US-12622910-B2 - Inhibitors of Bruton's tyrosine kinase and methods of their use

Abstract

The present disclosure is directed to the use of a compound of Formula (III) in the treatment of malignancies.

Inventors

• Sriram Balasubramanian
• Jennifer D. Venable
• John J. M. Wiener
• Xin Miao
• Ivo CORNELISSEN
• Yue Guo
• Jocelyn H. LEU
• Kathryn E. Packman
• James Alexander PALMER
• Ulrike Philippar
• Navin Rao
• Mark S. Tichenor

Assignees

• JANSSEN PHARMACEUTICA NV

Dates

Publication Date

20260512

Application Date

20220602

Claims (6)

1. 1 . A method of treating a B-cell malignancy selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom macroglobulinemia in an individual in need thereof, comprising administering twice daily a therapeutically effective amount of a compound of Formula (III): or a pharmaceutically acceptable salt, or hydrate thereof, wherein the therapeutically effective amount of the compound of Formula (III) is about 140 mg.
2. 2 . The method of claim 1 , further comprising administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide).
3. 3 . A method of treating a B-cell malignancy selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom macroglobulinemia in an individual in need thereof, comprising administering twice daily a therapeutically effective amount of a compound of Formula (III): or a pharmaceutically acceptable salt, or hydrate thereof, wherein the therapeutically effective amount of the compound of Formula (III) is about 280 mg.
4. 4 . The method of claim 3 , further comprising administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide).
5. 5 . A method of treating a B-cell malignancy selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom macroglobulinemia in an individual in need thereof, comprising administering twice daily a therapeutically effective amount of a compound of Formula (III): or a pharmaceutically acceptable salt, or hydrate thereof, wherein the therapeutically effective amount of the compound of Formula (III) is about 560 mg.
6. 6 . The method of claim 5 , further comprising administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide).

Description

CROSS REFERENCE TO OTHER APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/196,843 filed on Jun. 4, 2021 titled “Inhibitors Of Bruton's Tyrosine Kinase And Methods Of Their Use” which is incorporated herein by reference in its entiriety. TECHNICAL FIELD The present disclosure is directed to the use of small molecule tyrosine kinase inhibitors for the treatment of malignancies. BACKGROUND Malignancies, in particular diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, and other conditions such as chronic graft versus hos disease, continues to afflict patients. Alternative, effective treatments of cancer are still needed. Human Bruton's tyrosine kinase (“BTK”) is a ˜76 kDa protein belonging to the Tec family of non-receptor tyrosine kinases. Tec kinases form the second largest family of cytoplasmic tyrosine kinases in mammalian cells, which consists of four other members in addition to BTK: the eponymous kinase TEC, ITK, TXK/RLK and BMX. Tec kinases are evolutionarily conserved throughout vertebrates. They are related to, but structurally distinct from, the larger Src and Syk kinase families. Tec family proteins are abundantly expressed in hematopoietic tissues and play important roles in the growth and differentiation of blood and endothelial cells in mammals. Based upon BTK expression from IHC studies described in the art, Btk inhibition has the potential to modulate biology associated with B cells, macrophages, mast cells, osteoclasts, and platelet microparticles. Corneth, O. B., et al. Curr. Top. Microbiol. Immunol. BTK Signaling in B Cell Differentiation and Autoimmunity. 2015 Sept. 5. SUMMARY Compositions comprising the compound of Formula (III) are described. Methods of using the compound of Formula (III) are also within the scope of the disclosure. Also described are methods of treating a malignancy in an individual in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (III): or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof. In some aspects, the malignancy is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom macroglobulinemia, Chronic graft versus host disease. Some aspects are directed to methods of treating chronic graft versus host disease in an individual in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (III): or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof. In some aspects the therapeutically effective amount of the compound of Formula (III) is from about 140 mg to about 560 mg. In some aspects, the therapeutically effective amount of the compound of Formula (III) is administered once a day. In some aspects, the therapeutically effective amount of the compound of Formula (III) is administered twice daily. In some aspects, the therapeutically effective amount of the compound of Formula (III)is about 140 mg. In some aspects, the therapeutically effective amount of the compound of Formula (III) is about 280 mg. In some aspects, the therapeutically effective amount of the compound of Formula (III) is about 560 mg. In some aspects the therapeutically effective amount of the compound of Formula (III) is an amount that results in a C(max,day1) of about 59.992 ng/ml to about 2,377.2 ng/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a C(max,day1) of about 239.97 ng/ml to about 9,509 ng/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a C(max,ss) of about 66.855 ng/ml to about 2,395.4 ng/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a C(max,ss) of about 267.42 ng/ml to about 9,581.5 ng/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a AUC(day 1) of about 312.1 ng·hr/ml to about 11,517 ng·hr/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a AUC(day 1) of about 1,248.4 ng·hr/ml to about 46,068 ng·hr/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a AUC(ss) of about 312.27 ng·hr/ml to about 13,015 ng·hr/ml. In some aspects, the therapeutically effective amount of the compound of Formula (III) is an amount that results in a AUC(ss) of about 1,249.1 ng·hr/ml to about 52,061 ng·hr/ml. In some aspects, the therapeutically effective amo