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EP-4737443-A1 - SALT-INDUCIBLE KINASE INHIBITORY COMPOUND AND PHARMACEUTICAL COMPOSITION CONTAINING SAME

EP4737443A1EP 4737443 A1EP4737443 A1EP 4737443A1EP-4737443-A1

Abstract

An object is to provide a novel compound capable of effectively inhibiting all of SIK1, SIK2, and SIK3, and a pharmaceutical composition including the compound. A compound represented by formula (I) below or a pharmacologically acceptable salt thereof is provided: wherein the symbols are as defined in the description.

Inventors

  • NAKAJIMA, MOTOYUKI
  • SHITAMA, HIROAKI
  • ARAI, YUUKI
  • NAKATAKE, DAIKI
  • MIYAZAKI, HIROSHI
  • KODA, YUZO

Assignees

  • Tanabe Pharma Corporation

Dates

Publication Date
20260506
Application Date
20240523

Claims (20)

  1. A compound represented by formula (I) below or a pharmacologically acceptable salt thereof: wherein R 1 is a cyano group, a C 1-4 alkyl group optionally substituted with one to three halogen atoms, or a C 1-4 alkoxy group optionally substituted with one to three substituents independently selected from R 1a , wherein R 1a is a halogen atom; a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with one to three substituents independently selected from the group consisting of cyano groups, halogen atoms, and C 1-4 alkyl groups; a 4-membered monocyclic aliphatic heterocyclic group; a hydroxyl group; a C 3-4 cycloalkyl group; and a phenyl group, L is a single bond, a C 1-4 alkylene group, or a C 2-4 alkenylene group, R 2 is a 5-membered monocyclic aromatic heterocyclic group optionally substituted with R 2a , wherein R 2a is a C 1-5 alkyl group optionally substituted with one to four substituents independently selected from R 2b , or a 5-membered monocyclic aliphatic heterocyclic group, wherein R 2b is a hydroxyl group; a C 3-4 cycloalkyl group optionally substituted with a hydroxyl group; a halogen atom; a C 1-4 alkoxy group; a 4- to 6-membered monocyclic aliphatic heterocyclic group optionally substituted with one to three substituents independently selected from the group consisting of halogen atoms and oxo groups; an oxo group; an amino group optionally substituted with one or two C 1-4 alkyl groups; a phenyl group; a 5-membered monocyclic aromatic heterocyclic group; and a C 1-4 alkylsulfonyl group, R 3 is a hydrogen atom or a C 1-4 alkoxy group optionally substituted with one to three halogen atoms, R 4 is a C 1-4 alkoxy group optionally substituted with one to three halogen atoms, R 5 is a hydrogen atom, R 6 is a hydrogen atom; a C 1-4 alkyl group substituted with a halocyclopropyl group; or a cyclopropyl group substituted with one or two halogen atoms, or R 5 and R 6 , taken together with the nitrogen atom to which they are bonded, form an azetidine ring wherein the azetidine ring is substituted with one or two substituents independently selected from the group consisting of C 1-4 alkyl groups optionally substituted with one to three halogen atoms; hydroxyl groups; C 1-4 alkoxy groups optionally substituted with one or two halogen atoms; cyano groups; and amino groups, or R 4 and R 6 , taken together with the benzene ring to which R 4 is bonded, form a tetrahydroisoquinolin-1-one ring wherein the ring is substituted with one or two C 1-4 alkyl groups.
  2. The compound or the pharmacologically acceptable salt thereof according to claim 1, wherein R 1 is a cyano group, a C 1-4 alkyl group optionally substituted with one to three halogen atoms, or a C 1-4 alkoxy group optionally substituted with one to three halogen atoms, L is a single bond, R 2 is a pyrazolyl group optionally substituted with a C 1-4 alkyl group optionally substituted with a substituent R 2b' , wherein the substituent R 2b' is independently selected from the group consisting of a hydroxyl group, one to three halogen atoms, a C 1-4 alkoxy group, and a hydroxyl-substituted cyclobutyl group, R 3 is a C 1-4 alkoxy group optionally substituted with one to three halogen atoms, R 4 is a C 1-4 alkoxy group optionally substituted with one to three halogen atoms, R 5 is a hydrogen atom, R 6 is a hydrogen atom; a C 1-4 alkyl group substituted with a halocyclopropyl group; or a cyclopropyl group substituted with one or two halogen atoms, or R 4 and R 6 , taken together with the benzene ring to which R 4 is bonded, form a tetrahydroisoquinolin-1-one ring wherein the ring is substituted with one or two C 1-4 alkyl groups at the 4-position of the ring.
