Modulators of Rho-associated protein kinase
Inventors
Jones, Clifford D. • BUNYARD, PETER • Pitt, Gary • BYRNE, LIAM • Pesnot, Thomas • Guisot, Nicolas E. S.
Assignees
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Publication Number
US-11878020-B2
Publication Date
2024-01-23
Expiration Date
Abstract
This invention relates to novel compounds and pharmaceutical compositions comprising. Compounds of the invention useful as modulators of Rho-associated protein kinase (ROCK), for example ROCK1 and/or ROCK2 inhibitors. Methods of treatment employing the compounds are also contemplated by the present invention. The compounds of the invention are useful in treating ROCK mediated diseases.
Core Innovation
The invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. The compounds include defined ring systems for B, defined linker connectivity through R1 as L-R2, and enumerated substituent selections for multiple variables, while A1, A2, and A3 are each independently selected from specified carbon and nitrogen substituent sets.
B is restricted to particular aromatic or unsaturated 5 or 6 membered carbocyclic or heterocyclic ring systems, or 9 or 10 membered carbocyclic or heterocyclic bicyclic ring systems, with aromaticity and saturation relationships specified for the bicyclic case. The linker portion is defined with L1 and L2 selected from enumerated bond, carbon, oxygen, nitrogen, carbonyl, carboxyl, and sulfonyl-related connectivity patterns.
R2 is selected from a defined group of substituent classes including hydrogen, cyano, C1-6 alkyl, C1-6 haloalkyl, ring-substituted alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, carbocyclic ring systems, and 3 to 10 membered heterocyclic ring systems with additional permitted substitution patterns. Additional constraints define R4, R5, R6, R8, R9, n, and the remaining substituent group variables RA through RO, including rules for ring formation and optional cycloalkyl or heterocycloalkyl ring closure.
Claims Coverage
The provided claim set centers on one independent claim directed to a compound of formula (I) and pharmaceutically acceptable salts thereof, with dependent claims refining the scaffold and substituent definitions. The main inventive features are the constrained formula (I) scaffold, the defined ring system B, the linker-defined R1 as L-R2, the enumerated substituent rules for A1, A2, A3 and R2, and the further variable constraints across R4, R5, R6, R8, R9, n, and the remaining substituent groups.
Constrained formula (I) compound with defined ring B and substituent sets
A compound of formula (I) and pharmaceutically acceptable salts thereof, where A1, A2 or A3 are selected from the enumerated C-H, C-F, C-Cl, C-Me, C-Et, C-i-Pr, C-cyclopropyl, C-ethenyl, C-propenyl, C-CN, C-CF3, and N options, and B is a 5 or 6 membered carbocyclic or heterocyclic ring that is aromatic or unsaturated, or a 9 or 10 membered carbocyclic or heterocyclic bicyclic ring system with specified aromaticity and saturation relationships.
R1 defined as L-R2 with specific linker choices
R1 is L-R2, where L is a bond or -L1-L2-, L1 is selected from a bond, —(CRARB)1-3—, —O(CRARB)1-3—, —(CRARB)0-3O—, and —NRC(CRARB)1-3—, and L2 is selected from a bond and multiple heteroatom-containing connectivity options including —O—, —NRD—, —C(O)NRD—, —NRDC(O)—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)2NRD—, —NRDS(O)2—, —S(O)2(NRD)—, —NRDC(O)NRE—, —OC(O)NRD—, and —C(O)NRDS(O)2—.
R2 substituent and ring-system substitution rules
R2 is selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with —ORF, C1-6 alkyl substituted with —NRFRG, C1-4 haloalkyl substituted with —ORF, C3-8 cycloalkyl substituted with OH, C1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl, C1-4 alkyl substituted with 6 membered heteroaryl, —(CRHRI)1-3ORF, —(CRHRI)1-3NRFRG, —(CRNRO)1-3C(O)ORF, —(CRNRO)1-3C(O)NRFRG, C3-10 carbocyclic ring system, and 3 to 10 membered heterocyclic ring system, with additional substitution rules for these ring systems.
Coordinated constraints for R4, R5, R6, R8, R9, and n
R4 is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, —CN, C1-4 alkyl substituted with —ORJ, C1-4 alkyl substituted with —NRJRK, and 3 to 8 membered heterocycloalkyl; R5 is selected from H, C1-4 alkyl, substituted alkyl, C3-8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5 or 6 membered heteroaryl with 1 or 2 R9 substitutions; R6 is H or methyl; R8 is H, Cl, F, CN, or Me; R9 is halo or C1-4 alkyl; and n is 0, 1, or 2.
Substituent atom combination and ring-formation rules for RA/RB, RC/RD, and RH/RI
RA and RB are each selected from H, C1-4 alkyl, and C1-4 haloalkyl, or together with the attached atom form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; RC, RD, RE, RF, and RG are each independently H, C1-4 alkyl, or C1-4 haloalkyl; RH and RI are each H except one pair on the same carbon atom may, together with that carbon atom, form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring; and RJ, RK, RL, RM, RN, and RO are each independently H or C1-4 alkyl.
Across the independent claim coverage, the inventive concept centers on a compound of formula (I) and pharmaceutically acceptable salts with tightly defined scaffold variables, a linker-defined R1 as L-R2 with enumerated L1 and L2 options, and constrained substituent choices for R2 and the remaining R variables. Dependent claims further narrow ring topology, linker connectivity, and permissible substituent combinations.
Stated Advantages
Reduced cytotoxicity.
Improved solubility.
Convenient pharmacokinetics.
A metabolite GRAS profile.
ROCK2 binding affinity is described by category +++ or ++++, with ROCK2 IC50 values less than 3 μM and optionally less than 0.3 μM.
The compounds are stated to be at least five times more potent as inhibitors against ROCK2 than against ROCK1.
Documented Applications
Treatment of ROCK-mediated diseases, including diabetes.
Treatment of inflammation and autoimmune diseases.
Treatment of central nervous system disorders, including multiple sclerosis, Huntington disease, Parkinson’s disease, and Alzheimer’s disease.
Treatment of cardiovascular disease/hypertension.
Treatment of fibrosis.
Treatment of cancer.
Therapeutic uses/modulations are described via ROCK1/ROCK2 inhibition, including medicament use and combination pharmaceutical formulations, for fibrotic diseases, auto-immune, inflammatory conditions, central nervous system disorders, and cancer.
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