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-10000459-B2
Publication Date
2018-06-19
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 inflammatory bowel disease; ocular diseases such as diseases involving retinal degeneration; nerve diseases such as pruritus and pain. Non-limiting examples of those compounds include (RS)-3-Cyclopropyl-2-{4-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-benzyloxy}-propionic acid and (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid.
Core Innovation
The invention relates to compounds having the structure of Formula I, or pharmaceutically acceptable salts or prodrugs thereof. The compounds are defined by extensive structural variables including R_A, R_B, L1, L2, Ring A, Ring B, Ring C, R_C, R_D, R_E, R_F, R_G, CY, and substituent sets R_H, R_J, and R_L. Ring A is a 5-membered heteroarene attached to Ring B, and Ring B is substituted or unsubstituted arylene or heteroarylene with defined substitution limits.
R_A is selected from carboxylic acid and carboxylic acid isostere options, including —CO2H, —CO2R_B, —CN, tetrazolyl, —C(=O)NH2, —C(=O)NHR_B, —C(=O)NHSO2R_B, and —C(=O)NHCH2CH2SO3H. L1 is absent or substituted or unsubstituted C1-C6 alkylene, C3-C6 cycloalkylene, C1-C6 fluoroalkylene, or C1-C6 heteroalkylene, and L2 is absent. Ring A and Ring B are further defined by substituent patterns through R_C, R_D, and R_H, while Ring C is specified as substituted or unsubstituted cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.
The disclosure also defines R_D through multiple carbonyl-containing linkage patterns involving X and CY, where X is absent, —O—, —NH—, or —CH2—. R_E, R_F, and R_G further control substituent and cyclization options, including embodiments in which R_G, taken together with CY and the carbon atom of attachment, defines a substituted or unsubstituted carbocycle or heterocycle. The description presents a broad structural genus with multiple alternative embodiments for the Formula I scaffold.
Claims Coverage
The claim coverage is centered on a single independent claim to a Formula I compound with extensive variable substitution across the scaffold. The inventive features are centered on the Formula I structural definition, the ring/linker architecture, and the use of the compound in a lysophosphatidic-acid-dependent disease or condition.
Formula I compounds with defined R_A and carboxylic acid isostere selection
A compound having the structure of Formula I, including pharmaceutically acceptable salts or prodrugs, wherein R_A is —CO2H, —CO2R_B, —CN, tetrazolyl, —C(=O)NH2, —C(=O)NHR_B, —C(=O)NHSO2R_B, or —C(=O)NHCH2CH2SO3H or a carboxylic acid isostere, and R_B is —H or —C1-C4 alkyl.
Ring A as a 5-membered heteroarene with defined R_C and R_D
Ring A is a 5 membered heteroarene attached to Ring B, R_C is —CN, —F, —Cl, —Br, —I, —OC1-C4 alkyl, or C1-C4 fluoroalkyl, and R_D is defined by multiple carbonyl-containing patterns involving X and CY.
Ring B with limited substitution count
Ring B is substituted or unsubstituted arylene or heteroarylene, and when substituted is substituted with 1, 2, or 3 independently selected R_H.
Linkage variables L1 and L2 connecting Ring A to Ring B
L1 is absent or substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C1-C6 fluoroalkylene, or substituted or unsubstituted C1-C6 heteroalkylene, and L2 is absent.
Substituent pattern control via R_E, R_F, R_G, and CY
R_E is —H, —C1-C4 alkyl, or —C1-C4 fluoroalkyl; R_F is —H or C1-C4 alkyl; R_G is independently selected from R_E, or one R_G is C1-C4 alkyl and taken together with CY and the carbon atom to define a substituted or unsubstituted carbocycle or heterocycle; CY is substituted or unsubstituted C1-C6 alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl, optionally substituted by 1, 2, or 3 independently selected R_H.
Ring C substituent definition using enumerated R_H set
Ring C is substituted or unsubstituted C3-C10 cycloalkylene, C2-C10 heterocycloalkylene, arylene, or heteroarylene, with 1, 2, or 3 independently selected R_H when substituted.
Medicament for treating a lysophosphatidic-acid-dependent disease or condition
A medicament for treating a subject with a lysophosphatidic-acid-dependent disease or condition, wherein the medicament includes the compound of claim 1.
The claim coverage is concentrated in the Formula I scaffold, with the main inventive features being the defined R_A carboxylic acid or isostere options, the Ring A/Ring B framework, linker choices through L1 and L2, the R_D and CY linkage architecture, the permitted substitution patterns for R_E, R_F, R_G, R_H, and Ring C, and medicament use for a lysophosphatidic-acid-dependent disease or condition.
Stated Advantages
Prevention and/or treatment of lysophosphatidic acid (LPA)-mediated conditions, including LPA1R and/or LPA1R-dependent conditions.
Prevention and/or treatment of fibrosis, including heart, kidney, liver, and lung fibrosis and scleroderma.
Prevention and/or treatment of inflammation, including diabetic nephropathy and inflammatory bowel disease (IBD).
Prevention and/or treatment of ocular retinal degeneration.
Prevention and/or treatment of nerve pain and pruritus.
In vitro receptor binding and Ca2+ flux functional assay readouts are reported for representative Formula I compounds.
Potency is reported using IC50 values, including Hill coefficient (nH) and Ki calculation using the Cheng-Prusoff equation.
Documented Applications
Treating a subject with a lysophosphatidic-acid-dependent disease or condition.
Treating fibrosis, including liver, kidney, lung, heart, and eye fibrosis.
Treating chronic pain.
Treating pruritus.
Treating proliferative disease/cancer and metastasis.
Treating inflammatory diseases, including psoriasis, pneumonia, and nephropathy.
Treating gastrointestinal disease, including inflammatory bowel disease.
Treating ocular diseases, including AMD, diabetic retinopathy, PVR, glaucoma scarring, and uveitis.
Treating liver diseases, including hepatitis, cirrhosis, and NASH.
Treating renal diseases, including CKD, ESRD, and diabetic nephropathy.
Treating skin diseases, including scleroderma and atopic dermatitis.
Combination/co-administration treatment with currently used agents, including autotaxin/LPA-pathway agents and other therapeutic classes.
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