Heterocyclic compounds useful in the treatment of disease
Inventors
Beaton, Graham • Tucci, Fabio C. • RAVULA, SATHEESH B. • Shah, Chandravadan R. • LUU, Hiep
Assignees
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Publication Number
US-10526298-B2
Publication Date
2020-01-07
Expiration Date
Abstract
Heterocyclic compounds are described that are lysophosphatidic acid receptor ligands that are useful in the treatment of lysophosphatidic acid receptor-dependent diseases and conditions, including but not limited to diseases involving fibrosis, such as fibrosis of the heart, kidney, liver and lung, and scleroderma; inflammatory diseases such as diabetic nephropathy and nonalcoholic steatohepatitis (NASH); ocular diseases such as diseases involving retinal degeneration; nerve diseases such as pruritus and pain.
Core Innovation
The invention is directed to compounds having the structure of Formula X, or pharmaceutically acceptable salts or prodrugs thereof. The structure is defined by variable groups including R_A, R_B, R_C, R_D, R_E, R_F, R_G, L1, and related ring and phenyl moieties, with R_A including carboxylic acid, carboxylic acid derivatives, and carboxylic acid isostere groups.
A key structural component is R_D, which is defined as N(R_F)C(=O)XCH(R_G)CY, wherein X is O and CY is phenyl substituted with one R_H. The allowed substituent combinations are constrained by the definitions of R_E, R_F, R_G, R_H, and R_L, and by optional formation of a substituted or unsubstituted carbocycle or heterocycle taken together with the phenyl moiety of the R_D substituent and the carbon atom to which R_G and the phenyl moiety are attached.
The disclosure also specifies defined Ring A structures, linker patterns for L1, and permitted alternatives for R_L, including cases where R_L groups together with the N atom define a substituted or unsubstituted heterocycle. The document includes preferred structural embodiments using Formula XI and Formula XII, and relates to heterocyclic lysophosphatidic acid receptor ligands intended for treatment of lysophosphatidic acid receptor-dependent diseases and lysophosphatidic acid-dependent diseases.
Claims Coverage
The provided content supports one independent compound claim centered on Formula X and related claim coverage for pharmaceutical composition and treatment use. The claim set defines multiple inventive features through selectable substituent groups, ring construction rules, linker options, and the option for pharmaceutically acceptable salts or prodrugs.
Formula X compound with carboxylic acid or isostere at RA
A compound having the structure of Formula X, or a pharmaceutically acceptable salt or prodrug thereof, wherein R_A is selected from carboxylic acid, carboxylic acid derivative, or carboxylic acid isostere groups.
Ring A and substituent selection
Ring A is defined by one of the listed structures, with allowed substituent options including R_C groups such as cyano, halogen, alkoxy, cycloalkyl, and fluoroalkyl, and with A1 defined as N or C.
Defined linker L1 and R_B options
R_B is optionally substituted C1-C4 alkyl or a structure associated with L1, and L1 is selected from the defined linker patterns including heteroatom-containing options.
R_D motif with phenyl-substituted CY and carbocycle or heterocycle formation
R_D is N(R_F)C(=O)XCH(R_G)CY, wherein X is O and CY is phenyl substituted with one R_H, and one R_G together with the phenyl moiety and the attachment carbon atom define a substituted or unsubstituted carbocycle or heterocycle.
Conditional R_H and R_L constraints
R_H is independently selected from a defined set including halogen, cyano, nitro, hydroxyl, alkoxy, thioalkyl, sulfonyl, sulfonamido, carbonyl-containing groups, and alkyl/fluoroalkyl/alkoxy/heteroalkyl options, and R_L includes options that can define a substituted or unsubstituted heterocycle with the N atom.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the Formula X compound and a pharmaceutically acceptable excipient.
Method of treating lysophosphatidic acid-dependent disease
A method of treating a lysophosphatidic acid-dependent disease or condition by administering a therapeutically effective amount of the compound to a subject in need.
The claim coverage centers on a Formula X compound with defined R_A, Ring A, R_B, linker L1, and R_D/CY/R_H/R_G constraints, including optional carbocycle or heterocycle formation. The scope further includes pharmaceutical compositions and methods of treating lysophosphatidic acid-dependent disease or condition.
Stated Advantages
Provides selective LPA1R compounds with stated LPA1R-binding/selectivity requirements as described in the provided content.
Documented Applications
Treatment of lysophosphatidic acid-dependent or lysophosphatidic acid-mediated disease or condition by administering a therapeutically effective amount of the compound to a subject in need.
Pharmaceutical compositions comprising the Formula X compound and a pharmaceutically acceptable excipient.
LPA1R-binding/selectivity use as described in the provided content.
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