Crystalline forms of irak degraders

Abstract

The present disclosure relates generally to various forms, salts and compositions of compounds useful for the modulation of one or more interleukin-1 receptor-associated kinases (“IRAK”) via ubiquitination and/or degradation and uses of the same in the treatment various diseases.

1 - 58 . (canceled) 
     
     
         59 . A method of treating an inflammatory disorder in a patient, comprising administering to said patent a crystalline solid form of compound 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutical composition thereof, wherein the crystalline solid form is selected from the group consisting of Form A of compound 1 and Form B of compound 1; and wherein: 
         Form A of compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta; and 
         Form B of compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. 
       
     
     
         60 . The method according to  claim 59 , wherein said crystalline solid form is Form A of compound 1 having at least about 95% by weight of Form A of compound 1. 
     
     
         61 . The method according to  claim 59 , wherein the crystalline solid form is Form A of compound 1. 
     
     
         62 . The method according to  claim 61 , having four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. 
     
     
         63 . The method according to  claim 59 , wherein said crystalline solid form is Form B of compound 1 having at least about 95% by weight of Form B of compound 1. 
     
     
         64 . The method according to  claim 59 , wherein the crystalline solid form is Form B of compound 1. 
     
     
         65 . The method according to  claim 64 , having four or more peaks in its X-ray powder diffraction pattern selected from those at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. 
     
     
         66 . The method according to  claim 59 , wherein the inflammatory disorder is selected from the group consisting of ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, anterior uveitis, posterior uveitis, Sjogren's syndrome, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, silica induced diseases, COPD, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation, systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, Type 2 diabetes, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,  Pemphigus vulgaris, Pemphigus foliaceus , paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute gout, chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis. 
     
     
         67 . A method of treating an inflammatory disorder in a patient, comprising administering to said patent a crystalline solid form of compound 1: 
       
         
           
           
               
               
           
         
       
       selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutical composition thereof, wherein:
 the crystalline salt form of compound 2 is Form A of compound 2; 
 the crystalline salt form of compound 3 is Form A of compound 3; 
 the crystalline salt form of compound 4 is Form A of compound 4; and 
 
       wherein:
 Form A of compound 2 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees 2-theta; 
 Form A of compound 3 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta; and 
 Form A of compound 4 is characterized by three peaks in its X-ray powder diffraction pattern at about 3.3, about 6.4, and about 16.7 degrees 2-theta. 
 
     
     
         68 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 2 having at least about 95% by weight of Form A of compound 2. 
     
     
         69 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 2 having at least about 99% by weight of Form A of compound 2. 
     
     
         70 . The method according to  claim 67 , wherein said crystalline salt form is Form A of Compound 2. 
     
     
         71 . The method according to  claim 70 , having four or more peaks in its X-ray powder diffraction pattern selected from those at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees 2-theta. 
     
     
         72 . The method according to  claim 70 , having the XRPD pattern as depicted in  FIG.  3 A  wherein each peak is within +/−0.2 degrees 2-theta. 
     
     
         73 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 3 having at least about 95% by weight of Form A of compound 3. 
     
     
         73 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 3 having at least about 99% by weight of Form A of compound 3. 
     
     
         74 . The method according to  claim 67 , wherein said crystalline salt form is Form A of Compound 3. 
     
     
         75 . The method according to  claim 74 , having four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.9, about 16.2, about 17.2, and about degrees 2-theta. 
     
     
         76 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 4 having at least about 95% by weight of Form A of compound 4. 
     
     
         77 . The method according to  claim 67 , wherein said crystalline salt form is Form A of compound 4 having at least about 99% by weight of Form A of compound 4. 
     
     
         78 . The method according to  claim 67 , wherein said crystalline salt form is Form A of Compound 4. 
     
     
         79 . The method according to  claim 67 , wherein the inflammatory disorder is selected from the group consisting of ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, anterior uveitis, posterior uveitis, Sjogren's syndrome, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, silica induced diseases, COPD, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation, systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, Type 2 diabetes, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,  Pemphigus vulgaris, Pemphigus foliaceus , paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute gout, chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.