WO2023225586A2

WO2023225586A2 - Novel azaphenantrhene derivatives as inhibitors of glycogen synthase kinase 3 for therapeutic use

Info

Publication number: WO2023225586A2
Application number: PCT/US2023/067159
Authority: WO
Inventors: Pablo LAPUERTA; Daniel E. Levy
Original assignee: 4M Therapeutics Inc.
Priority date: 2022-05-19
Filing date: 2023-05-18
Publication date: 2023-11-23
Also published as: WO2023225586A3

Abstract

Aspects of this invention are related to novel compounds of Formula I and compositions thereof that are inhibitors of glycogen synthase kinase 3 beta (GSK3β). Some aspects of the invention relate to novel compounds and compositions having a better pharmacokinetic profile than previous GSK3β inhibitors, a pharmacokinetic profile more suitable to therapeutic use.

Description

NOVEL AZAPHENANTRHENE DERIVATIVES AS INHIBITORS OF GLYCOGEN SYNTHASE KINASE 3 FOR THERAPEUTIC USE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63/364,983, filed May 19, 2022. The foregoing application is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] Aspects of this invention are related to novel compositions for treating neurological disease or psychiatric disorders, including Alzheimer's disease, bipolar disorder, depression, schizophrenia, Parkinson's disease, or neuroinflammation, and for treating diabetes mellitus and its complications, or ischemia, inflammation, pulmonary hypertension, congestive heart failure, cardiovascular disease, dermatological disease, cancer, or GM2 gangliosidosis, or other conditions where modulation of GSK-3β signaling is clinically useful.

BACKGROUND OF THE INVENTION

[0003] GSK-3 inhibitors have been proposed as a treatment of subjects having a neurological disease and/or psychiatric disorder, including Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression, schizophrenia, Parkinson's disease, or neuroinflammation. Inhibitors of GSK-3 are known to increase the expression of WNT proteins, thereby enhancing a pathway in regenerative medicine that has been broadly proposed to treat neurological and psychiatric disorders. GSK-3 inhibition or enhancement of WNT signaling has been linked to the potential treatment of type 2 diabetes and renal disorders including diabetic nephropathy, chronic kidney disease, polycystic kidney disease, and focal segmental glomerulosclerosis, and atherosclerosis, alopecia, bone and joint disorders including osteoarthritis and osteoporosis, inflammatory disorders including alcoholic hepatitis, inflammatory bowel disease, and septic shock, disorders of the eye including wet age-related macular degeneration, dry age-related macular degeneration, diabetic macular edema, Fuch's dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, and Sjogren's syndrome. GSK-3 inhibition or enhancement of WNT signaling has been linked to the potential treatment of ear disorders including sensorineural hearing loss and conductive hearing loss, pulmonary disorders including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis, short bowel syndrome, and cancers including melanoma, pancreatic cancer, prostate cancer, colon cancer, and leukemia. GSK-3 inhibitors have been proposed as a monotherapy for treating bipolar disorder, or in combination with lithium, or in combination with other bipolar disorder treatments.

[0004] Highly potent and selective radioactive inhibitors of GSK3β have been developed for use in positron emission tomography (PET) as a diagnostic tool for Alzheimer's disease. PET imaging of GSK3β is also of interest as a diagnostic tool identifying cancers that express GSK3. PET imaging of GSK3β can also aid in the development of therapeutic agents. PET imaging of GSK3β in the brain could ensure adequate dosing of a GSK3β inhibitor for the treatment of a neurological or psychiatric disorder. PET imaging of GSK3β in the brain or elsewhere could ensure adequate dosing of a GSK3 Inhibitor for the treatment of cancer. The imaging could be used in animal studies as part of drug discovery, in clinical trials to establish therapeutic dose ranges, or in clinical practice to ensure optimal dosing of a therapeutic.

[0005] However, the development of highly potent and selective inhibitors of GSK3β as therapeutics has not been successful to date. One of the challenges has been safety, and development of some GSK3β inhibitors has been abandoned for safety reasons. The obstacle of developing safe GSK3β inhibitors has been described as "insurmountable." Safety issues are lower for PET imaging applications than for therapeutic use because PET studies are done only once or twice. Short-term safety data are sufficient for development of a PET ligand, and a short half-life of a compound is attractive for PET imaging because there is less of a safety issue if the imaging agent is rapidly metabolized and cleared.

