Methods of preparing macrocyclic indoles
Inventors
Thede, Kai • Wittrock, Sven • Mengel, Anne • McKinney, David • Lemke, Christopher • Ferrara, Steven J. • Furst, Laura • Wei, Guo • McCarren, Patrick R.
Assignees
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Publication Number
US-12338250-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The present invention relates to methods of preparing substituted indole derivatives of general formula (I): in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, and intermediate compounds useful for preparing said compounds. These compounds are useful for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
Core Innovation
The invention relates to macrocyclic compounds of Formula (I) and intermediates, with a fused pyrazole-indole framework and a macrocycle defined by R6 and R7, together with two carbon atoms of the pyrazole ring, two carbon atoms of the indole moiety, and the nitrogen atom to which R6 is attached, to form a ring of specified size. The point of attachment to the indole carbon atom bearing the A substituent is defined as *.
The scaffold connectivity and structural scope are controlled by definitions of substituents R1-R4, R5, R6-R9, R14, and R16-R23, together with linker group L and connecting element E. L is defined as -(CH2)m-E-, with E selected from a bond, oxygen atom, sulfur atom, -S(O)- group, -S(O)2- group, or -NR14- group, and m constrained within the stated ranges; optional embodiments include different structural representations for A1/A2, linkage motifs for -R6-R7-, and possible tautomer, N-oxide, and salt forms.
The method scope is further specified by contacting Formula (IIA) or Formula (IIB) with a di-functionalized alkane reagent bearing leaving groups LG1 and LG2, where LG1 and LG2 are each independently halo or sulfonate. The structural outcome is governed by the defined substituent variables on the di-functionalized alkane, including R5, q, and other listed structural variables, and by integers that constrain ring formation.
The invention further relates to macrocyclic indole derivatives of Formula (I) described as MCL-1 inhibitors with anti-apoptotic activity inhibition, thereby inducing apoptosis / programmed cell death, and includes therapeutic context for hyperproliferative diseases, including cancer. The ring-size relationships are stated as 9-membered to 16-membered, 9-membered to 13-membered, or 10-membered to 12-membered ring formations.
Claims Coverage
The consolidated content includes three independent claims that share the same core method structure: contacting a Formula (IIA) or Formula (IIB) intermediate with a di-functionalized alkane having leaving groups LG1 and LG2, each independently halo or sulfonate, to prepare a compound of Formula (I). Across the claims, the inventive coverage is anchored by macrocyclic fused pyrazole-indole ring-size constraints and by defined substituent and linker classes that govern the resulting Formula (I) structure.
Method of preparing formula (I) with fused pyrazole-indole ring formation
A method for preparing a compound of Formula (I) wherein R6 and R7, together with two carbon atoms of the pyrazole ring, two carbon atoms of the indole moiety and the nitrogen atom to which R6 is attached, form a ring of specified size, with * as the point of attachment to the indole carbon atom bearing the A substituent.
Contacting formula (IIA) or formula (IIB) with a di-functionalized alkane having halo or sulfonate leaving groups
A method comprising contacting a compound of formula (IIA) when A is A1, or formula (IIB) when A is A2, with a di-functionalized alkane wherein LG1 and LG2 are each independently halo or sulfonate.
Defined structural connectivity via L and E
L is a group -(CH2)m-E- and E is defined according to the claim scope as a bond or a specific heteroatom-containing connecting element, with m constrained to yield the claimed fused pyrazole-indole framework.
Restricted substituent scope for Formula (I)
The method further requires defined choices for variables including R5, q, m, t, and E, together with the stated structural variables on the di-functionalized alkane and the resulting Formula (I) product.
Across the independent claims, the essential coverage is for producing Formula (I) compounds via a contacting step between a defined Formula (IIA)/(IIB) scaffold and a di-functionalized alkane bearing LG1 and LG2. The claims maintain a defined fused indole-pyrazole macrocyclic framework governed by A, L, E, ring-size relationships, and related substituent definitions.
Stated Advantages
Inducing apoptosis / programmed cell death by acting as MCL-1 inhibitors with anti-apoptotic activity inhibition for hyperproliferative diseases, including cancer.
More efficient and cleaner synthesis, including less metal-catalysis.
Documented Applications
Treatment or prophylaxis of hyperproliferative disorders, including cancer, using the described MCL-1 inhibitors.
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