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US-20260125401-A1 - BORON-CONTAINING RHO KINASE INHIBITORS

US20260125401A1US 20260125401 A1US20260125401 A1US 20260125401A1US-20260125401-A1

Abstract

The present invention provides boron-containing isoquinoline compounds as protein kinase-modulating compounds. These compounds are useful as neuroprotective and neuro-regenerative agents for the amelioration of glaucoma and other ocular neuropathies.

Inventors

  • Robert Eugene Hormann
  • Malla Padidam

Assignees

  • PERCIPIAD, INC.

Dates

Publication Date
20260507
Application Date
20251106

Claims (12)

  1. 1 . A method of treating a para-ocular rho kinase-modulated disease, disorder, injury, or condition in a subject, comprising the steps of administering to the subject a compound of Formula 1: or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein: E is selected from the group consisting of CH, C—OH, N, or NH, G is CH, or, when E is NH, G is absent; J is —(CH 2 ) n -A 6 , or A 1 , A 2 , R 2 and R 3 are each —H or C1-C6 alkyl; A 3 and A 4 are each selected from the group consisting of hydrogen, halo, C1-C6 alkyl, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkenyl, dialkylaminoalkenyl, R 5a and R 5b are selected from a side chain of any natural amino acid, C1-C6 alkyl, trifluoro-C1-C6 alkyl, —(CH 2 ) n SH, —(CH 2 ) n NH—C(═NH)NH 2 , —(CH 12 ) n CO 2 H, —(CH 2 ) n NH 2 , —(CH 2 ) n CH(NH 2 )(CO 2 H), —(CH 2 ) n SO 3 H, —(CH 2 ) n NR 6 R 7 , —(CH 2 ) n -pyridyl, —(CH 2 ) n ONO 2 ; A 6 is —(CR 6 R 4 ) n B(R 8 R 9 ), or; or A 6 together with either A 3 or A 4 form BR 8 O(CR 6 R 8 ) n O—, —BR 8 O(CR 6 R 7 ) n NR 6 —, —BR 8 O(CR 6 R 7 ) n —, —BR 8 NR 6 (CR 6 R 7 ) n O—, —BR 8 NR 6 (CR 6 R 7 ) n NR 6 —, —BR 8 NR 6 (CR 6 R 7 ) n —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n NR 6 —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—N═CH—, —BR 8 NR 6 N═CH—, —B(R 8 ) 2 N(R 6 ) 2 N═CH—, —BR 8 —O—CR 6 ═N—, —BR 8 NR 6 CR 6 ═N—, —BR 8 —O—C(═O)NR 6 —, —BR 8 NR 6 C(═O)NR 6 —, —BR 8 —O—C(NR 6 )═N—, —BR 8 NR 6 C(NR 6 )═N—, —B(R 8 ) 2 N(R 6 ) 2 CR 6 ═N—, —B(R 8 ) 2 N(R 6 ) 2 C(═O)—N—, —B(R 8 ) 2 N(R 6 ) 2 C(NR 6 )═N—, —BR 8 —O—NR 6 —, —B(OH)—O—NH—C(O)—, —B(OH)NR 6 NHC(O)—, —B(OH) 2 N(R 6 ) 2 NHC(O)—, —OBR 8 CH═CH—, —NR 6 BR 8 CH═CH—, —N(R 6 ) 2 B(R 8 ) 2 CH═CH—, —OBR 8 (CR 6 R 7 ) n O—, —OBR 8 (CR 6 R 7 ) n NR 6 —, —OBR 8 (CR 6 R 7 ) n —, —NR 6 BR 8 (CR 6 R 7 ) n CO—, —NR 6 BR 8 (CR 6 R 7 ) n NR 6 —, —NR 6 BR 8 (CR 6 R 7 ) n —, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n O—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n NR—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—CH═CH—, —BR 8 NR 6 CH═CH—, —B(R 8 ) 2 N(R 6 ) 2 CH═CH—; R 6 and R 7 are each H, C1-C6 alkyl, C-1-C6 alkenyl, C1-C6 alkynyl, trifluoro C1-C6 alkyl, acetyl, phenyl, C1-C6 alkylsulfonyl; R 8 and R 9 are each fluoro, hydroxy or alkoxy; or —B(R 8 R 9 ) forms a fluoride adduct, hydroxy acid adduct, or an amino acid adduct; n and m are each 0, 1, 2, 3, or 4.
  2. 2 . The method according to claim 1 , wherein the compound of Formula I is
  3. 3 . The method according to claim 1 , wherein the compound of Formula 1 is administered in conjunction with one or more additional therapeutic agents.
  4. 4 . The method according to claim 3 , wherein the additional therapeutic agent is selected from the group consisting of prostaglandin-like compounds, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, miotic or cholinergic agonists, sympathomimetics, Rho kinase inhibitors, and A1 adenosine receptor agonists.
