Important Compound Classes
Title
Substituted 1,6-Naphthyridine Inhibitors of CDK5
Patent Publication Number
WO 2021/067569 A1
Publication Date
April 8, 2021
Priority Application
US 62/908,952 and US 63/050,384
Priority Date
October 1, 2019 and July 10, 2020
Inventors
Malojcic, G.; Daniels, M. H.; Williams, B. D.; Yu, M.; Ledeboer, M. W.; Harmange, J. P.; Wang, J. L.
Assignee Company
Goldfinch Bio Inc., USA
Disease Area
Kidney diseases
Biological Target
CDK5
Summary
Cyclic-dependent kinases (CDKs) belong to a family of proline-directed serine/threonine kinases that play important roles in controlling cell cycle progression and transcriptional control. Cyclic-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase is unique due to its indispensable role in neuronal development and function. Due to its key physiological roles, uncontrolled activity of CDK5 has been linked to various diseases; thus, CDK5 has emerged as a potential molecular target for therapeutic drugs. In neurons, CDK5 deregulation triggers neuronal apoptosis suggesting that aberrant regulation of CDK5 activity is responsible for the progression of Alzheimer’s disease (AD) and Parkinson’s disease (PD). CDK5 has also been implicated in other neurodegenerative disorders such as Huntington’s disease, amyotrophic lateral sclerosis, and ischemic injury.
Aberrant CDK5 activity is linked to cancer development, progression and metastasis such as prostate and thyroid carcinoma. Aberrant CDK5 activity has also linked to the pathogenesis of diabetes mellitus (type-2 diabetes). Recent studies suggest that CDK5 inhibitors may be of benefit in the management of acute pain. New therapeutic approaches aimed at the restoration of cellular differentiation are likely to yield effective treatments for cystic kidney diseases.
The present application describes a series of novel substituted 1,6-naphthyridines as CDK5 inhibitors for the treatment of kidney diseases such as kidney failure, kidney stones, cystic kidney disease, renal fibrosis, diabetic nephropathy, parenchymal renal disease, and chronic kidney disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
ring A = a monocyclic or bicyclic cycloalkyl or a monocyclic or bicyclic saturated heterocyclyl;
ring B = a monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic saturated heterocyclyl;
R1 = −N(R5)–, −C(O)–, −S–, −S(O)–, −S(O)2–, −[C(R4)2]1–2–, −[C(R4)2]0–1–CH= , −N(R5)–S(O)2–, −S(O)2–N(R5), C(R4)2–N(R5)–, −N(R5)–C(R4)2–, −C(R4)2–S(O)2–, −C(=N–OH)–, −C(=N–O–C1–C4 alkyl)–, or −S(O)2–C(R4)2–;
R2 = halo, −OH, −C1–C6 alkyl, −C1–C6 haloalkyl, −C1–C6 hydroxyalkyl, −(−C0–C4 alkylene)–C(O)–OH, −(−C0–C4 alkylene)–C(O)–O–C1–C4 alkyl, −(−C0–C4 alkylene)–O–C1–C4 alkyl, −(−C0–C4 alkylene)–O–C1–C4 hydroxyalkyl, −(−C0–C4 alkylene)–C(O)–N(R6)2, −(−C0–C4 alkylene)–N(R6)2, or −(−C0–C4 alkylene)-saturated heterocyclyl, wherein saturated heterocyclyl is optionally substituted with halo, −OH or CH3;
R3 = halo, −OH, −N(R6)2, −C1–C4 alkyl, −O–C1–C4 alkyl, −O–C1–C4 alkylene–C(O)–N(R6)2, −C(O)–O–C1–C4 alkyl, −C(O)–N(R6)2, −S(O)2–N(R6)2, −S(O)2–C1–C4 alkyl, C2–C4 alkynyl optionally substituted with one or more −OH, 1,2,4-triazol-1-ylmethyl, morpholinylmethyl, cyclopropyl, =O, −CH2CH2–C(O)–O–CH3, −N(R6)–S(O)2–CH3, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, wherein any alkyl portion of R3 is optionally substituted with one or more halo, −CN, −N(R6)2, or −OH;
m = 0, 1, 2, 3, 4, 5 or 6; and n = 0, 1, 2, 3, 4, 5 or 6.
Key Structures
Biological Assay
The CDK5 mobility shift assay was performed. The compounds described in this application were tested for their ability to inhibit CDK5. The CDK5 IC50 (nM) are shown in the following table.
Biological Data
The table below shows representative compounds were tested for CDK5 inhibition. The biological data obtained from testing representative examples are listed in the following table.
For CDK5 IC50: “A” means <10 nM; “B”
means 10–100 nM; “C” means >100 nM to ≤
1 μM; “D” means >1 μM.
Claims
Total claims: 28
Compound claims: 18
Pharmaceutical composition claims: 1
Method of treatment claims: 9
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The author declares no competing financial interest.