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CA-2989651-C - PYRIMIDINE DERIVATIVES AS BTK INHIBITORS AND USES THEREOF

CA2989651CCA 2989651 CCA2989651 CCA 2989651CCA-2989651-C

Abstract

The present invention relates to pyrimidine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.

Inventors

  • Hui Qiu
  • Richard D. Caldwell
  • Lesley Liu-Bujalski

Assignees

  • MERCK PATENT GMBH

Dates

Publication Date
20260505
Application Date
20160708
Priority Date
20150709

Claims (20)

  1. 71 CLAIMS We claim: 1. A compound of formula I-b, N N F NH N R1 R2 O O I-b or a pharmaceutically acceptable salt thereof, wherein: R1 is: (a) N O R5 ; (b) cyclopentyl or cyclohexyl; or (c) or ; R2 is hydrogen; or R1 and R2 taken together with the atom to which they are attached, form a ring selected from N N HN O R5 NH O R5 N N HN O R5 NH R5 O 72 or ; and wherein, each R5 is independently: or . .
  2. 2. The compound according to claim 1, of formula I-a, I-a; or a pharmaceutically acceptable salt thereof; wherein R is -(CH2)2OCH3; and wherein the ring formed by N, R1, and R2, is: 73 N N N N O R5 N N O R5 N N O R5 N R5 O N O R5 or .
  3. 3. A compound, wherein the compound is: 1 2 3 - rac 74 5 - rac 7 – rac 8 – rac 9 75 10 11 12 13 14 76 15 16 – rac 17 - rac 18 77 21 22 23 24 – diast 1 78 25 – diast 2 26 - rac 27 – rac 29 – rac 30, or 79 31, or a pharmaceutically acceptable salt thereof.
  4. 4. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 3 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
  5. 5. An in vitro or ex vivo method for inhibiting BTK, or a mutant thereof, activity in a biological sample, comprising the step of contacting said biological sample with the compound as defined in any one of claims 1 to 3, or the physiologically acceptable salt thereof.
  6. 6. Use of the compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for inhibition of BTK, or a mutant thereof, activity in a patient.
  7. 7. Use of the compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for treatment of a BTK-mediated disorder.
  8. 8. The use of claim 7, wherein the disorder is inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), 80 autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosis fungoides, an acute inflammatory response, or Graves' disease, or any combination thereof.
  9. 9. The use according to claim 8, wherein the acute inflammatory response is an acute respiratory distress syndrome or an ischemia/reperfusion injury.
  10. 10. Use of the compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for treatment of lupus.
  11. 11. A compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for use in inhibition of BTK, or a mutant thereof, activity in a patient.
  12. 12. A compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for use in treatment of a BTK-mediated disorder.
  13. 13. The compound for use according to claim 12, wherein the disorder is inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, 81 Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosis fungoides, an acute inflammatory response, or Graves' disease, or any combination thereof.
  14. 14. The compound for use according to claim 13, wherein the acute inflammatory response is an acute respiratory distress syndrome or an ischemia/reperfusion injury.
  15. 15. A compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for use in treatment of lupus.
  16. 16. A process for manufacturing a compound of formula I-b as defined in claim 1, comprising the steps of: reacting a compound of formula (A): A; with NH(R1)(R2); wherein R1 and R2 are as defined in claim 1; to provide a compound of formula (B): B; and reacting the compound of formula (B) with 82 ; to provide a compound of formula I-b: ; wherein R1 and R2 are as defined in claim 1.
  17. 17. Use of the compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting BTK, or a mutant thereof, activity in a subject.
  18. 18. Use of the compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a BTK-mediated disorder.
  19. 19. The use of claim 18, wherein the disorder is inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, 83 Behcet's disease, scleraderma, mycosis fungoides, an acute inflammatory response, or Graves' disease, or any combination thereof.
  20. 20. The use according to claim 19, wherein the acute inflammatory response is an acute respiratory distress syndrome or an ischemia/reperfusion injury.

Description

1 PYRIMIDINE DERIVATIVES AS BTK INHIBITORS AND USES THEREOF RELATED APPLICATION [0001] The present application claims priority to U.S. Provisional Application 62/190,350, filed on July 9, 2015. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to pyrimidine compounds that are useful as inhibitors of Bruton’s Tyrosine Kinase (BTK). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION [0003] Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically, tyrosine kinases phosphorylate proteins on the phenolic moiety of tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in a variety of human diseases including cancers, autoimmune and inflammatory diseases. Since protein kinases are among the key regulators of cell signaling, they provide a target to modulate cellular function with small molecular kinase inhibitors and thus make good drug targets. In addition to treatment of kinasemediated disease processes, selective and efficacious inhibitors of kinase activity are also useful for investigation of cell signaling processes and identification of other cellular targets of therapeutic interest. [0004] There is good evidence that B-cells play a key role in the pathogenesis of autoimmune and/or inflammatory disease. Protein-based therapeutics that deplete B cells such as Rituxan™ are effective against autoantibody-driven inflammatory diseases such as rheumatoid arthritis (Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of the protein kinases that play a role in B-cell activation should be useful therapeutics for B-cell mediated disease pathology, such as autoantibody production. 2 [0005] Signaling through the B-cell receptor (BCR) controls a range of B-cell responses including proliferation and differentiation into mature antibody producing cells. The BCR is a key regulatory point for B-cell activity and aberrant signaling can cause deregulated B-cell proliferation and formation of pathogenic autoantibodies that lead to multiple autoimmune and/or inflammatory diseases. Bruton's Tyrosine Kinase (BTK) is a non-BCR associated kinase that is membrane proximal and immediately downstream from BCR. Lack of BTK has been shown to block BCR signaling and therefore inhibition of BTK could be a useful therapeutic approach to block B-cell mediated disease processes. Also, BTK has been reported to play a role in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49,) and thus BTK inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias (Feldhahn et al. J. Exp. Med. 2005 201:1837). [0006] BTK is a member of the Tec family of tyrosine kinases, and has been shown to be a critical regulator of early B-cell development and mature B-cell activation and survival (Khan et al. Immunity 1995 3:283; Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of BTK in humans leads to the condition X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol. Rev. 2005 203:200). These patients are immunocompromised and show impaired maturation of B-cells, decreased immunoglobulin and peripheral B-cell levels, diminished T-cell independent immune responses as well as attenuated calcium mobilization following BCR stimulation. [0007] Evidence for a role for BTK in autoimmune and inflammatory diseases has also been provided by BTK-deficient mouse models. In preclinical murine models of systemic lupus erythematosus (SLE), BTK-deficient mice show marked amelioration of disease progression. In addition, BTK-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). A selective BTK inhibitor has demonstrated dose-dependent efficacy in a mouse arthritis model (Z. Pan et al., Chem. Med Chem. 2007 2:58-61). [0008] BTK is also expressed by cells other than B-cells that may be involved in disease processes. BTK is key component of Fc-gamma signaling in myeloid cells. For example, BTK is expressed by mast cells and BTK-deficient bone marrow derived mast cells demonstrate impaired antigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280:40261). This shows BTK could be useful to treat pathological mast cells responses such as allergy and asthma. Also monocytes from XLA patients, in which BTK activity is absent, show decreased TNF alpha 3 production following stimulation (Horwood et al. J Exp Med 197:1603, 2003). Therefore TNF alpha mediated inflammation could be modulated by small molecular BTK inhibitors. SUMMARY OF THE INVENTION [0009] It has now been fou