Search

CN-121985945-A - Pharmaceutical compounds and compositions as inhibitors of c-KIT kinase

CN121985945ACN 121985945 ACN121985945 ACN 121985945ACN-121985945-A

Abstract

The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods of using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods of using such compounds to treat, ameliorate or prevent diseases or disorders involving abnormal activation of c-kit or c-kit, CSF1R and PDGFR (pdgfra, pdgfrβ) kinases.

Inventors

  • ZHANG JIAJUN
  • SCOTT MITCHELL
  • XIAO XUMING
  • XU PEILIN
  • Matthew C. Roz
  • CAO HUI
  • Ke Rixin
  • GAO XURI
  • LI WEI
  • XING XUECHAO

Assignees

  • 英安塔制药有限公司

Dates

Publication Date
20260505
Application Date
20240808
Priority Date
20230809

Claims (16)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: , Wherein: Each R 1 is independently selected from the group consisting of deuterium, halogen, -CN, optionally substituted-C 1 -C 6 alkyl, optionally substituted-C 1 -C 6 alkoxy, optionally substituted-C 3 -C 12 cycloalkyl, optionally substituted-C 5 -C 12 cycloalkenyl, optionally substituted 3-to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C (O) R 4 、-C(O)OR 4 、-C(O)NR 4 R 5 、-C(S)NR 4 R 5 , and-NR 4 R 5 ; Alternatively, two adjacent R 1 groups together with the atoms to which they are attached form a fused ring which is optionally substituted C 5 -C 8 cycloalkenyl or optionally substituted 5-to 8-membered heterocycloalkyl; m is selected from the group consisting of 0,1,2,3 and 4; Each R 4 and R 5 is independently selected from the group consisting of hydrogen, optionally substituted-C 1 -C 6 alkyl, optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, alternatively R 4 and R 5 together with the nitrogen atom to which they are attached form an optionally substituted-C 3 -C 12 heterocycle; Each R 2 is independently selected from the group consisting of deuterium, halogen, -CN, optionally substituted-C 1 -C 6 alkyl, optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted-C 1 -C 6 alkoxy, and optionally substituted-C 3 -C 8 cycloalkoxy; n is 0,1, 2, 3 or 4; L is absent 、-(CR 6 R 7 ) p -、-(CR 7 R 8 ) q O-、-(CR 7 R 8 ) q NR 4 -、-(CR 7 R 8 ) q C(O)NR 4 - or- (CR 7 R 8 ) q NR 4 C (O) -; p is selected from the group consisting of 1, 2, 3 and 4; q is selected from the group consisting of 0,1,2,3 and 4; R 6 is selected from the group consisting of hydrogen, optionally substituted-C 1 -C 6 alkyl, optionally substituted-C 1 -C 6 alkoxy, -NHC (O) OR 4 ; R 7 and R 8 are each independently selected from the group consisting of hydrogen, fluorine, and optionally substituted-C 1 -C 6 alkyl; R 3 is selected from the group consisting of optionally substituted-C 1 -C 8 alkyl, optionally substituted-C 2 -C 8 alkenyl, optionally substituted-C 3 -C 12 cycloalkyl, optionally substituted-C 5 -C 12 cycloalkenyl, optionally substituted 3-to 12-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Is optionally substituted aryl or optionally substituted heteroaryl, and When the presence of L is indicated, it is, Absent or optionally substituted heteroaryl, and when L is absent, Is optionally substituted heteroaryl, alternatively, when L is absent, And R 2 together form an optionally substituted fused 5-to 8-membered heterocyclyl or an optionally substituted fused heteroaryl, and Is optionally substituted heteroaryl, provided that Not be 。
  2. 2. The compound of formula (I), represented by formula (XIV): , Wherein, the R 1 、m、R 2 and R 3 are defined according to claim 1.
  3. 3. The compound of formula (I) is represented by formula (XXIV-1) or formula (XXIV-2): , Wherein at least one T is CR 21 R 22 and the other T is 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 alkoxy, and optionally substituted-C 3 -C 8 cycloalkyl, 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 , v is 1,2, 3, or 4;R 2 、R 3 、R 4 、R 5 , n, And As defined in claim 1.
  4. 4. The compound of formula (I) is represented by formula (XXX-1) or formula (XXX-8): , Wherein T is O 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 alkoxy and optionally substituted-C 3 -C 8 cycloalkyl, R 2 、R 3 and R 22 As defined in claim 1.
