EP-4739315-A1 - PHARMACEUTICAL COMPOSITIONS FOR INHIBITORS OF NEK7 KINASE

Abstract

Provided are pharmaceutical compositions for compounds which are inhibitors of NEK7. The compounds are a structure of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein. Provided herein are also methods of treatment comprising the pharmaceutical compositions described herein.

Inventors

• BEARSS, DAVID JAMES
• JANAT-AMSBURY, Margit

Assignees

• Halia Therapeutics, Inc.

Dates

Publication Date

20260513

Application Date

20240705

Claims (1)

1. WSGR Docket No. 63243-701.601 CLAIMS What is claimed is: 1. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R 6 ; X is CH or N; Y is NH; R 1 is H; R 2 is C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy and 3- to 8-membered heterocyclyl; R 3 is H; R 4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 cyanoalkyl, 3- to 8-membered heterocyclyl, C 3 -C 8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R 5 is H; and each R 6 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 1 -C 6 hydroxylalkyl or C1-C6 haloalkyl; and WSGR Docket No. 63243-701.601 at least one pharmaceutically acceptable excipient, wherein the amount of a compound of Formula (I) in the pharmaceutical composition is from about 0.5 to about 5 mg. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof. 3. A method of treating an NLRP3-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 or claim 2. 4. The method of claim 3, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome. 5. The pharmaceutical composition of claim 1 or claim 2, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: R 2a is C 3 -C 4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy and 3-8 membered heterocyclyl; and R 4a is isoxazolyl optionally substituted with one more substituents selected from C1- C 6 haloalkyl, C 3 -C 8 cycloalkyl or C 3 -C 8 haloalkylcycloalkyl. 6. The pharmaceutical composition of claim 1 or claim 2, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. WSGR Docket No. 63243-701.601 7. The pharmaceutical composition of claim 1 or claim 2, wherein the compound WSGR Docket No. 63243-701.601 pharmaceutically acceptable salt or solvate thereof. 8. The pharmaceutical composition of any one of claims 1-2 or 5-7, wherein the compound of Formula (I) is Compound 10 of Table 1. 9. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 4 mg. 10. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 5 mg 11. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 2 mg. 12. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 0.5 mg 13. The pharmaceutical composition of any one of claims 1-2 or 5-12, wherein the pharmaceutical composition is in a tablet. 14. The pharmaceutical composition of claim 13, wherein the tablet is a film- coated immediate-release tablet. 15. The pharmaceutical composition of claim 13 or claim 14, wherein the tablet is coated with Opadry II. 16. The pharmaceutical composition of any one of claims 13-15, wherein the tablet has a diameter of about 7 mm. WSGR Docket No. 63243-701.601 17. The pharmaceutical composition of any one of claims 1 or 5-16, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre- gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof. 18. The pharmaceutical composition of any one of claims 1-2 or 5-17, wherein the pharmaceutically acceptable excipient comprises at least three ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 19. The pharmaceutical composition of any one of claims 1-2 or 5-18, wherein the pharmaceutically acceptable excipient comprises at least four ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 20. The pharmaceutical composition of any one of claims 1-2 or 5-19, wherein the pharmaceutically acceptable excipient comprises at least five ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 21. The pharmaceutical composition of any one of claims 1-2 or 5-20, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre- gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 22. The pharmaceutical composition of any one of claims 2 or 17-21, wherein the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.1% w/w. 23. The pharmaceutical composition of any one of claims 2 or 17-22, wherein the partially pre-gelatinized maize starch is in an amount of about 30% w/w to about 50% w/w. 24. The pharmaceutical composition of any one of claims 2 or 17-23, wherein the microcrystalline cellulose is in an amount of about 30% w/w to about 50% w/w. 25. The pharmaceutical composition of any one of claims 2 or 17-24, wherein the sodium starch glycolate is in an amount of about 1% w/w to about 5% w/w. 26. The pharmaceutical composition of any one of claims 2 or 17-25, wherein the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 5% w/w. WSGR Docket No. 63243-701.601 27. The pharmaceutical composition of any one of claims 2 or 17-26, wherein the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 5% w/w. 28. The pharmaceutical composition of any one of claims 2 or 17-27, wherein the magnesium stearate is in an amount of about 0.5% w/w to about 5% w/w. 29. The pharmaceutical composition of claim 21, wherein the sodium lauryl sulfate is in the amount of about 0.01% w/w to about 0.1% w/w, the partially pre-gelatinized maize starch is in the amount of about 43% w/w to about 44% w/w, the microcrystalline cellulose is in the amount of about 44% w/w to about 48% w/w, the sodium starch glycolate is in the amount of about 3% w/w to about 4% w/w, the hydroxypropyl cellulose LF is in the amount of about 2% w/w to about 3% w/w, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w, and the magnesium stearate is in the amount of about 1% w/w to about 1.5% w/w. 30. The pharmaceutical composition of any one of claims 1-2 or 5-29, wherein the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. 