  3. The compound or the pharmacologically acceptable salt thereof according to claim 2, wherein R 1 is a cyano group, a C 1-2 alkyl group optionally substituted with one to three fluorine atoms, or a C 1-2 alkoxy group optionally substituted with one to three fluorine atoms, L is a single bond, R 2 is a pyrazolyl group optionally substituted with a C 1-3 alkyl group optionally substituted with a substituent R 2b" , wherein the substituent R 2b" is independently selected from the group consisting of a hydroxyl group, one to three fluorine atoms, a methoxy group, and a hydroxyl-substituted cyclobutyl group, R 3 is a methoxy group optionally substituted with one to three fluorine atoms, R 4 is a methoxy group optionally substituted with one to three fluorine atoms, R 5 is a hydrogen atom, R 6 is a hydrogen atom; a fluorocyclopropyl-substituted methyl group; or a cyclopropyl group substituted with one or two fluorine atoms, or R 4 and R 6 , taken together with the benzene ring to which R 4 is bonded, form a tetrahydroisoquinolin-1-one ring wherein the ring is substituted with one or two methyl groups at the 4-position of the ring.
  4. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is a cyano group, -CHF 2 , -OCHF 2 , or -OC 2 H 5 .
  5. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 -L- is: or R 2a wherein R 2a is -CH 3 , -CHF 2 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 CH 3 , - CH 2 CH 2 OCH 3 , -CH 2 CH(CH 3 )OH, or a 3-hydroxycyclobutylmethyl group.
  6. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3 is -OCH 3 or -OCHF 2 .
  7. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein R 4 is -OCH 3 or -OCHF 2 , R 5 is a hydrogen atom, R 6 is a hydrogen atom, or R 4 and R 6 , taken together with the benzene ring to which R 4 is bonded, form a tetrahydroisoquinolin-1-one ring wherein the ring is substituted with one -CH 3 at the 4-position of the ring.
  8. The compound or the pharmacologically acceptable salt thereof according to claim 3, wherein R 1 is a cyano group, -CHF 2 , -OCHF 2 , or -OC 2 H 5 , R 2 -L- is: R 2a or wherein R 2a is -CH 3 , -CHF 2 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 CH 3 , - CH 2 CH 2 OCH 3 , -CH 2 CH(CH 3 )OH, or a 3-hydroxycyclobutylmethyl group, R 3 is -OCH 3 or -OCHF 2 , R 4 is -OCH 3 or -OCHF 2 , R 5 is a hydrogen atom, R 6 is a hydrogen atom, or R 4 and R 6 , taken together with the benzene ring to which R 4 is bonded, form a tetrahydroisoquinolin-1-one ring wherein the ring is substituted with one -CH 3 at the 4-position of the ring.
  9. A compound selected from the group consisting of compounds illustrated below, or a pharmacologically acceptable salt thereof: or an enantiomer thereof, and a mixture of stereoisomers thereof, or an enantiomer thereof, or an enantiomer thereof, or an enantiomer thereof, or an enantiomer thereof,
  10. A pharmaceutical composition comprising the compound or the pharmacologically acceptable salt thereof described in any one of claims 1 to 9 as an active ingredient.
  11. The pharmaceutical composition according to claim 10, for use in the prevention or treatment of a disease and/or an accompanying symptom that can be improved by inhibiting salt-inducible kinases (SIK) or in the improvement of a prognosis of such a disease and/or an accompanying symptom.
  12. The pharmaceutical composition according to claim 10, which is a preventive or therapeutic agent for a disease selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejections, diseases involving cartilage turnover disorders, congenital cartilage malformations, diseases involving bone turnover disorders, diseases associated with hypersecretion of TNF-α, interferon, IL-6, IL-12, and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, skin diseases, and abnormal angiogenesis-related diseases.
  13. The pharmaceutical composition according to claim 10, which is a preventive or therapeutic agent for a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, chronic inflammatory demyelinating polyneuropathy, ulcerative colitis, Crohn's disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, type 1 diabetes mellitus, type 2 diabetes mellitus, pancreatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, central nervous system lupus, lupus nephritis, antiphospholipid antibody syndrome, chronic kidney disease, acute kidney disease, sarcoidosis, systemic scleroderma, localized scleroderma, Sjogren's syndrome, ANCA-associated vasculitis, immune complex small vessel vasculitis, polyarteritis nodosa, Kawasaki disease, Takayasu arteritis, giant cell arthritis, idiopathic inflammatory muscle disease (polymyositis, dermatomyositis, inclusion body myositis), IgG4-related diseases, juvenile Still's disease, pelvic inflammatory disease, psoriasis, pustular psoriasis, atopic dermatitis, asthma, allergic rhinitis, relapsing polychondritis, mixed connective tissue disease, graft-versus-host disease, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease, myelofibrosis, multiple sclerosis, cerebral infarction, ischemic stroke, Alzheimer's disease, Parkinson's disease, depression, developmental epilepsy, Meniere's disease, narcolepsy, macrophage activation syndrome, sepsis, pulmonary hypertension, hyperlipidemia, Behcet's disease, uveitis, osteoporosis, bone fracture, osteosarcoma, cardiac insufficiency, hypertrophic myocardiopathy, atherosclerosis, female gestosis, ovarian cancer, breast cancer, prostate cancer, malignant lymphoma, leukemia, multiple myeloma, lung cancer, granuloma annulare, esophageal cancer, colorectal cancer, pancreatic cancer, gastric cancer, hepatocellular cancer, melanoma, and secondary hemophagocytic lymphohistiocytosis.
