Boron Containing PDE4 Inhibitors

Abstract

The present invention relates to boron containing compounds of Formula (I)X—Y—Z   Formula (I)that inhibit phosphodiesterase 4 (PDE4). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating diseases, conditions, or disorders ameliorated by inhibition of PDE4.

What is claimed is: 
     
         1 . A method for treating or preventing an inflammatory disease in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of Formula (IA) or Formula (IB): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein:
 B is boron; 
 A 1  and A 2  are each independently O or S; 
 R 1 , R 2 , and R 5  are each independently H, deuterium, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkenylthio, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-d 1-13 , (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-d 1-13 , (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkynyl, (C 2 -C 6 )alkynyloxy, (C 2 -C 6 )alkynylthio, aryl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkylthio, aryloxy, arylthio, carboxy, carboxy(C 1 -C 6 )alkoxy, carboxy(C 1 -C 6 )alkyl, cyano, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 8 )cycloalkyl(C 1 -C 6 ) alkylthio, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 8 )cycloalkylthio, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkylthio, (5-6 membered)heteroaryl, (5-6 membered)heteroaryl(C 1 -C 6 )alkoxy, (5-6 membered)heteroaryl(C 1 -C 6 )alkyl, (5-6 membered)heteroaryl(C 1 -C 6 )alkylthio, (5-6 membered)heteroaryloxy, (5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing at least one heteroatom independently selected from the group consisting of O, N, and S, (4-7 membered)heterocycle(C 1 -C 6 )alkoxy, (4-7 membered)heterocycle(C 1 -C 6 )alkyl, (4-7 membered)heterocycle(C 1 -C 6 )alkylthio, (4-7 membered)heterocycleoxy, (4-7 membered)heterocyclethio, hydroxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, thio(C 1 -C 6 )alkyl, —NR A R B , NR A R B (C 1 -C 6 )alkoxy, NR A R B (C 1 -C 6 )alkyl, or (NR A R B )carbonyl; 
 R A  and R B  are each independently H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 )alkylcarbonyl; 
 R 3  and R 4  are each independently H, D, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl-d 1-7 , (C 1 -C 6 )alkyl-d 1-13 , (C 3 -C 8 )cycloalkyl, halo(C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl; 
 R 6 , R 7 , and R 9  are each independently H, D, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-d 1-13 , (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylthio, carboxy, carboxy(C 1 -C 6 )alkoxy, carboxy(C 1 -C 6 )alkyl, cyano, halogen, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, mercapto, nitro, —NR C R D , NR C R D (C 1 -C 6 )alkoxy, NR C R D (C 1 -C 6 )alkyl, or (NR C R D )carbonyl; 
 R 10  is D, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl-d 1-7 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-d 1-13 , (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, or thio(C 1 -C 6 )alkyl; 
 R C  and R D  are each independently H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 )alkylcarbonyl; and 
 p is 0, 1, 2, 3, 4, or 5. 
 
 
     
     
         2 . The method of  claim 1 , wherein A 1  and A 2  are each independently O. 
     
     
         3 . The method of  claim 1 , wherein R 1 , R 2 , and R 5  are each independently H. 
     
     
         4 . The method of  claim 1 , wherein R 3  and R 4  are each independently (C 1 -C 3 )alkyl. 
     
     
         5 . The method of  claim 1 , wherein R 6 , R 7 , and R 9  are each independently H. 
     
     
         6 . The method of  claim 1 , wherein p is 0. 
     
     
         7 . The method of  claim 1 , wherein the compound is of Formula (IA) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method of  claim 7 , wherein:
 A 1  is O;   A 2  is O;   R 1  is H, cyano, halogen, or halo(C 1 -C 6 )alkyl;   R 2  is H, cyano, halogen, or halo(C 1 -C 6 )alkyl;   R 3  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl;   R 4  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl;   R 5  is H, cyano, halogen, or halo(C 1 -C 6 )alkyl;   R 6  is H, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 ) alkyl, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or hydroxy(C 1 -C 6 )alkoxy;   R 7  is H, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 ) alkyl, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or hydroxy(C 1 -C 6 )alkoxy;   R 9  is H, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 ) alkyl, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or hydroxy(C 1 -C 6 )alkoxy;   R 10  is (C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; and   p is 0 or 1.   
     
     
         9 . The method of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
 A 1  is —O—;   A 2  is —O—;   R 1  is H;   R 2  is H;   R 3  is (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, or (C 3 -C 8 )cycloalkyl;   R 4  is (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, or (C 3 -C 8 )cycloalkyl;   R 5  is H;   R 6  is H or (C 1 -C 3 )alkyl;   R 7  is H or (C 1 -C 3 )alkyl;   R 9  is H or (C 1 -C 3 )alkyl;   R 10  is CH 3 ; and   p is 0, 1, or 2.   
     
     
         10 . The method of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
 A 1  is —O—;   A 2  is —O—;   R 1  is H;   R 2  is H;   R 3  is (C 1 -C 3 )alkyl;   R 4  is (C 1 -C 3 )alkyl;   R 5  is H;   R 6  is H or (C 1 -C 3 )alkyl;   R 7  is H or (C 1 -C 3 )alkyl;   R 9  is H or (C 1 -C 3 )alkyl; and   p is 0.   
     
     
         11 . The method of  claim 1 , wherein the compound is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein the compound is (R)-4-(5-(4-methoxy-3-propoxyphenyl) pyridin-3-yl)-1,2-oxaborolan-2-ol, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 1 , wherein the compound is crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl) pyridin-3-yl)-1,2-oxaborolan-2-ol. 
     
     
         14 . The method of  claim 1 , wherein the inflammatory disease is selected from the group consisting of atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, and inverse psoriasis. 
     
     
         15 . The method of  claim 1 , wherein the inflammatory disease is atopic dermatitis. 
     
     
         16 . The method of  claim 1 , wherein the administering is topical. 
     
     
         17 . A method of treating atopic dermatitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 17 , wherein the (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol is crystalline (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol. 
     
     
         20 . The method of  claim 17 , wherein the administering is topical.