KR-20260068071-A - Pharmaceutical compounds and compositions as c-kit kinase inhibitors

Abstract

The present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof, and The above compounds are useful as protein kinase inhibitors and also provide a method for treating, improving, or preventing diseases associated with abnormal or unregulated kinase activity using said compounds. In some embodiments, the present invention provides a method for treating, improving, or preventing diseases or disorders associated with abnormal activation of c-kit or c-kit, CSF1R, and PDGFR (PDGFRα, PDGFRβ) kinases using said compounds.

Inventors

• 장, 지아준
• 미첼, 스코트
• 시우, 육, 밍
• 슈, 페이린
• 로즈, 매슈 씨.
• 카오, 후이
• 오, 얏 선
• 가오, 슈리
• 리, 웨이
• 싱, 슈에차오

Assignees

• 이난타 파마슈티칼스, 인코포레이티드

Dates

Publication Date

20260513

Application Date

20240808

Priority Date

20230809

Claims (16)

1. Compound of the following chemical formula (I) or its pharmaceutically acceptable salt: Here, each R1 is independently selected from the group consisting of deuterium, halogen, -CN, optionally substituted -C1 - C6 alkyl, optionally substituted -C1 - C6 alkoxy, optionally substituted -C3 - C12 cycloalkyl, optionally substituted -C5- C12 cycloalkenyl, optionally substituted 3 to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C(O) R4 , -C(O) OR4 , -C( O ) NR4R5 , -C( S ) NR4R5 , and -NR4R5 ; Or, two adjacent R1 groups bond together with the atoms they are bonded to form an optionally substituted C5 - C8 cycloalkenyl or an optionally substituted 5 to 8-membered heterocycloalkyl ring; The above m is selected from a group consisting of 0, 1, 2, 3, and 4; Each R4 and R5 is independently selected from the group consisting of hydrogen, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or, R4 and R5 are bonded together with the nitrogen atoms to which they are bonded to form an optionally substituted C3 - C12 heterocyclic ring; Each R2 is independently selected from the group consisting of deuterium, halogen, -CN, optionally substituted -C1 - C6 alkyl, optionally substituted -C3 - C8 cycloalkyl, optionally substituted -C1 - C6 alkoxy, and optionally substituted -C3 - C8 cycloalkoxy; The above n is 0, 1, 2, 3, or 4; The above L is absent, or -(CR 6 R 7 )p-, -(CR 7 R 8 )qO-, -(CR 7 R 8 )qNR 4 -, -(CR 7 R 8 )qC(O)NR 4 -, or -(CR 7 R 8 )qNR 4 C(O)-; The above p is selected from a group consisting of 1, 2, 3, or 4; The above q is selected from the group consisting of 0, 1, 2, 3, and 4; The above R6 is selected from the group consisting of hydrogen, optionally substituted -C1 - C6 alkyl, optionally substituted -C1 - C6 alkoxy, and -NHC(O) OR4 ; The above R7 and R8 are each independently selected from the group consisting of hydrogen, fluorine, and optionally substituted -C1 - C6 alkyls; The above R3 is selected from the group consisting of optionally substituted -C1 - C8 alkyl, optionally substituted -C2 - C8 alkenyl, optionally substituted -C3 - C12 cycloalkyl, optionally substituted -C5 - C12 cycloalkenyl, optionally substituted 3 to 12 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The above A is an optionally substituted aryl or an optionally substituted heteroaryl; The above B is a heteroaryl that is absent or optionally substituted when L is present, and an optionally substituted heteroaryl when L is absent; Or, in the case where the above L is absent and R2 is taken together to form an optionally substituted fused 5- to 8-membered heterocyclic compound or an optionally substituted fused heteroaryl compound; and The above C is an optionally substituted heteroaryl compound; provided that C is It is not.
2. The compound of the above chemical formula (I) is represented by the following chemical formula (XIV): Here, C, R1 , m, R2 , and R3 are as defined in claim 1.
3. The compound of the above chemical formula (I) is represented by the following chemical formula (XXIV-1) or (XXIV-2): Herein, at least one T is CR 21 R 22 , and the remaining T are each independently O, NR 23 , -SO 2- , or CR 21 R 22 ; R 21 and R 22 are each independently selected from the group consisting of hydrogen, OH, optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 1 -C 6 alkoxyl, and optionally substituted -C 3 -C 8 cycloalkyl; said R 23 is hydrogen, optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 3 -C 8 cycloalkyl, -C(O)R 4 , -C(O)OR 4 , or -C(O)NR 4 R 5 ; The above v is 1, 2, 3 or 4, and the above R 2 , R 3 , R 4 , R 5 , n, A and B are as defined in claim 1.