[0006] PF-048O2367 (also known as PF-367), an oxazole-4-carboxamide, was reported to have binding kinetics in brain tissue too fast for an effective therapeutic agent but ideal for discovery of radiopharmaceuticals for GSK-3 In the central nervous system. Subsequent efforts further explored optimization of oxazole carboxamides (OCMs) beyond PF-367, resulting in the greatest potency and selectivity in a compound referenced herein as OCM-51, or compound 1:

[0007] However, because of its rapid clearance, compound 1 is not suitable to serve as an inhibitor of GSK3β for therapeutic use. BRIEF SUMMARY OF THE INVENTION

[0008] Compounds have now been developed that overcome these shortcomings. Compounds and compositions of the present invention are provided that surprisingly and unexpectedly have been found to have good potency and selectivity against GSK3β while providing improved in vivo stability (slower clearance) that is necessary for therapeutic use. One aspect of the invention is directed to an inhibitor of GSK3β for therapeutic use, having the structure of Formula I:

where

R¹ is L-R²;

R² is a 5-6 membered heteroaryl ring or a 6-membered aryl or heteroaryl ring;

R³ is H or C₁-C₆ alkyl;

L is -(CH₂)_n-, a 4-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring;

X Is O or N-R³; each Y joins together forming a 5-6 membered heteroaryl ring or a 6-membered aryl or heteroaryl ring; each Z joins together forming a 5-6 membered heteroaryl ring or a 6-membered aryl or heteroaryl ring; n is an integer from 0-5

[0009] An inhibitor of GSK3β according to the present invention can also have any one of the structures 41 or 42:

3 BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows a diagram of the therapeutic window for a drug on a graph of % maximum effect versus drug concentration.

[0011] FIG. 2 shows the radioactivity time curves of a related C¹¹ compound in rhesus monkey.

[0012] FIG. 3 shows the concentrations in plasma, brain and CSF hourly after injection of 50 mg/kg of a related compound in mice.

[0013] FIG. 4 shows a representative synthetic route to compound 41

[0014] FIG. 5 shows a representative synthetic route to compound 42

DETAILED DESCRIPTION

[0015] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0016] As disclosed herein, a number of ranges of values are provided. It is understood that each

Intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges can independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. The term "about" generally includes up to plus or minus 10% of the indicated number. For example, "about 10%” can indicate a range of 9% to 11%, and "about 20" can mean from 18 to 22.

Preferably "about" includes up to plus or minus 6% of the Indicated value. Alternatively, "about" includes up to plus or minus 5% of the indicated value. Other meanings of “about" may be apparent from the context, such as rounding off, so, for example "about 1" can also mean from 0.5 to 1.4.

[0017] The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Such salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-

(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which Is incorporated herein by reference.

[0018] One problem with a short half-life in a therapeutic agent is that it may require dosing several times a day. If a compound with a short half-life is administered only once or twice a day, then the peak concentration may be many times higher than the trough concentration at the end of the dosing interval.

[0019] For example, a drug with a half-life of 24 hours can be given once a day with a peak drug concentration that is about 2 to 3 times the trough concentration. In contrast, a drug with a half-life of 6 hours, if given once a day, will have a peak concentration approximately 16 times the trough concentration.

[0020] A smaller ratio of peak to trough concentration is generally desirable as a principle of drug development because it keeps drug concentrations within the therapeutic window (see FIG. 1). The window is described by the dose response for efficacy and a dose response for toxicity. A lower peak/trough ratio helps keep a drug concentration at levels that provide efficacy throughout the dosing interval without being so high as to cause toxicity.

[0021] During the medicinal chemistry effort, there was evidence that the oxazole carboxamides that were developed have a short half-life. A compound in the program was evaluated in rhesus monkeys, where a rapid decline in radioactivity was seen, a decline more rapid than expected from the half-life of C¹¹ (see FIG. 2). Injection of 50 mg/kg of the same compound in mice also showed rapid declines in plasma and brain concentrations on an hourly basis (see FIG. 3).

[0022] While levels remained above the IC₅₀ for the full seven hours measured, this was due to the large dose injected. Results were consistent with a peak/trough ratio of about 100 in mice for administration every 6 hours. Compounds that are potent and selective inhibitors of GSK3β will be more appropriate for therapeutic use if they have greater stability, providing a better pharmacokinetic profile that includes a lower peak/trough ratio.

[0023] For this reason, one aspect of the invention includes administration of the following compounds 41 and 42 (compound 1 is OCM-51) at a total daily dose of about 0.1 to about 4 mg/kg by injection, or about 0.125 to about 10 mg/kg administered orally.

