KRAS G12C inhibitors and methods of using the same
Inventors
Shin, Youngsook • Cee, Victor J. • Tegley, Christopher M. • Lanman, Brian Alan • Wurz, Ryan Paul • Yang, Kevin C. • Ma, Vu Van • Erlanson, Daniel • Jeong, Joon Won • FUCINI, Raymond V. • IWIG, Jeffrey
Assignees
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Publication Number
US-11053226-B2
Publication Date
2021-07-06
Expiration Date
Abstract
Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.
Core Innovation
The invention relates to compounds having a structure of formula (I), including stereoisomers, atropisomers, and pharmaceutically acceptable salts of these forms. The formula (I) structure is defined by multiple substituents R1, R1A, R1B, R2, R3, R4, R4A, R4B, R5, R6, R7, R8, R9, R10, and R11, where each substituent is selected from broad lists of allowed groups, including C1-6 alkyl and alkylene, halo and cyano options, and aryl, heteroaryl, cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups.
A key part of the structure definition is that R4 and R4A can together form a 6- to 12-membered aryl or heteroaryl, a 3- to 8-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 8-membered monocyclic or bicyclic heterocycloalkyl group. These aryl, heteroaryl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C(=O) group, while spiroheterocycloalkyl and heterocycloalkyl groups may include a S(=O) or SO2 group.
Further, R9 and R10 can together form a ring selected from a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 3- to 8-membered cycloalkyl, or a 3- to 8-membered heterocycloalkyl group. When ring formation occurs, the ring is unsubstituted or substituted with 1, 2, or 3 R11 groups, and the disclosure also includes ring closure by adjacent atoms on an R9 group to form a 5- to 6-membered ring system. The compounds are provided as stereoisomers, atropisomers, and pharmaceutically acceptable salts, including salts of the stereoisomers and atropisomers.
Claims Coverage
The consolidated independent claims include one broad compound-structure claim and one therapeutic-use claim. Together they cover a formula (I) compound defined by extensive substituent and ring-forming constraints, and a method for treating cancer in subjects having KRAS, HRAS, or NRAS G12C mutations by administering a therapeutically effective amount of the compound.
Formula (I) compound with defined substituents and ring-forming options
A compound having a structure of formula (I) wherein R1, R1A and R1B are independently selected from H, C1-6 alkyl, C1-6 alkylene-OH, C1-6 alkylene-O-C1-6 alkyl, or C1-6 alkylene-NR10R11; R2 is independently H or C1-6 alkyl; R3 is independently H, C1-6 alkyl, or C1-6 alkyl-OH; R4 and R4A are independently H or C1-6 alkyl, or R4 and R4A together with the atoms to which they are attached form a 6- to 12-membered aryl or heteroaryl, a 3- to 8-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 8-membered monocyclic or bicyclic heterocycloalkyl group with heteroatom-count constraints and optional C(=O), S(=O), or SO2 features; and R4B, R5, R6, R7, R8, R9, R10 and R11 are defined by broad substituent sets, including ring-forming options for R9 and R10 and additional substitution by R11 groups.
Treating cancer with a KRAS, HRAS, or NRAS G12C mutation
A method for treating cancer in a subject by administering a therapeutically effective amount of the compound of claim 1 when the subject has a KRAS, HRAS, or NRAS G12C mutation.
The claim coverage is anchored by a broad structural definition of compounds of formula (I) with extensive substituent variability, heteroatom-count limits, and optional C(=O) and S(=O)/SO2 features in specified ring systems, together with a therapeutic method for treating cancer in subjects with KRAS, HRAS, or NRAS G12C mutations by administering the compound.
Stated Advantages
The disclosed compounds are used for inhibiting KRAS G12C in a cell.
The disclosed compounds are used for treating cancer in a subject.
Not explicitly described in patent.
Documented Applications
Methods of inhibiting KRAS G12C in a cell.
Treating cancer in a subject, with examples including lung cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, and endometrial cancer.
Combination-therapy context involving additional pharmaceutically active compounds.
A kit for treating cancer.
Treating cancer in a subject by administering a therapeutically effective amount of the compound of claim 1 when the subject has a KRAS, HRAS, or NRAS G12C mutation.
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