4. The compound of the above chemical formula (I) is represented by the following chemical formula (XXX-1) or (XXX-8): Herein, T is O or CR 21 R 22 , and R 21 and R 22 are each independently selected from the group consisting of hydrogen, OH, optionally substituted -C 1 -C 6 alkyl groups, optionally substituted -C 1 -C 6 alkoxy groups, or optionally substituted -C 3 -C 8 cycloalkyl groups; and R 2 , R 3 and B are as defined in claim 1.
5. The compound of the above chemical formula (I) is represented by the following chemical formula (XXV): Here, U3 is an optionally substituted 3 to 12-membered heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and R2 , R3 , n, A, and B are as defined in claim 1.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
7. A pharmaceutical product for treating a kinase-mediated disease, wherein the pharmaceutical product comprises a therapeutically effective amount of a compound according to any one of claims 1 to 5, wherein the kinase is selected from c-kit, CSF1R, PDGFRα, and PDGFRβ, and the disease is a mast cell-associated disease, a respiratory disease, an inflammatory disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), an autoimmune disease, a metabolic disease, a fibrotic disease, a skin disease, pulmonary arterial hypertension (PAH), or primary pulmonary hypertension (PPH).
8. In Paragraph 7, The above diseases are asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin disease, type 1 diabetes or type 2 diabetes, and the medicine.
9. A pharmaceutical product characterized by manufacturing a drug that treats a patient's kinase-mediated disease or disorder using a compound of any one of claims 1 to 5, wherein the kinase is selected from c-kit, CSF1R, PDGFRα, and PDGFRβ.
10. A method for treating a patient with a kinase-mediated disease or disorder, comprising administering an effective amount of a compound according to any one of claims 1 to 5 to the patient, wherein the kinase is selected from c-kit, CSF1R, PDGFRα, and PDGFRβ.
11. In Paragraph 10, The above disease is a mast cell-related disease, respiratory disease, inflammatory disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune disease, metabolic disease, fibrotic disease, skin disease, pulmonary arterial hypertension (PAH), or primary pulmonary hypertension (PPH).
12. In Paragraph 11, The above disease is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin disease, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, food allergy, anaphylaxis syndrome, type 1 diabetes or type 2 diabetes, method.
13. A method for controlling kinase activity comprising administering an effective amount of a compound according to any one of claims 1 to 5 to a system or target, wherein the kinase is c-kit, CSF1R, PDGFRα, and PDGFRβ.
14. A compound according to any one of claims 1 to 5 for use in the treatment of a disease mediated by c-kit, CSF1R, PDGFRα and PDGFRβ or a combination thereof, wherein the disease is a mast cell-associated disease, respiratory disease, inflammatory disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune disease, metabolic disease, fibrotic disease, skin disease, bone marrow disease, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH).
15. In Paragraph 14, A compound characterized in that the above disease is asthma, atopic dermatitis, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), chronic obstructive pulmonary disease (COPD), osteoarthritis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), eosinophilic gastrointestinal disorders (EGIDs), eosinophilic esophagitis (EoE), chronic urticaria, skin disease, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, interstitial cystitis, psoriasis, hidradenitis suppurativa (HS). Chronic pruritus, nasal polyps, insect bites, food allergies, allergic rhinoconjunctivitis, pancreatitis, anaphylaxis, myelodysplastic syndrome (MDS), severe combined immunodeficiency (SCID), Fanconi anemia, chronic granulomatous disease (CGD), sickle cell disease, type 1 diabetes or type 2 diabetes.
16. A compound according to any one of claims 1 to 5 used for the treatment of a disease mediated by c-kit, CSF1R, PDGFRα and PDGFRβ or a combination thereof, wherein the disease is selected from melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, and mast cell activation syndrome (MCAS).

