CA-3046578-C - IMIDAZOPYRAZINE INHIBITORS OF BRUTON'S TYROSINE KINASE

Abstract

In some embodiments, the invention relates to the compounds of Formula (I) and (II) or a pharmaceutically acceptable salt thereof, or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, in some embodiments, the present invention relates to the compounds of Formula (I) and (II), pharmaceutical compositions thereof, and the use of the compounds and pharmaceutical compositions in the treatment of a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder.

Inventors

• Terry Podoll
• Jerry Evarts
• Allard Kaptein

Assignees

• ACERTA PHARMA B.V.

Dates

Publication Date

20260505

Application Date

20171221

Priority Date

20161221

Claims (20)

1. Claims 1.
2. 2.
3. 3.
4. 4.
5. 5. A compound of Formula (I) or Formula (II) having the structures: or a pharmaceutically acceptable salt thereof. , or (I) (II) The compound of Claim 1, wherein the compound is the compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compound of Claim 1, wherein the compound is the compound of Formula (II) or a pharmaceutically acceptable salt thereof. The compound of Claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder. The compound of Claim 2 or a pharmaceutically acceptable salt thereof for use in the treatment of a hyperproliferative disorder selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia, Burkitt’s lymphoma, Waldenström's macroglobulinemia, multiple myeloma, myelodysplastic syndromes, and myelofibrosis. 44
6. 6. The compound for use of Claim 5, wherein the hyperproliferative disorder is chronic lymphocytic leukemia.
7. 7.
8. 8.
9. 9. The compound for use of Claim 5, wherein the hyperproliferative disorder is small lymphocytic leukemia. The compound for use of Claim 5, wherein the hyperproliferative disorder is mantle cell lymphoma. The compound for use of Claim 5, wherein the hyperproliferative disorder is diffuse large B cell lymphoma.
10. 10. The compound for use of Claim 5, wherein the hyperproliferative disorder is Waldenström's macroglobulinemia.
11. 11. The compound of Claim 3 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, Type 1 diabetes, Type 2 diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s Disease, lupus, lupus nephritis, human leukocyte antigen associated diseases, autoantibodies, immunotherapy, Addison's disease, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, Grave’s disease, Hashimoto’s thyroiditis, polyendocrine autoimmunity, iatrogenic autoimmunity, idiopathic hypoparathyroidism, vitiligo and lupus nephritis.
12. 12. A pharmaceutical composition comprising a compound of Claim 2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
13. 13. The pharmaceutical composition of Claim 12, for use in the treatment of a hyperproliferative disorder in a patient in need thereof, wherein the hyperproliferative disorder is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia, Burkitt’s lymphoma, Waldenström's macroglobulinemia, multiple myeloma, myelodysplastic syndromes, and myelofibrosis.
14. 14. A pharmaceutical composition comprising a compound of Claim 3 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 45
15. 15. The pharmaceutical composition of Claim 14 for use in the treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, Type 1 diabetes, Type 2 diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s Disease, lupus, lupus nephritis, human leukocyte antigen associated diseases, autoantibodies, immunotherapy, Addison's disease, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, Grave’s disease, Hashimoto’s thyroiditis, polyendocrine autoimmunity, iatrogenic autoimmunity, idiopathic hypoparathyroidism, vitiligo and lupus nephritis.
16. 16. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof for treatment of a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder.
17. 17. Use of the compound of Claim 2 or a pharmaceutically acceptable salt thereof for treatment of a hyperproliferative disorder selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia, Burkitt’s lymphoma, Waldenström's macroglobulinemia, multiple myeloma, myelodysplastic syndromes, and myelofibrosis.
18. 18. Use of the compound of Claim 3 or a pharmaceutically acceptable salt thereof for treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, Type 1 diabetes, Type 2 diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s Disease, lupus, lupus nephritis, human leukocyte antigen associated diseases, autoantibodies, immunotherapy, Addison's disease, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, Grave’s disease, Hashimoto’s thyroiditis, polyendocrine autoimmunity, iatrogenic autoimmunity, idiopathic hypoparathyroidism, vitiligo and lupus nephritis. 46
19. 19. Use of the pharmaceutical composition of Claim 12, for treatment of a hyperproliferative disorder in a patient in need thereof, wherein the hyperproliferative disorder is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia, Burkitt’s lymphoma, Waldenström's macroglobulinemia, multiple myeloma, myelodysplastic syndromes, and myelofibrosis.
20. 20. Use of the pharmaceutical composition of Claim 14 for treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, Type 1 diabetes, Type 2 diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s Disease, lupus, lupus nephritis, human leukocyte antigen associated diseases, autoantibodies, immunotherapy, Addison's disease, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, Grave’s disease, Hashimoto’s thyroiditis, polyendocrine autoimmunity, iatrogenic autoimmunity, idiopathic hypoparathyroidism, vitiligo and lupus nephritis. 47

