Chemical compounds

Abstract

The present invention describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the invention have activity as Janus kinase (JAK) inhibitors and are useful in the in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.

1 . A compound of formula (I) or (II): 
       
         
           
           
               
               
           
         
         wherein: 
         each X independently is selected from the group consisting of O and NR a ; 
         each Z independently is selected from the group consisting of hydrogen, fluorine, and CH 3 ; 
         each Y independently is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, and (CH 2 ) 3 OH, or Y and the oxygen atom depicted as OH together form a 6 to 8 membered ring; 
         each R a  is independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 15  alkyl, substituted or unsubstituted C 2-15  alkenyl, substituted or unsubstituted C 2-15  alkynyl, substituted or unsubstituted C 3-15  cycloalkyl, and substituted or unsubstituted aryl; 
         A is
 (i) hydrogen, or 
 (ii) when X is NR a , A may be absent and R a  and is taken together with the depicted oxygen to form a substituted or unsubstituted 6 to 8 membered ring; and 
 
         each R 1  independently is selected from the group consisting of unsubstituted or substituted:
 (i) C 1 -C 15  alkyl, 
 (ii) C 2-15  alkenyl, 
 (iii) C 2-15  alkynyl, 
 (iv) C 1 -C 15  alkyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized, 
 (v) C 2-15  alkenyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized, 
 (vi) C 2-15  alkynyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized, 
 (vii) C 3-15  cycloalkyl, 
 (viii) heterocyclyl, 
 (ix) aryl, and 
 (x) heteroaryl, 
 
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of formula (I). 
     
     
         3 . The compound of  claim 1 , wherein the compound is a compound of formula (II). 
     
     
         4 . The compound of  claim 1 , wherein Y is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein X is O. 
     
     
         6 . The compound of  claim 1 , wherein X is NR a , and R a  is hydrogen or C 1-8  alkyl. 
     
     
         7 . The compound of  claim 1 , wherein the compound is a compound of formula (I), A is hydrogen, X is NR a , and R a  is selected from the group consisting of: hydrogen, C 1 -C 6  alkyl, and C 3-6  cycloalkyl. 
     
     
         8 . The compound of  claim 1 , wherein Z is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein the compound is a compound of formula (I), X is NR a , A is absent, and R a  is taken together with the depicted oxygen to form a 6-membered ring. 
     
     
         10 . The compound of  claim 9 , wherein the compound is selected from the group consisting of formulae (Ia), (Ib), (Ic), and (Id): 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein R 1  is unsubstituted or substituted C 3-15  cycloalkyl. 
     
     
         12 . The compound of  claim 11 , wherein R 1  individually is unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, or adamantyl. 
     
     
         13 . The compound of  claim 12 , wherein the compound is of formula (I), R 1  is substituted adamantyl, and R a  is substituted alkyl. 
     
     
         14 . The compound of  claim 1 , wherein R 1  is unsubstituted or substituted heterocyclyl. 
     
     
         15 - 21 . (canceled) 
     
     
         22 . The compound of  claim 1 , wherein R 1  is substituted with NHS(O) 2 (C 1 -C 6  alkyl), NHS(O) 2 (C 1 -C 6  partially or fully fluorinated alkyl), NHS(O) 2 (C 1 -C 6  cycloalkyl), NHS(O) 2 (C 1 -C 6  partially or fully fluorinated cycloalkyl), OH, CH 2 S(O) 2 NH(C 1 -C 6  alkyl), CH 2 S(O) 2 NH(C 1 -C 6  partially or fully fluorinated alkyl), CH 2 S(O) 2 N(C 1 -C 6  alkyl) 2 , CH 2 S(O) 2 N(C 1 -C 6  partially fluorinated alkyl) 2 , N(C 1 -C 6  alkyl) 2 , or N(C 1 -C 6  partially fluorinated alkyl) 2 . 
     
     
         23 . The compound of  claim 1 , wherein R 1  is substituted with NHSO 2 R′, wherein R′ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. 
     
     
         24 . The compound of  claim 23 , wherein R′ is C 1-8  alkyl, C 2-8  alkenyl, or C 2-8  alkynyl. 
     
     
         25 . The compound of  claim 13 , wherein each of R 1  and R a  is substituted with OH. 
     
     
         26  - 28 . (canceled) 
     
     
         29 . The compound of  claim 3 , wherein R 1  is R 1a -L-R 1b , wherein
 R 1a  is independently any R 1  group as defined,   L is a polar linking group, and   R 1b  is independently any R 1  group as defined.   
     
     
         30 . The compound of  claim 29 , wherein
 (i) R 1a  is C 3-15  cycloalkyl,
 L is —(CH 2 ) p -L 1 -,
 wherein p is 0, 1, or 2, 
 L 1  is selected from the group consisting of —O—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R′)—, —OC(O)N(R′)—, —N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —SO 2 —, —S(O)—, —SO 2 N(R′)—, —N(R′)SO 2 —, and —N(R′)SO 2 (NR′)—; and 
 
 R 1b  is selected from the group consisting of unsubstituted or substituted C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-15  cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; 
   or   (ii) R 1a  is heterocyclyl;
 L is —(CH 2 ) p -L 1 -,
 wherein p is 0, 1, or 2, 
 L 1  is selected from the group consisting of —O—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R′)—, —OC(O)N(R′)—, —N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —SO 2 —, —S(O)—, —SO 2 N(R′)—, —N(R′)SO 2 —, and —N(R′)SO 2 (NR′)—; and 
 
 R 1b  is selected from the group consisting of unsubstituted or substituted C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-15  cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, 
 wherein each R′ individually is as defined. 
   
     
     
         31 . The compound of  claim 30 , wherein L 1  is selected from the group consisting —O—, —C(O)—, —C(O)O—, —CON(R′)—, —NR′C(O)—, —NR′CO 2 —, —S(O) 2 —, —SO 2 N(R′)—, —N(R′)CON(R′)—, and —NR′S(O) 2 —. 
     
     
         32 - 36 . (canceled) 
     
     
         37 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         38 - 42 . (canceled) 
     
     
         43 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         44 . The compound of  claim 43 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         45 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         46 . The compound of  claim 45 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         47 . The compound of  claim 46 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof. 
     
     
         48 - 51 . (canceled) 
     
     
         52 . A method for treating a patient having a disease or disorder susceptible to modulation of JAK comprising
 administering a therapeutically effective amount of a compound of  claim 1 ,   wherein the disease or disorder is one or more of atopic dermatitis, psoriasis, psoriatic arthritis, Bechet's disease, pityriasis rubra pilaris, alopecia areata, discoid lupus erythematosus, vitiligo, palmoplantar pustulosis, mucocutaneous disease erythema multiforme, mycosis fungoides, graft-versus-host disease, cutaneous lupus, rheumatoid arthritis (RA), arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), transplant rejection, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, dry eye disease, secondary hypereosinophilic syndrome (HES), allergy, allergic dermatitis, asthma, vasculitis, multiple sclerosis, diabetic nephropathy, cardiovascular disease, artherosclerosis, and cancer.   
     
     
         53 - 54 . (canceled) 
     
     
         55 . The method according to  claim 52 , wherein the compound is administered in an amount to perturb an immune regulatory pathway in a cell, and wherein the perturbation results in an effect on the JAK-STAT pathway. 
     
     
         56 - 71 . (canceled)