  14. The pharmaceutical composition according to claim 10, which is a preventive or therapeutic agent for a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, ulcerative colitis, primary biliary cholangitis, primary sclerosing cholangitis, pancreatitis, systemic lupus erythematosus, lupus nephritis, systemic scleroderma, Sjogren's syndrome, psoriasis, pustular psoriasis, Behcet's disease, ovarian cancer, and acute myeloid leukemia.
  15. The pharmaceutical composition according to claim 10, which is a preventive or therapeutic agent for a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, ulcerative colitis, pancreatitis, systemic lupus erythematosus, lupus nephritis, systemic scleroderma, Sjogren's syndrome, pustular psoriasis, and Behcet's disease.
  16. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, for use in the prevention or treatment of a disease and/or an accompanying symptom that can be improved by inhibiting salt-inducible kinases (SIK) or in the improvement of a prognosis of such a disease and/or an accompanying symptom.
  17. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, for use in the prevention or treatment of a disease selected from inflammatory diseases, auto inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejections, diseases involving cartilage turnover disorders, congenital cartilage malformations, diseases involving bone turnover disorders, diseases associated with hypersecretion of TNF-α, interferon, IL-6, IL-12, and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, skin diseases, and abnormal angiogenesis-related diseases.
  18. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, for use in the prevention or treatment of a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, chronic inflammatory demyelinating polyneuropathy, ulcerative colitis, Crohn's disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, type 1 diabetes mellitus, type 2 diabetes mellitus, pancreatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, central nervous system lupus, lupus nephritis, antiphospholipid antibody syndrome, chronic kidney disease, acute kidney disease, sarcoidosis, systemic scleroderma, localized scleroderma, Sjogren's syndrome, ANCA-associated vasculitis, immune complex small vessel vasculitis, polyarteritis nodosa, Kawasaki disease, Takayasu arteritis, giant cell arthritis, idiopathic inflammatory muscle disease (polymyositis, dermatomyositis, inclusion body myositis), IgG4-related diseases, juvenile Still's disease, pelvic inflammatory disease, psoriasis, pustular psoriasis, atopic dermatitis, asthma, allergic rhinitis, relapsing polychondritis, mixed connective tissue disease, graft-versus-host disease, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease, myelofibrosis, multiple sclerosis, cerebral infarction, ischemic stroke, Alzheimer's disease, Parkinson's disease, depression, developmental epilepsy, Meniere's disease, narcolepsy, macrophage activation syndrome, sepsis, pulmonary hypertension, hyperlipidemia, Behcet's disease, uveitis, osteoporosis, bone fracture, osteosarcoma, cardiac insufficiency, hypertrophic myocardiopathy, atherosclerosis, female gestosis, ovarian cancer, breast cancer, prostate cancer, malignant lymphoma, leukemia, multiple myeloma, lung cancer, granuloma annulare, esophageal cancer, colorectal cancer, pancreatic cancer, gastric cancer, hepatocellular cancer, melanoma, and secondary hemophagocytic lymphohistiocytosis.
  19. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, for use in the prevention or treatment of a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, ulcerative colitis, primary biliary cholangitis, primary sclerosing cholangitis, pancreatitis, systemic lupus erythematosus, lupus nephritis, systemic scleroderma, Sjogren's syndrome, psoriasis, pustular psoriasis, Behcet's disease, ovarian cancer, and acute myeloid leukemia.
  20. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, for use in the prevention or treatment of a disease selected from rheumatoid arthritis, arthritis deformans, psoriatic arthritis, ulcerative colitis, pancreatitis, systemic lupus erythematosus, lupus nephritis, systemic scleroderma, Sjogren's syndrome, pustular psoriasis, and Behcet's disease.