  5. 5 . A method of treating a neurodegenerative ocular disease, disorder, injury, or condition in a subject, comprising the steps of administering to the subject a compound of Formula 1: or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein: E is selected from the group consisting of CH, C—OH, N, or NH, G is CH, or, when E is NH, G is absent; J is —(CH 2 ) n -A 6 , or A 1 , A 2 , R 2 and R 3 are each —H or C1-C6 alkyl; A 3 and A 4 are each selected from the group consisting of hydrogen, halo, C1-C6 alkyl, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkenyl, dialkylaminoalkenyl, R 5a and R 5b are selected from a side chain of any natural amino acid, C1-C6 alkyl, trifluoro-C1-C6 alkyl, —(CH 2 ) n SH, —(CH 2 ) n NH—C(═NH)NH 2 , —(CH 2 ) n CO 2 H, —(CH 2 ) n NH 2 , —(CH 2 ) n CH(NH 2 )(CO 2 H), —(CH 2 ) n SO 3 H, —(CH 2 ) n NR 6 R 7 , —(CH 2 ) n -pyridyl, —(CH 2 ) n ONO 2 ; A 6 is —(CR 6 R 7 ) n B(R 8 R 9 ), or A 6 together with either A 3 or A 4 form —BR 8 O(CR 6 R 7 ) n O—, —BR 8 O(CR 6 R 7 ) n NR 6 —, —BR 8 O(CR 6 R 7 ) n —, —BR 8 NR 6 (CR 6 R 7 )O—, —BR 8 NR 6 (CR 6 R 7 ) n NR 6 —, —BR 8 NR 6 (CR 6 R 7 ) n —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n O—, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n NR 6 —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—N═CH—, —BR 8 NR 6 N═CH—, —B(R 8 ) 2 N(R 6 ) 2 N═CH—, —BR 8 —O—CR 6 ═N—, —BR 8 NR 6 CR 6 ═N—, —BR 8 —O—C(═O)NR 6 —, —BR 8 NR 6 C(═O)NR 6 —, —BR 8 —O—C(NR 6 )═N—, —BR 8 NR 6 C(NR 6 )═N—, —B(R 8 ) 2 N(R 6 ) 2 CR 6 ═N—, —B(R 8 ) 2 N(R 6 ) 2 C(═O)—N—, —B(R 8 ) 2 N(R 6 ) 2 C(NR 6 )═N—, —BR 8 —O—NR 6 —, —B(OH)—O—NH—C(O)—, —B(OH)NR 6 NHC(O)—, —B(OH) 2 N(R 6 ) 2 NHC(O)—, —OBR 8 CH═CH—, —NR 6 BR 8 CH═CH—, —N(R 6 ) 2 B(R 8 ) 2 CH═CH—, —OBR 8 (CR 6 R 7 ) n O—, —OBR 8 (CR 6 R 7 ) n NR 6 —, —OBR 8 (CR 6 R 7 ) n —, —NR 6 BR 8 (CR 6 R 7 ) n O—, —NR 6 BR 8 (CR 6 R 7 ) n NR 6 —, —NR 6 BR 8 (CR 6 R 7 ) n − , —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n O—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n NR—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—CH═CH—, —BR 8 NR 6 CH═CH—, —B(R 8 ) 2 N(R 6 ) 2 CH═CH—; R 6 and R 7 are each H, C1-C6 alkyl, C-1-C6 alkenyl, C1-C6 alkynyl, trifluoro C1-C6 alkyl, acetyl, phenyl, C1-C6 alkylsulfonyl; R 8 and R 9 are each fluoro, hydroxy or alkoxy; or —B(R 8 R 9 ) forms a fluoride adduct, hydroxy acid adduct, or an amino acid adduct; n and m are each 0, 1, 2, 3, or 4.
  6. 6 . The method according to claim 5 , wherein the compound of Formula 1 is
  7. 7 . The method according to claim 5 , wherein the compound of Formula 1 is administered in conjunction with one or more additional therapeutic agents.
  8. 8 . The method according to claim 7 , wherein the additional therapeutic agent is selected from the group consisting of prostaglandin-like compounds, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, miotic or cholinergic agonists, sympathomimetics, Rho kinase inhibitors, and A1 adenosine receptor agonists.
  9. 9 . A method of treating, preventing or ameliorating a symptom associated with a disease, disorder or condition involving aberrant rho kinase activity, comprising administering to a subject in need thereof, an effective amount of a compound of Formula 1: or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein: E is selected from the group consisting of CH, C—OH, N, or NH, G is CH, or, when E is NH, G is absent; J is —(CH 2 ) n -A 6 , or A 1 , A 2 , R 2 and R 3 are each —H or C1-C6 alkyl; A 3 and A 4 are each selected from the group consisting of hydrogen, halo, C1-C6 alkyl, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkenyl, dialkylaminoalkenyl, R 5a and R 5b are selected