Pyrazole compounds as modulators of fshr and uses thereof

Abstract

The present invention relates to pyrazole compounds, and pharmaceutically acceptable compositions thereof, useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR).

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is O, S, SO, SO 2 , or NR; 
         Y is O, S, or NR; 
         Z is O, S, SO, SO 2 , or N; wherein when Z is O, S, SO, or SO 2 , then p is 0; 
         each R is independently hydrogen, C 1-6  aliphatic, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form an aryl ring, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         Ring A is a fused aryl, a fused 3-8 membered saturated or partially unsaturated carbocyclic ring, a fused 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a fused 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 1  is —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 2  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 3  is an optionally substituted aryl; 
         each R 4  is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 5  is C 1-6  aliphatic, —SO 2 R, —SOR, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         R 6  is hydrogen, C 1-6  aliphatic, —SO 2 R, —SOR, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         or R 5  and R 6 , together with the atom to which each is attached, form a 3-8 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-8 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         n is 0, 1, or 2; and 
         p is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein X is O, Y is O, and Z is N. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein Ring A is phenyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is —OR, and R 2  is aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted. 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 7 , wherein R 2  is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein R 3  is an optionally substituted phenyl. 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein R 5  is optionally substituted C 1_6  aliphatic. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein Z is N and R 5 , R 6 , and Z together with the atoms to which each is attached form an optionally substituted 3-8 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein R 6  is optionally substituted C 1-6  aliphatic or —SO 2 R. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . A compound of formula II, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is O, S, SO, SO 2 , or NR; 
         Y is O, S, or NR; 
         Z is O, S, SO, SO 2 , or N; wherein when Z is O, S, SO, or SO 2 , then p is 0; 
         each R is independently hydrogen, C 1-6  aliphatic, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form an aryl ring, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         Ring A is a fused aryl, a fused 3-8 membered saturated or partially unsaturated carbocyclic ring, a fused 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a fused 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 1  is —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 2  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 3  is an optionally substituted 5-6 membered monocyclic heteroaryl ring; 
         each R 4  is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         R 5  is C 1-6  aliphatic, —SO 2 R, —SOR, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         R 6  is hydrogen, C 1-6  aliphatic, SO 2 R, —SOR, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         or R 5  and R 6 , together with the atom to which each is attached, form a 3-8 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-8 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         n is 0, 1, or 2; and 
         p is 0 or 1. 
       
     
     
         20 . The compound of  claim 19 , wherein X is O, Y is O, and Z is N. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The compound of  claim 19 , wherein Ring A is phenyl and R 1  is —OR, and R 2  is —OR, C 1-6  aliphatic, aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The compound of  claim 19 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 19 , wherein R 3  is thiophenyl or pyridyl. 
     
     
         28 - 35 . (canceled) 
     
     
         36 . The compound of  claim 1 , selected from Table 1. 
     
     
         37 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         38 . A method for modulating FSHR, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of  claim 1  or a physiologically acceptable salt thereof. 
     
     
         39 . A method for treating a FSHR-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of  claim 1 . 
     
     
         40 . A method for treating fertility disorders in a subject, comprising the step of administering to said subject a compound of  claim 1 , or a physiologically acceptable salt thereof. 
     
     
         41 . (canceled) 
     
     
         42 . A process for manufacturing a compound of formula I according to  claim 1 , comprising the steps of:
 reacting a compound of formula (III)   
       
         
           
           
               
               
           
         
         wherein X, Y, R 1 , R 3 , R 4 , and n are as defined in  claim 1 , and LG is a leaving group; 
         with a compound of formula ZH(R 5 )(R 6 ) p    
         wherein Z, R 5 , R 6 , and p are as defined in  claim 1 ; 
         to yield a compound of formula I or formula II: 
       
       
         
           
           
               
               
           
         
         wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p, are as defined in  claim 1 .