Inhibitors of ror gamma

Abstract

The present disclosure relates to salts and crystalline forms of a compound having the formula: Also described are processes for the production of the salts and crystalline forms described herein.

1 . A mono-hydrogen bromide salt having the formula: 
       
         
           
           
               
               
           
         
         wherein the mono-hydrogen bromide salt has a purity of >95%. 
       
     
     
         2 . A bis-hydrogen bromide salt having the formula: 
       
         
           
           
               
               
           
         
         wherein the bis-hydrogen bromide salt has a purity of >95%. 
       
     
     
         3 . The bis-hydrogen bromide salt of  claim 2 , wherein the bis-hydrogen bromide salt is crystalline and the crystalline form is crystalline Form A, C, or E. 
     
     
         4 . The crystalline Form A of  claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. 
     
     
         5 . The crystalline Form A of  claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. 
     
     
         6 . The crystalline Form A of  claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. 
     
     
         7 . The crystalline Form A of  claim 3 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. 
     
     
         8 . The crystalline Form C of  claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46°. 
     
     
         9 . The crystalline Form C of  claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46. 
     
     
         10 . The crystalline Form C of  claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46. 
     
     
         11 . The crystalline Form C of  claim 3 , wherein the crystalline form is characterized by at x-ray powder diffraction peaks at 2Θ angles at 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46. 
     
     
         12 .- 15 . (canceled) 
     
     
         16 . The crystalline Form E of  claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. 
     
     
         17 . The crystalline Form E of  claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. 
     
     
         18 . The crystalline Form E of  claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. 
     
     
         19 . The crystalline Form E of  claim 3 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. 
     
     
         20 . The crystalline Form A, C, or E of  claim 3 , wherein the crystalline form is a solvate. 
     
     
         21 . The crystalline Form A, C, or E of  claim 3 , wherein the crystalline form is a hydrate. 
     
     
         22 . The mono-hydrogen bromide salt of  claim 1 , wherein the mono-hydrogen bromide salt is crystalline and the crystalline form is crystalline Form B. 
     
     
         23 . The crystalline Form B of  claim 22 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. 
     
     
         24 . The crystalline Form B of  claim 22 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. 
     
     
         25 . The crystalline Form B of  claim 22 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. 
     
     
         26 . The crystalline Form B of  claim 22 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. 
     
     
         27 . The crystalline Form B of  claim 22 , wherein the crystalline form is an isopropanol solvate. 
     
     
         28 . A pharmaceutical composition comprising the hydrogen bromide salt of  claim 2 ; and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of treating a disease or disorder associated with the expression of RORγ in a subject, comprising administering to the subject the hydrogen bromide salt of  claim 2 . 
     
     
         30 . The method of  claim 29 , wherein the disease or disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adipose tissue-associated inflammation, insulin resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular degeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease, scleritis, major depression, seasonal affective disorder, PTSD, bipolar disorder, autism, epilepsy, Alzheimer's, CNS disorders associated with altered sleep and/or circadian rhythms, endometriosis, obstructive sleep apnea syndrome (OSAS), Behcet's disease, dermatomyositis, polymyocitis, graft versus host disease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), sarcoidosis, primary sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis, myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, and cancer. 
     
     
         31 . The method of  claim 30 , wherein the disease or disorder is selected from asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, and rheumatoid arthritis. 
     
     
         32 . A method of forming a mono-hydrogen bromide salt of Compound 1, comprising the steps of
 i) reductively aminating an aldehyde compound represented by the following structural formula:   
       
         
           
           
               
               
           
         
       
       with an amine compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein the reductive amination is carried out in the presence of an imine reducing agent to form Compound 1: 
       
         
           
           
               
               
           
         
         ii) adding after the formation of Compound 1, sufficient hydrobromic acid to form the mono-hydrogen bromide salt of Compound 1 having the formula: 
       
       
         
           
           
               
               
           
         
       
       and
 iii) isolating the mono-hydrogen bromide salt of Compound 1. 
 
     
     
         33 . The method of  claim 32 , wherein in step ii) Compound 1 is dissolved in a mixture of isopropanol and acetic acid prior to the addition of hydrobromic acid. 
     
     
         34 . The method of  claim 32 , wherein in step ii) the mono-hydrogen bromide salt of Compound 1 is precipitated via the addition of the hydrobromic acid. 
     
     
         35 . The method of  claim 32 , wherein the amine compound is formed in situ from treating an acid salt form of the amine with a tertiary amine base. 
     
     
         36 . The method of  claim 32 , wherein the amine is formed in situ from treating a di-hydrochloric acid salt form of the amine with diisopropylethylamine. 
     
     
         37 .- 38 . (canceled) 
     
     
         39 . The method of  claim 32 , wherein said sufficient amount of hydrobromic acid comprises 1 to 2 weight equivalents of 35% to 55% hydrobromic acid or 35% to 55% hydrogen bromide in acetic acid. 
     
     
         40 . The method of  claim 32 , wherein the imine reducing agent is sodium triacetoxyborohydride. 
     
     
         41 . (canceled) 
     
     
         42 . A pharmaceutical composition comprising the hydrogen bromide salt of  claim 1 ; and a pharmaceutically acceptable carrier. 
     
     
         43 . A method of treating a disease or disorder associated with the expression of RORγ in a subject, comprising administering to the subject the hydrogen bromide salt of  claim 1 .