Description

Pharmaceutical compounds and compositions as c-kit kinase inhibitors Related applications This application enjoys priority to U.S. Preliminary Application No. 63/531,637, filed August 9, 2023; U.S. Preliminary Application No. 63/607,506, filed December 7, 2023; and U.S. Preliminary Application No. 63/667,539, filed July 3, 2024. All contents of the above applications are incorporated herein by reference. Technology field The present invention relates to compounds and pharmaceutical compositions that are generally useful as CSF1R, PDGFR, and/or c-kit kinase inhibitors. Protein kinases (PKs) are a large group of phosphotransferases that are structurally similar and have very well-conserved catalytic functions. As enzymatic components of signaling pathways, protein kinases catalyze the transfer of the terminal phosphate group of ATP to the hydroxyl group of a tyrosine, serine, and/or threonine residue in a protein. Therefore, protein kinases are classified into protein tyrosine kinases (PTKs) and protein serine/threonine kinases depending on the substrate they phosphorylate. Protein kinases play a crucial role in regulating cell growth and differentiation and control various cell signaling processes. In particular, protein kinases are key mediators of cell signaling that induce the production of growth factors and cytokines. Overexpression or inappropriate expression of normal or mutant protein kinases plays a significant role in the development of many diseases and disorders, including central nervous system diseases such as Alzheimer's disease, inflammatory diseases such as arthritis, bone diseases such as osteoporosis, metabolic diseases such as diabetes, angioplasty diseases such as neovascularization, autoimmune diseases such as rheumatoid arthritis, ophthalmic diseases, cardiovascular diseases, atherosclerosis, cancer, thrombosis, psoriasis, restenosis, schizophrenia, pain, organ transplant rejection, and infectious diseases such as viral or fungal infections. Mast cells are immune cells present in tissues throughout the body that secrete chemical mediators in response to specific stimuli. Inflammatory mediators are stored in granules within mast cells. When mast cells are activated, a degranulation process occurs, releasing these chemical substances into the extracellular space. Mast cell dysfunction is associated with a wide range of allergic and inflammatory diseases, including skin and eye diseases such as chronic urticaria, systemic sclerosis, atopic dermatitis, and allergic conjunctivitis; respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps; and gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel disease, eosinophilic esophagitis, and food allergies. KIT (also known as CD117) is a receptor tyrosine kinase and is considered a key regulator of mast cell activity. Stem cell factor (SCF) is an intrinsic ligand of KIT, and KIT activation by SCF is crucial for the migration, differentiation, and proliferation of circulating mast cell precursors, as well as the survival of mature mast cells within tissues. KIT is also important for mast cell activation, degranulation, and downstream cytokine release. Compounds that inhibit KIT activity have been reported and some have been approved as treatments for certain types of cancer or tumors, but they have not been approved as treatments for the treatment, remission, or prevention of autoimmune diseases or disorders associated with the abnormal activation of c-kit or c-kit, CSF1R,ne, and PDGFR (PDGFRα, PDGFRβ) kinases (WO 2013/033070, WO 2013/033116, WO 2013/033167, WO 2013/033203, WO 2013/033620, WO 2022/109595, WO 2022016021, WO 2022/182982, WO 2023/205226, WO 2023/212612, WO 2024/118887, WO 2024/123966, and see WO 2024/124002). In one embodiment of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In a specific embodiment of the compound of formula (I), A is an aryl, and preferably A is a phenyl. In a specific embodiment of the compound of the above chemical formula (I), Is is. In certain embodiments, R2 is a methyl group, a difluoromethyl group, or a halogen. In certain embodiments, R2 is a methyl group or a halogen. In certain embodiments, R2 is a methyl group, a difluoromethyl group, or chlorine. In certain embodiments, R2 is methyl. In a specific embodiment of the compound of the above formula (I), A is selected from the following groups: . In a specific embodiment of the compound of the above formula (I), A is or am. In a specific embodiment of the compound of the above chemical formula (I), Is , , and It is selected from among the groups consisting of. In a specific embodiment of the compound of the above chemical formula (I), Is or is. In certain embodiments, R2 is methyl or halogen. In certain embodiments, R2 is difluoromethyl. In certain embodiments, R2 is methyl, chloro, or difluoromethyl. In a specific embodiment of the compound of the