  5. 5. The compound of formula (I) is represented by formula (XXV): , Wherein U 3 is optionally substituted 3-to 12-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, R 2 、R 3 , n, And As defined in claim 1.
  6. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
  7. 7. A medicament for treating a kinase-mediated disease in a patient in need thereof, wherein the medicament 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, PDGFR α and pdgfrβ, and the disease is a mast-cell related disease, a respiratory disease, an inflammatory disorder, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), an autoimmune disorder, a metabolic disease, a fibrotic disease, a skin disease, pulmonary Arterial Hypertension (PAH) or primary pulmonary arterial hypertension (PPH).
  8. 8. The medicament of claim 7, wherein the disease is asthma, allergic rhinitis, pulmonary Arterial Hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), urticaria, skin disease, type I diabetes or type II diabetes.
  9. 9. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for treating a disease or condition mediated by a kinase in a patient, wherein the kinase is selected from c-kit, CSF1R, PDGFR a and pdgfrβ.
  10. 10. A method of treating a disease or disorder mediated by a kinase in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 5, wherein the kinase is selected from c-kit, CSF1R, PDGFR a and pdgfrβ.
  11. 11. The method of claim 10, wherein the disease is a mast cell related disease, a respiratory disease, an inflammatory disorder, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), an autoimmune disorder, a metabolic disease, a fibrotic disease, a skin disease, pulmonary Arterial Hypertension (PAH), or primary pulmonary arterial hypertension (PPH).
  12. 12. The method of claim 11, wherein the disease is asthma, allergic rhinitis, pulmonary Arterial Hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), urticaria, skin disease, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, food allergy, severe allergic syndrome, type I diabetes, or type II diabetes.
  13. 13. A method of modulating kinase activity comprising administering to a system or subject in need thereof an effective amount of a compound of any one of claims 1 to 5, wherein the kinase is c-kit, CSF1R, PDGFR a, and pdgfrβ.
  14. 14. The compound of any one of claims 1 to 5 for use in the treatment of a disease mediated by c-kit, CSF1R, PDGFR a and pdgfrβ or a combination thereof, wherein the disease is selected from mast cell related disease, respiratory disease, inflammatory disorder, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), autoimmune disorder, metabolic disease, fibrotic disease, skin disease, bone marrow disease, pulmonary Arterial Hypertension (PAH) or primary pulmonary arterial hypertension (PPH).
  15. 15. The compound of claim 14, wherein the disease is asthma, atopic dermatitis, allergic rhinitis, pulmonary Arterial Hypertension (PAH), pulmonary fibrosis, idiopathic Pulmonary Fibrosis (IPF), systemic sclerosis-related interstitial lung disease (SSc-ILD), chronic Obstructive Pulmonary Disease (COPD), osteoarthritis, liver fibrosis, myocardial fibrosis, scleroderma, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), eosinophilic gastrointestinal disease (EGID), eosinophilic esophagitis (EoE), chronic urticaria, skin disease, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, interstitial cystitis, psoriasis, suppurative sweat gland (HS), chronic prurigo, polyps, insect bites, food allergies, allergic rhinoconjunctivitis, pancreatitis, severe allergies, myelodysplastic syndrome (MDS), severe Combined Immunodeficiency Disease (SCID), van der-type granulomatosis, anemia, CGD, diabetes mellitus type I, or diabetes mellitus type II.
  16. 16. A compound according to any one of claims 1 to 5 for use in the treatment of a disease mediated by c-kit, CSF1R, PDGFR a and pdgfrβ or a combination thereof, wherein the disease is selected from melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, mast Cell Activation Syndrome (MCAS).