from a side chain of any natural amino acid, C1-C6 alkyl, trifluoro-C1-C6 alkyl, —(CH 2 ) n SH, —(CH 2 ) n NH—C(═NH)NH 2 , —(CH 2 ) n CO 2 H, —(CH 2 ) n NH 2 , —(CH 2 ) n CH(NH 2 )(CO 2 H), —(CH 2 ) n SO 3 H, —(CH 2 ) n NR 6 R 7 , —(CH 2 ) n -pyridyl, —(CH 2 ) n ONO 2 ; A is —(CR 6 R 7 ) n B(R 8 R 9 ), or A 6 together with either A 3 or A 4 form BR 8 O(CR 6 R 7 ) n O—, —BR 8 O(CR 6 R 7 ) n NR—, —BR 8 O(CR 6 R 7 ) n —, —BR 8 NR 6 (CR 6 R 7 ) n —, —BR 8 NR 6 (CR 6 R 7 ) n NR 6 —, —BR 8 NR 6 (CR 6 R 7 ) n —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n O—, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n NR 6 —, —B(R 8 ) 2 N(R 6 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—N═CH—, —BR 8 NR 6 N═CH—, —B(R 8 ) 2 N(R 6 ) 2 N═CH—, —BR 8 —O—CR 6 ═N—, —BR 8 NR 6 CR 6 ═N—, —BR 8 —O—C(═O)NR 6 , —BR 8 NR 6 C(═O)NR 6 —, —BR 8 —O—C(NR 6 )═N—, —BR 8 NR 6 C(NR 6 )═N—, —B(R 8 ) 2 N(R 6 ) 2 CR 6 ═N—, —B(R 8 ) 2 N(R 6 ) 2 C(═O)—N—, —B(R 8 ) 2 N(R 6 ) 2 C(NR 6 )═N—, —BR 8 —O—NR 6 —, —B(OH)—O—NH—C(O)—, —B(OH)NR 6 NHC(O)—, —B(OH) 2 N(R 6 ) 2 NHC(O)—, —OBR 8 CH═CH—, —NR 6 BR 8 CH═CH—, —N(R 6 ) 2 B(R 8 ) 2 CH═CH—, —OBR 8 (CR 6 R 7 ) n O—, —OBR 8 (CR 6 R 7 ) n NR 6 —, —OBR 8 (CR 6 R 7 ) n —, —NR 6 BR 8 (CR 6 R 7 ) n O—, —NR 6 BR 8 (CR 6 R 7 ) n NR 6 —, —NR 6 BR 8 (CR 6 R 7 ) n − , —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n O—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n NR—, —N(R 6 ) 2 B(R 8 ) 2 (CR 6 R 7 ) n —, —BR 8 —O—CH═CH—, —BR 8 NR 6 CH═CH—, —B(R 8 ) 2 N(R 6 ) 2 CH═CH—; R 6 and R 7 are each H, C1-C6 alkyl, C-1-C6 alkenyl, C1-C6 alkynyl, trifluoro C1-C6 alkyl, acetyl, phenyl, C1-C6 alkylsulfonyl; R 8 and R 9 are each fluoro, hydroxy or alkoxy; or —B(R 8 R 9 ) forms a fluoride adduct, hydroxy acid adduct, or an amino acid adduct; n and m are each 0, 1, 2, 3, or 4.
  10. 10 . The method according to claim 9 , wherein the compound of Formula 1 is
  11. 11 . The method according to claim 9 , wherein the compound of Formula 1 is administered in conjunction with one or more additional therapeutic agents.
  12. 12 . The method according to claim 11 , wherein the additional therapeutic agent is selected from the group consisting of prostaglandin-like compounds, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, miotic or cholinergic agonists, sympathomimetics, Rho kinase inhibitors, and A1 adenosine receptor agonists.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/627,537, filed Jan. 14, 2022, which is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2020/042538, filed Jul. 17, 2020, which in turn claims the benefit of priority from U.S. Provisional Application No. 62/875,270, filed Jul. 17, 2019, the contents of which are hereby incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure generally relates to protein kinase-modulating compounds including boron-containing compounds, which are useful as neuroprotective and neuro-regenerative agents for the amelioration of glaucoma and other ocular neuropathies. BACKGROUND Glaucoma is a worldwide health issue with significant economic burden. Glaucoma is one of the major causes of blindness worldwide; greater than 60 million people are affected. According to a 2006 estimate irreversible sight impairment costs the United States approximately $50B annually, with glaucoma as a significant contributor. The market for glaucoma medications in the U.S. was ca. $2.5B in 2015. Commercial glaucoma medications are designed to reduce intraocular pressure. Drugs for glaucoma can be organized according to target class: alpha adrenergic agonists (reduce aqueous humor production, increases