Therapeutic compounds and compositions, and methods of use thereof

Abstract

Methods of using compounds and salts thereof as JAK kinase inhibitors are described herein, including methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

What is claimed is: 
     
         1 . A method of preventing, treating or lessening the seventy of cancer, the method comprising administering to a patient in need thereof a compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
 R 1  is hydrogen or CH 3 ; 
 R 2  is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R a  is C 1 -C 6 alkyl, -phenyl-COR b R c , -phenyl-(3-6-membered heterocyclyl), or 3-11-membered heterocyclyl, wherein R a  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R b  and R are each independently hydrogen or CH 3 ; 
 R 3  is hydrogen or NH 2 ; 
 R 4  is hydrogen or CH 3 ; and 
 R 5  is hydrogen or NH 2 . 
 
       
     
     
         2 . The method of  claim 1 , wherein the cancer is squamous cell cancer, lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, skin keratoacanthoma, follicular carcinoma, hairy cell leukemia, or cancer of the buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, central nervous system, brain, head and neck, Hodgkin's disease, polycythemia vera, essential thrombocytosis, myelofibrosis, multiple myeloma, B-cell lymphoma, and chronic myelogenous leukemia (CML), or cancer of the buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, central nervous system, brain, head or neck. 
     
     
         3 . A method of preventing, treating or lessening the severity of an inflammatory disease, the method comprising administering to a patient in need thereof a compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
 R 1  is hydrogen or CH 3 ; 
 R 2  is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R a  is C 1 -C 6 alkyl, -phenyl-COR b R c , -phenyl-(3-6-membered heterocyclyl), or 3-11-membered heterocyclyl, wherein R a  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R b  and R c  are each independently hydrogen or CH 3 ; 
 R 3  is hydrogen or NH 2 ; 
 R 4  is hydrogen or CH 3 ; and 
 R 5  is hydrogen or NH 2 . 
 
       
     
     
         4 . The method of  claim 3 , wherein the inflammatory disease is allergic rhinitis, allergic airway syndrome, atopic dermatitis, bronchitis, rheumatoid arthritis, psoriasis, contact dermatitis, chronic obstructive pulmonary disease (COPD) or delayed hypersensitivity reaction. 
     
     
         5 . A kit can comprising:
 (a) a first pharmaceutical composition comprising a compound of Formula (I)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
 R 1  is hydrogen or CH 3 ; 
 R 2  is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R a  is C 1 -C 6 alkyl, -phenyl-COR b R c , -phenyl-(3-6-membered heterocyclyl), or 3-11-membered heterocyclyl, wherein R a  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R b  and R c  are each independently hydrogen or CH 3 ; 
 R 3  is hydrogen or NH 2 ; 
 R 4  is hydrogen or CH 3 ; and 
 R 5  is hydrogen or NH 2 ; 
 
         (b) instructions for use; and 
         (c) a second pharmaceutical composition comprising an agent for treatment of an inflammatory disorder, or a chemotherapeutic agent. 
       
     
     
         6 . A method of making a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 1  is hydrogen or CH 3 ; 
 R 2  is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R a  is C 1 -C 6 alkyl, -phenyl-COR b R c , -phenyl-(3-6-membered heterocyclyl), or 3-11-membered heterocyclyl, wherein R a  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R b  and R are each independently hydrogen or CH 3 ; 
 R 3  is hydrogen or NH 2 ; 
 R 4  is hydrogen or CH 3 ; and 
 R 5  is hydrogen or NH 2 ; 
 
         the method comprising reacting a compound of formula (i) 
       
       
         
           
           
               
               
           
         
         with 
       
       
         
           
           
               
               
           
         
       
       in the presence of cesium carbonate, to form the compound of formula (I).