of existing phospholipids after cell activation; for example, the sn-2 position often loses fatty acid residues due to deacylation, leaving only the sn-1 hydroxyl group esterified to the fatty acid. Furthermore, since many tumor types upregulate autotaxin, autotaxin (lysoPLD/NPP2), the major enzyme in LPA production, may be an oncogeneic product (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). The concentrations of LPA in human plasma and serum, as well as in human bronchoalveolar lavage fluid (BALF), have been reported, including determinations performed using sensitive and specific LC/MS and LC/MS/MS procedures (Baker et al. Anal. Biochem., 2001, 292, 287-295; Onorato et al., J. Lipid Res., 2014, 55, 1784-1796). LPA influences a wide range of biological responses, including the induction of cell proliferation, stimulation of cell migration and neurite contraction, gap synaptic closure, and even slime mold chemotaxis (Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4). As LPA responsiveness is tested for an increasing number of cellular systems, the body of knowledge regarding LPA biology continues to grow. For example, in addition to currently stimulating cell growth and proliferation, LPA is known to promote cell tension and cell surface fibronectin binding, which are important events in wound repair and regeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). More recently, it has been reported that anti-apoptotic activity is also attributed to LPA, and that PPARγ is a receptor/target for LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662). Fibrosis results from an uncontrolled tissue healing process, causing excessive accumulation of the extracellular matrix (ECM) and insufficient reabsorption, which ultimately leads to terminal organ failure (Rockey, DC, et al., New Engl. J. Med., 2015, 372, 1138-1149). LPA1 receptors have been reported to be overexpressed in patients with idiopathic pulmonary fibrosis (IPF). LPA1 receptor knockout mice were protected from bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45-54). The LPA1 antagonist BMS-986020 was shown to significantly reduce the rate of decline in FVC (forced vital capacity) in a 26-week clinical trial of IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069). LPA pathway inhibitors (e.g., LPA 1 antagonists) have been shown to be chemopreventive antifibrotic agents in the treatment of hepatocellular carcinoma in rat models (Nakagawa et al., Cancer Cell, 2016, 30, 879-890). Therefore, antagonizing the LPA 1 receptor may be useful for