outflow) beta-adrenergic blockers (reduce aqueous humor production), carbonic anhydrase inhibitors (reduce aqueous humor production), miotics (increase aqueous humor outflow), prostaglandins (increase uveoscleral outflow), sympathomimetics (reduce aqueous humor production, increase outflow) and more recently under development, adenosine A1 receptor agonists (increase aqueous humor outflow) and rho kinase inhibitors (increase aqueous humor outflow, decreased production). Several of these classes have multiple targets and modes of action. As is the case with many ocular medications, some glaucoma medications were originally considered for systemic indications and have been repurposed for ophthalmology. One developmental medication designed to ameliorate increased ocular pressure (IOP) also demonstrates neuroprotection in the posterior eye: Rhopressa (netarsudil). Netarsudil is an IOP-lowering agent that also has been shown to promote blood flow to the optic nerve head, retinal ganglion cell survival, and axon regeneration in rats. In its primary IOP-lowering function, netarsudil inhibits rho kinase (ROCK) in the trabecular meshwork to increase aqueous humor outflow and also the norepinephrine transporter (NET) in the ciliary body to reduce aqueous humor production. Hence, the primary IOP targets (ROCK, NET) are in the anterior segment of the eye. In contrast, the secondary neuroprotective targets are in the posterior of the eye (ROCK). A primary endpoint in clinical trials of netarsudil has been the reduction of IOP. Toward this end, netarsudil is constructed as a lipophilic pro-drug administered as a topical solution. The pro-moiety increases log P in order to maximize transcellular permeability. Since lipophilic molecules tend to favor corneal rather than conjunctival permeation, and since the IOP-lowering targets are anterior, the presumptive route of entry is through the cornea. Importantly, both the parent molecule and more polar pro-drug analogs are much less effective in lowering IOP in rabbit studies, a reflection of bioavailability rather than potency. Despite the design orientation toward the anterior eye, in rats, netarsudil must also reach the retina, as evidenced by retinal ganglion cell survival, and axon regeneration. A common but mild side effect of netarsudil is conjunctival hyperemia. AR-13154, another ROCK inhibitor, also targets Janus kinase (JAK), platelet-derived growth factor kinase (PDGFR), protein kinase C (PKC), and also ROCK. AR-13154 is intended for treatment of wet age-related macular degeneration (AMD) and retinal neovascularization in proliferative diabetic retinopathy (PDR). The sponsors of AR-13154 intend that it be administered as an implant to reach its retinal targets. Numerous design strategies have been implemented to improve the bioavailability and convenience of ocular drugs. These can be categorized according to two parameters: (a) elaborations of the active ingredient, i.e., API, API modifications such as pro-drug moieties, drug delivery systems, and (b) mode/locus of administration. Because the eye is externally visible and because geometrical distances to interior ocular compartments are short, the human eye gives the impression of accessibility. Quite to the contrary, effective drug delivery to eye tissue is very difficult due to multiple, layered, and orthogonally-selective static and dynamic barriers. Delivery to posterior tissues of the eye is especially difficult. Therefore, there remains a need to achieve or increase the neuroprotective effect of topical ROCK inhibitors; and reduce the side effects (e.g. hyperemia, e