31. A method of treating an NLRP3-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-2 or 5-30. 32. The method of claim 31, wherein the NLRP3-mediated disease or disorder is a myelodysplastic syndrome, an inflammatory disease or disorder, an auto-immune disease or disorder, a cardiovascular disease, a neurodegenerative disease or disorder, a bacterial and/or viral infection, an allergy, asthma, pancreatitis, multi-organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, a lung injury, a respiratory disease, an ischemic condition, or a combination thereof. 33. The method of claim 31, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder. 34. The method of claim 33, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome. 35. The method of claim 34, where the myelodysplastic syndrome is myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic WSGR Docket No. 63243-701.601 syndrome with excess blasts, myelodysplastic syndrome with isolated del, or myelodysplastic syndrome unclassifiable. 36. The method of claim 33, wherein the NLRP3-mediated disease or disorder is an inflammatory disease or disorder. 37. The method of claim 36, wherein the inflammatory disease or disorder is acute inflammatory pain. 38. The method of any one of claims 31-37, wherein the pharmaceutical composition is administered daily. 39. The method of any one of claims 31-38, wherein the pharmaceutical composition is administered daily for about 1 week to about 12 weeks. 40. The method of any one of claims 31-38, wherein the pharmaceutical composition is administered daily for about 12 or more weeks. 41. A method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R 6 ; X is CH or N; Y is NH; R 1 is H; R 2 is C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy and 3- to 8-membered heterocyclyl; R 3 is H; WSGR Docket No. 63243-701.601 R 4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4- triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5- thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C 3 -C 8 haloalkylcycloalkyl, C 3 -C 8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C 3 -C 8 halocycloalkyl; R 5 is H; and each R 6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; wherein: (i) the subject has symptomatic anemia; (ii) the subject is refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), optionally wherein the subject has discontinued prior ESA at least two weeks prior to the administering; (iii) the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS; (iv) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject; (v) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject daily; or (vi) a combination of two or more of (i) to (v). 42. The method of claim 41, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily. 43. The method of claim 41 or claim 42, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for about 1 week to about 12 weeks. WSGR Docket No. 63243-701.601 44. The method of claim 41 or claim 42, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for 12 or more weeks. 45. The method of any one of claims 41-44, wherein administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject. 46. The method of any one of claims 41-45, wherein each dose of the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is about 0.5 mg to about 5 mg. 47. The method of any one of claims 41-46, wherein the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: R 2a is C 3 -C 4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R 4a is isoxazolyl optionally substituted with one more substituents selected from C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or C 3 -C 8 haloalkylcycloalkyl. 48. The method of any one of claims 41-47, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. 49. The method of any one of claims 41-47, wherein the compound of Formula (I) is Compound 10 of Table 1, or a pharmaceutically acceptable salt or solvate thereof. WSGR Docket No. 63243-701.601 50. The method of any one of claims 41-46, wherein the compound of Formula (I) is WSGR Docket No. 63243-701.601 pharmaceutically acceptable salt or solvate thereof.

Description

WSGR Docket No. 63243-701.601 PHARMACEUTICAL COMPOSITIONS FOR INHIBITORS OF NEK7 KINASE CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/512,188 filed July 6, 2023 and U.S. Provisional Patent Application No.63/657,018 filed June 6, 2024, both of which are incorporated by reference herein in their entirety. BACKGROUND [0002] The NLRP3 inflammasome is a multi-protein complex comprising NLRP3, ASC, and caspase-1. NEK7 is a member of the family of NIMA-related kinases (NEKs) and acts as an NLRP3-binding protein to regulate its oligomerization and activation. SUMMARY [0003] Provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R3 is H; WSGR Docket No. 63243-701.601 R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises no more than 10 mg of Formula (I). [0004] An aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; WSGR Docket No. 63243-701.601 R3 is H; R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the amount of a compound of Formula (I) in the pharmaceutical composition is from about 0.5 to about 5 mg. [0005] In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof. [0006] An aspect of the present disclosure provides a method of treating an NLRP3- mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein. [0007] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome. [0008] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: WSGR Docket N