Description

Technical Field The present invention relates to a salt-inducible kinase inhibitor compound and a pharmaceutical composition including the compound. Background Art Salt-inducible kinases (SIK) belong to the AMP-activated protein kinase (AMPK) family and have functions mainly involved in regulating energy response-related physiological processes, such as gluconeogenesis and lipid metabolism. The SIK family consists of three isoforms, SIK1, SIK2, and SIK3. All these isoforms are known to act as metabolic transmitters. Salt-inducible kinases undergo autophosphorylation and play an important role in regulating the adrenocortical functions upon high salt intake or under stimulus of adrenocorticotropic hormones (ACTH). All the three SIK family members, namely, SIK1, SIK2, and SIK3, are expressed widely. The expression of SIK1 mRNA is regulated by a plurality of stimuli, such as high salt intake, ACTH signals, glucagon signals, excitable cell depolarization, and circadian rhythms. On the other hand, the expression of SIK2 and SIK3 is constitutive in tissues in which these kinases are expressed. In humans, SIK2 and SIK3 are expressed ubiquitously. The expression level is highest in adipose tissues for SIK2 and at brains for SIK3. Furthermore, these SIK family members show abnormal regulations in various types of cancers, such as ovarian cancer, breast cancer, prostate cancer, and lung cancer. This fact suggests that SIK play important roles in the occurrence and progress of cancers. SIK regulate a new molecular switch that regulates the polarity of macrophages. Pharmacological inhibition of SIK induces a macrophage phenotype characterized by high-level secretion of anti-inflammatory cytokines, such as interleukin (IL)-10, and extremely low secretion of inflammatory cytokines, such as tumor necrosis factor α. However, it has been unknown which one of the three isoforms, SIK1, SIK2, and SIK3, is the appropriate target. Non Patent Literature 1 addresses this problem and discloses a study using mouse macrophages. As compared to SIK2-inactivated macrophages, SIK1- and SIK2-inactivated macrophages that had been stimulated by lipopolysaccharide (LPS) suppressed the production of inflammatory cytokines (TNF-α, IL-12p40) and promoted the anti-inflammatory cytokine (IL-10) production. This has shown that the inhibition of both SIK1 and SIK2 is medicinally more important than the inhibition of SIK2 alone. Furthermore, an SIK1/2/3 inhibitor (HG-9-91-01, a compound having the following structure: was added to SIK1- and SIK2-inactivated macrophages. As compared to SIK1- and SIK2-inactivated macrophages, the macrophages in which SIK1, SIK2, and SIK3 had been all inactivated suppressed the production of TNF-α and IL-12p40 and promoted the anti-inflammatory cytokine (IL-10) production. This has shown that the inhibition of all SIK1, SIK2, and SIK3 is most important to benefit from the medicinal effects of macrophages. Patent Literatures 1 to 5 disclose compounds that exhibit certain levels of SIK inhibitory effects. Citation List Patent Literature Patent Literature 1: WO 2019/105886Patent Literature 2: WO 2019/238424Patent Literature 3: WO 2020/239658Patent Literature 4: WO 2020/239660Patent Literature 5: CN 115448881 A Non Patent Literature Non Patent Literature 1: Darling NJ, Toth R, Arthur JS, and Clark K., Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages., Biochem J. 2017; 474(4): 521-537 Summary of Invention It has been suggested that the inhibition of all of SIK1, SIK2, and SIK3 is important for pharmaceutical usefulness of an SIK inhibitor compound. The development of such a compound capable of effectively inhibiting all of SIK1, SIK2, and SIK3 is desired. It is therefore an object of the present invention to provide a novel compound capable of effectively inhibiting all of SIK1, SIK2, and SIK3, and a pharmaceutical composition including the compound. Studies of the present invention have found that the object is achieved by the following specific configurations. An aspect of the present invention resides in a compound represented by formula (I) below or a pharmacologically acceptable salt thereof: wherein R1 is a cyano group, a C1-4 alkyl group optionally substituted with one to three halogen atoms, or a C1-4 alkoxy group optionally substituted with one to three substituents independently selected from R1a,wherein R1a is a halogen atom; a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with one to three substituents independently selected from the group consisting of cyano groups, halogen atoms, and C1-4 alkyl groups; a 4-membered monocyclic aliphatic heterocyclic group; a hydroxyl group; a C3-4 cycloalkyl group; and a phenyl group,L is a single bond, a C1-4 alkylene group, or a C2-4 alkenylene group,R2 is a 5-membered monocyclic aromatic heterocyclic group optionally substituted with R2a,wherein R2a is a C1-5 alkyl group optionally s