Description

Pharmaceutical compounds and compositions as inhibitors of c-KIT kinase RELATED APPLICATIONS Priority is claimed for U.S. provisional application No. 63/531,637 filed on 8/9 of 2023, U.S. provisional application No. 63/607,506 filed on 12/7 of 2023, and U.S. provisional application No. 63/667,539 filed on 3/7 of 2024. The entire teachings of the above application are incorporated herein by reference. Technical Field The present invention relates generally to compounds and pharmaceutical compositions useful as inhibitors of CSF1R, PDGFR and/or c-kit kinase. Background Protein Kinases (PKs) are a large group of structurally related phosphotransferases with highly conserved structure and catalytic functions. Protein kinases are enzymatic components of the signal transduction pathway that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins, and are therefore classified into the families of Protein Tyrosine Kinases (PTKs) and protein serine/threonine kinases according to their phosphorylating substrates. Protein kinases play a key role in controlling cell growth and differentiation and are responsible for controlling various cellular signal transduction processes, where protein kinases are key mediators of cellular signals that lead to growth factors and cytokine production. Over-expression or inappropriate expression of normal or mutant protein kinases plays an important role in the development of many diseases and conditions, including, for example, central nervous system disorders such as alzheimer's disease, inflammatory disorders (such as arthritis), bone diseases such as osteoporosis, metabolic disorders such as diabetes, vascular proliferative disorders such as angiogenesis, autoimmune diseases such as rheumatoid arthritis, ocular diseases, cardiovascular diseases, atherosclerosis, cancer, thrombosis, psoriasis, restenosis, schizophrenia, pain, transplant rejection, and infectious diseases such as viral or fungal infections. Mast cells are immune cells that are present in whole body tissue and release chemical mediators under certain stimuli. Inflammatory mediators are stored in granules within mast cells. Activation of mast cells results in a degranulation process that releases these chemicals into the extracellular space. Mast cell dysfunction is associated with a variety of allergic and inflammatory conditions including skin and eye diseases such as chronic urticaria, systemic sclerosis, atopic dermatitis and allergic conjunctivitis, respiratory diseases such as asthma and chronic sinusitis with nasal polyposis, and gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, eosinophilic esophagitis and food allergy. 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 a natural ligand for KIT, and activation of KIT by SCF plays an important role in migration, differentiation and proliferation of circulating mast cell progenitors, and survival of mature mast cells within a tissue. KIT is also important for mast cell activation, degranulation and downstream cytokine release. Although compounds have been reported to inhibit KIT activity, and some of them have been approved for the treatment of certain types of cancers or tumors, they have not been approved as therapies for the treatment, amelioration or prevention of autoimmune diseases or disorders involving abnormal activation of c-KIT or c-KIT, CSF1R, ne and PDGFR (pdgfra ) kinases. (cf. 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 WO 2024/124002). Disclosure of Invention In its main aspect, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 is independently selected from the group consisting of deuterium, halogen, -CN, optionally substituted-C 1-C6 alkyl, optionally substituted-C 1-C6 alkoxy, optionally substituted-C 3-C12 cycloalkyl, preferably optionally substituted C 3-C8 -cycloalkyl, -optionally substituted-C 5-C12 cycloalkenyl, preferably optionally substituted C 5-C8 -cycloalkenyl, optionally substituted 3-to 12-membered heterocycloalkyl, preferably optionally substituted 3-to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C (O) R 4、-C(O)OR4、-C(O)NR4R5、-C(S)NR4R5, and-NR 4R5; Alternatively, two adjacent R 1 groups together with the atoms to which they are attached form a fused ring which is optionally substituted C 5-C8 cycloalkenyl or optionally substituted 5-to 8-membered heterocycloalkyl; m is selected from the group consisting of 0,1,2,3 and 4; Each R 4 and R 5 is independently selected from the group consisting of hydrogen