Description

IMIDAZOPYRAZINE INHIBITORS OF BRUTON'S TYROSINE KINASE FIELD OF THE INVENTION [001] In some embodiments, the present invention relates to the compounds of Formula (I) and (II), to pharmaceutical compositions comprising these compounds, and to their use in therapy. In some embodiments, the present invention relates to the use of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt in the treatment of a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder. BACKGROUND OF THE INVENTION [002] Bruton's tyrosine kinase (BTK) is a Tee family non-receptor protein kinase expressed in B cells and myeloid cells. Research findings support a key role for BTK in the regulation of the production of auto-antibodies in autoimmune diseases. Also, inhibition of BTK seems to be relevant in particular for B cell lymphomas due to chronic active BCR signaling, as described in Davis, et al., Nature, 2010, 463, 88-94. [003] In many solid tumors, the supportive microenvironment (which may make up the majority of the tumor mass) is a dynamic force that enables tumor survival. The tumor microenvironment is generally defined as a complex mixture of "cells, soluble factors, signaling molecules, extracellular matrices, and mechanical cues that promote neoplastic transformation, support tumor growth and invasion, protect the tumor from host immunity, foster therapeutic resistance, and provide niches for dominant metastases to thrive," as described in Swartz, et al., Cancer Res., 2012, 72, 2473. Although tumors express antigens that should be recognized by T cells, tumor clearance by the immune system is rare because of immune suppression by the microenvironment. Addressing the tumor cells themselves with e.g. chemotherapy has also proven to be insufficient to overcome the protective effects of the microenvironment. New approaches are thus urgently needed for more effective treatment of solid tumors that take into account the role of the microenvironment. SUMMARY OF THE INVENTION [004] In one aspect, the BTK inhibitor is a compound of Formula (I) having the structure: I q NH (I) or a pharmaceutically acceptable salt thereof. [005] In another aspect, the BTK inhibitor is a compound of Formula (II) having the structure: q NH (II) or a pharmaceutically acceptable salt thereof. [006] In yet another aspect, the invention relates to the use of the compound of Formula (I) or 2 (II) in the treatment of a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder. BRIEF DESCRIPTION OF THE DRAWINGS [007] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. FIG. 1 illustrates 1H-13C two/three-bond correlation NMR spectrum of the compound of Formula (I). FIG. 2 illustrates the activities of the compound of Formula (I) with variation of pre-incubation time (0, 30, or 60 min) and ATP concentration (5, 25, or 100 μM) in the BTK IMAP assay. FIG. 3 illustrates the apparent IC50 of the compound of Formula (I) over time on BTK wild type (BTK-WT) and the BTK mutant Cys481Ser (BTK-C481S) using the LanthaScreen assay. FIG. 4 illustrates the dose response of the compound of Formula (I) on BTK target occupancy in Ramos B cells. FIG. 5 illustrates the primary metabolic routes of acalabrutinib. FIG. 6 illustrates the major oxidation metabolic pathway to M27 from acalabrutinib. FIG. 7 illustrates the metabolic pathways to M23 from acalabrutinib. FIG. 8A and FIG. 8B together illustrate the biotransformation pathways of acalabrutinib in human. FIG. 9 illustrates acalabrutinib and M27 are covalent inhibitors of BTK. The left figure shows increase in potency over time for BTK-WT due to covalent binding over time. The right figure shows reversible binding (affinity) of compounds to BTK-C481S and does not change over time. Difference in potency between BTK-WT and BTK-C481 S shows effect of covalent binding. FIG. 10 illustrates BTK target occupancy (BTK TO) of acalabrutinib and M27 in Ramos cells. FIG. 11 illustrates KINOMEscan profiling at a single dose (1 μM) of M27 (DiscoveRx scanMAX). FIG. 12 illustrates the metabolic pathways to the compound of Formula (II) from Formula (III). 3 WO 2018/116259 PCT/IB2017 /058319 DETAILED DESCRIPTION OF THE INVENTION [008] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. [009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties. [0010] Th