US2019300490A1PendingUtilityA1

Saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds and pharmaceutical use thereof

Assignee: JAPAN TOBACCO INCPriority: Feb 28, 2018Filed: Feb 27, 2019Published: Oct 3, 2019
Est. expiryFeb 28, 2038(~11.6 yrs left)· nominal 20-yr term from priority
C07D 239/80C07D 491/052C07D 498/04C07D 239/70C07D 487/04C07D 491/048C07D 239/82A61P 9/12A61P 37/00A61K 31/53A61K 31/517C07D 253/06A61P 35/00A61P 37/08A61P 9/10A61P 1/02A61P 27/02A61K 31/519Y02A50/30
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Claims

Abstract

wherein each substituent is defined as defined in the description.

Claims

exact text as granted — not AI-modified
1 : A compound of Formula [I]: 
       
         
           
           
               
               
           
         
         wherein R 1  is 
         (1) C 1-8  alkyl, 
         (2) halo-C 1-8  alkyl, 
         (3) C 3-8  cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 , or 
         (4) C 3-8  cycloalkyl-C-4 alkyl wherein the C 3-8  cycloalkyl moiety may be optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 ,
 Group A 1  is 
 
         (1) halogen, 
         (2) C 1-4  alkyl, or 
         (3) halo-C 1-4  alkyl,
 X 1  is 
 
         (1) a bond, or 
         (2) —O—,
 R 2  is 
 
         (1) hydrogen, or 
         (2) halogen,
 R 3  is 
 
         (1) hydrogen, or 
         (2) —Y 3 —COO—R 30 ,
 Y 3  is 
 
         (1) C 1-8  alkylene, 
         (2) C 5-8  cycloalkylene, 
         (3) bridged C 5-8  cycloalkylene, or 
         (4) C 6-14  arylene,
 R 30  is 
 
         (1) hydrogen, or 
         (2) C 1-4  alkyl,
 X 2  is 
 
         (1) ═C(R 4 )—, or 
         (2) ═N—,
 R 4  is 
 
         (1) hydrogen, or 
         (2) C 1-4  alkyl,
 X 3  is 
 
         (1) —C(R 5 )(R 6 )—,
 X 4  is 
 
         (1) a bond, or 
         (2) —C(R 7 )(R 8 )—,
 X 5  is 
 
         (1) —C(R 9 )(R 10 )— 
         (2) —N(R 11 )—, or 
         (3) —O—,
 R 5  and R 6  are each independently 
 
         (1) hydrogen, 
         (2) C 1-4  alkyl, 
         (3) halo-C 1-4  alkyl, 
         (4) cyano-C 1-4  alkyl, or 
         (5) C 1-4  alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 )(R 72 ), —CO—N(R 73 )(R 74 ), —N(R 75 )—CO—R 62 , —N(R 76 )—COO—R 53 , and —O—S(O) 2 —R 63 ,
 R 7 , R 8 , R 9  and R 10  are each independently 
 
         (1) hydrogen, 
         (2) halogen, 
         (3) cyano, 
         (4) hydroxy, 
         (5) C 1-4  alkyl, 
         (6) halo-C 1-4  alkyl, 
         (7) cyano-C 1-4  alkyl, 
         (8) C 1-4  alkoxy, or 
         (9) C 1-4  alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 )(R 72 ), —CO—N(R 73 )(R 74 ), —N(R 75 )—CO—R 62 , —N(R 76 )—COO—R 53 , and —O—S(O) 2 —R 3 ,
 R 51 , R 52 , and R 53  are each independently 
 
         (1) hydrogen, 
         (2) C 1-4  alkyl, or 
         (3) C 6-14  aryl-C 1-4  alkyl,
 R 61 , R 62 , and R 63  are each independently 
 
         (1) C 1-4  alkyl,
 R 71 , R 72 , R 73 , R 74 , R 75 , and R 76  are each independently 
 
         (1) hydrogen, or 
         (2) C 1-4  alkyl,
 R 11  is 
 
         (1) —CO—R 111 , or 
         (2) —COO—R 112 ,
 R 111  is 
 
         (1) C 1-4  alkyl, and
 R 112  is 
 
         (1) C 1 -4 alkyl, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 : The compound according to  claim 1 , having a structure of Formula [II]: 
       
         
           
           
               
               
           
         
         wherein each variable is defined as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 : The compound according to  claim 1 , wherein X 2  is ═N—, or a pharmaceutically acceptable salt thereof. 
     
     
         4 : The compound according to  claim 1 , wherein X 2  is —C(R 4 )— and R 4  is hydrogen, or a pharmaceutically acceptable salt thereof. 
     
     
         5 : The compound according to  claim 1 , wherein R 3  is hydrogen, or a pharmaceutically acceptable salt thereof. 
     
     
         6 : The compound according to  claim 1 , wherein R 3  is —Y 3 —COO—R 3 ,
 Y 3  is 
 
       (1) C 1-8  alkylene, 
       (2) Cm cycloalkylene, or 
       (3) bridged C 5-8  cycloalkylene, and
 R 30  is hydrogen or C 1-4  alkyl, or a pharmaceutically acceptable salt thereof. 
 
     
     
         7 : The compound according to  claim 1 , wherein R 2  is halogen, or a pharmaceutically acceptable salt thereof. 
     
     
         8 : The compound according to  claim 1 , wherein R 1  is C 1-8  alkyl and X 1  is a bond, or a pharmaceutically acceptable salt thereof. 
     
     
         9 : The compound according to  claim 1 , wherein R 5  and R 6  are each independently hydrogen or C 1-4  alkyl, or a pharmaceutically acceptable salt thereof. 
     
     
         10 : The compound according to  claim 1 , wherein X 4  is a bond or —C(R 7 )(R 8 )— and both of R 7  and R 8  are hydrogen, or a pharmaceutically acceptable salt thereof. 
     
     
         11 : The compound according to  claim 1 , wherein X 5  is —C(R 9 )(R 10 )— or —O— and both of R 9  and R 10  are hydrogen, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . (canceled) 
     
     
         13 : A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         14 : An RORγ antagonist comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         15 . (canceled) 
     
     
         16 : A method of antagonizing RORγ, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a mammal. 
     
     
         17 : A method of treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a mammal. 
     
     
         18 - 21 . (canceled) 
     
     
         22 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         37 : The compound according to  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.

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