[0024] As part of the medicinal chemistry exploration of the OCM-51 lead, compound 1, confirmational rigidity of the oxazole carboxamide structure is explored in compounds 41 and 42. Compounds of the present invention have surprisingly and unexpectedly have been found to have good potency and selectivity against GSK-3β while providing the improved stability (slower clearance) that is necessary for therapeutic use.

[0025] Without wishing to be bound by any particular theory, one skilled in the art will recognize that

ATP competitive kinase inhibitors generally interact with the “hinge region* of a given kinase. The kinase hinge region is a region critical to binding of ATP - the natural kinase substrate. Typically, the hinge region provides a hydrogen bond donor and a hydrogen bond acceptor - both being generally presented as part of the kinase protein backbone. In order to capitalize on this feature, a common strategy for the design of kinase inhibitors is to include a combination of a hydrogen bond donor and a hydrogen bond acceptor that is complementary to that of the kinase hinge region. Specifically, the hydrogen bond donor of the inhibitor will form a hydrogen bond with the hydrogen bond acceptor of the kinase hinge region. Simultaneously, the hydrogen bond acceptor of the inhibitor will form a hydrogen bond with the hydrogen bond donor of the kinase hinge region.

[0026] Hinge region binding alone is generally insufficient for development of a suitable kinase inhibiting therapeutic as all kinases possess hinge regions. In order to impart druggable characteristics of a given Inhibitor, substituents on either side of the hinge binder are optimized to the structure of a specific kinase. In this way, selective inhibition can be achieved between different kinases and also between isoforms of specific kinases.

[0027] The compounds of the present invention utilize aminopyridines and related structures as hinge region binders. One skilled in the art will recognize that additional useful functional groups and structures exist that are useful for kinase inhibitor hinge region binding.

[0028] A generic structure encompassing the compounds of the invention is represented by Formula I:

wherein

R¹ is L-R²; R² is a 5-6 membered heteroaryl ring or a 6-membered aryl or heteroaryl ring;

R³ is H or C₁-C₆ alkyl;

[0029] Specific compounds are represented by compounds 41 and 42:

[0030] The compounds of the present invention and pharmaceutical compositions thereof are relevant wherever inhibition of GSK-3 may be clinically useful, Including psychiatric and neurological disorders, such as bipolar disorder, depression, Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, autism spectrum disorder, Fragile X syndrome, Pitt Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy-induced neuropathy, and chemotherapyinduced cognitive impairment. They are relevant to conditions where GSK-3 inhibition and or enhancement of WNT signaling have been proposed, including alopecia, osteoarthritis, osteoporosis, alcoholic hepatitis, inflammatory bowel disease, wet age-related macular degeneration, dry age-related macular degeneration, diabetic macular edema, Fuch's dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, Sjogren's syndrome, sensorineural hearing loss, conductive hearing loss, schizophrenia, Parkinson's disease, polycystic kidney disease, focal segmental glomerulosclerosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, short bowel syndrome, melanoma, pancreatic cancer, prostate cancer, colon cancer, leukemia, septic shock, and ischemia/reperfusion injury.

[0031] Furthermore, a response to either a presently disclosed compound or the combination of said compound with lithium can serve to establish a diagnosis of bipolar disorder and other conditions where GSK3 inhibition is clinically useful. In Alzheimer's disease, positron emission tomography (PET) of GSK3β activity is being developed as a diagnostic. Presently disclosed compounds, alone or in combination with lithium, may be administered to subjects with excess GSK3β activity on PET in order to treat Alzheimer's disease, and a reduction in GSK3β activity on PET after administration of a disclosed compound can support its use (alone or in combination with lithium) as an appropriate therapy administered at a suitable dose.

[0032] The presently disclosed compositions and treatment methods also have use in veterinary applications for improving the health and well-being of livestock and companion animals by treating any of the foregoing indications that occur in animals.

EXAMPLES

Synthetic Protocols:

C0MPOUND41

Compound 42

[0033] Any of compounds 41 and 42 can be formulated as a pharmaceutically acceptable salt and/or solvate thereof.

[0034] The presently disclosed compounds, compositions and treatment methods also have use in veterinary applications for improving the health and well-being of livestock and companion animals by treating conditions they suffer from that respond to treatment with a GSK-3β inhibitor.

[0035] It will be understood by those of ordinary skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the various embodiments of the present invention described herein are illustrative only, and are not intended to limit the scope of the present invention.

Claims

CLAIMS What is claimed is:

1. An inhibitor of GSK-3β for therapeutic use, having the structure of Formula I:

Formula I wherein

R¹ is L-R²;

R² is a 5-6 membered heteroaryl ring or a 6-membered aryl or heteroaryl ring;

R³ is H or C₁-C₆ alkyl;

2. The inhibitor of GSK-3β of claim 1, having any one of the structures 41 and 42:

3. A method of treating a disorder comprising aberrant signaling of GSK-3, the method comprising administering to a subject in need thereof a therapeutically effective dose of a GSK-3P inhibitor listed in either one of Claims 1 or 2.

4. The method of Claim 3, wherein the subject has a neurological disease and/or psychiatric disorder.

5. The method of Claim 4, wherein disease/disorder is selected from Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression, schizophrenia, Parkinson's disease, neuroinflammation, autism spectrum disorder, Fragile X syndrome,

Pitt Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy-induced neuropathy, and/or chemotherapy-induced cognitive impairment.

6. The method of Claim 3, wherein disease/disorder is selected from type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic macular edema, diabetic nephropathy, chronic kidney disease, polycystic kidney disease, and/or focal segmental glomerulosclerosis.

7. The method of Claim 3, wherein disease/disorder is selected from atherosclerosis, alopecia, bone and joint disorders including osteoarthritis and osteoporosis, inflammatory disorders including alcoholic hepatitis inflammatory bowel disease, and septic shock.

8. The method of Claim 3, wherein disease/disorder is selected from disorders of the eye including wet age-related macular degeneration, dry age-related macular degeneration, Fuch's dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, and Sjogren's syndrome, and/or ear disorders including sensorineural hearing loss and conductive hearing loss.

9. The method of Claim 3, wherein disease/disorder is selected from pulmonary disorders including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and/or cancers including melanoma, pancreatic cancer, prostate cancer, colon cancer, and leukemia, and/or short bowel syndrome, ischemia, inflammation, cardiovascular disease, congestive heart failure, dermatological disease, inflammation, or GM2 gangliosidosis.

10. The method of any one of the above Claims, wherein the GSK-3β inhibitor is administered in an amount of about 32 to about 320 mg once daily, or about 16 to about 160 mg twice daily.

11. The method of any one of Claims 3 to 9, wherein the compound is administered in combination with lithium.

12. The method of any one of Claims 3 to 9, wherein the subject is non-responsive to lithium.

13. The method of Claim 11, wherein the subject is lithium responsive.

14. The method of Claim 11, wherein lithium is administered at a sub-effective dose based on monotherapy, and wherein the compound is administered at a sub-effective dose based on monotherapy.

15. The method of Claim 14, wherein the sub-effective dose of lithium is about 60 mg to about 600 mg once daily, or about 30 mg to about 300 mg twice daily.

16. The method of Claim 14, wherein a sub-effective dose of the GSK-3β inhibitor is administered in about 8 to about 32 mg once daily, or about 4 to about 16 mg twice daily.

17. A method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of a compound listed and evaluating the subject's clinical response.

18. A method of establishing an appropriate therapeutic dose of a GSK-3β inhibitor listed in either one of Claims 1 or 2 in a subject, comprising administering increasing doses of the GSK-3P inhibitor and assessing response using GSK-3 imaging or GSK-3 serology.

19. A method of treating a subject with Alzheimer's disease, bipolar disorder, or depression who shows evidence of elevated GSK-3, comprising administering to the subject a therapeutically effective dose of the crystal form of a GSK-3β inhibitor listed in either one of Claims 1 or 2 and evaluating and monitoring the subject using positron emission tomography (PET) or serology.

20. A method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of a GSK-3β inhibitor listed in either one of Claims 1 or 2 with a therapeutically effective dose of lithium, and evaluating the subject's clinical response.

21. The method of claim 20, wherein the dose of both the GSK-3β and lithium are sub-effective based on monotherapy.

22. A method of treating a subject with Alzheimer's disease who has evidence of elevated GSK-3 beta activity, comprising administering to the subject a therapeutically effective dose of a GSK-3β inhibitor listed in either one of Claims 1 or 2 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a therapeutically effective dose of lithium, and monitoring the subject using positron emission topography (PET).

23. The method of claim 22, wherein the dose of both the GSK-3β inhibitor and lithium are subeffective based on monotherapy.

24. A method of establishing an appropriate therapeutic dose of a GSK-3β inhibitor listed in either one of Claims 1 or 2 in a subject, comprising administering increasing doses of the crystal form of the GSK-3β inhibitor and lithium to the subject and assessing response using positron emission topography (PET).