N-methyl-d-aspartate receptor modulators and methods of making and using same

Abstract

Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorders, such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . A compound having formula (II): 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, 
       wherein:
 R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen; halogen; C 1-6 alkyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S, and N(R x ) 2 ; C 1-6  perfluoroalkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; phenyl; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; —OR x ; —C(O)R x ; —CO 2 (R x ); —C(O)N(R x ) 2 ; —C(NR x )N(R) 2 ; —OC(O)R x ; —OCO 2 R x ; —OC(O)N(R) 2 ; —N(R x ) 2 ; —NR x C(O)R x ; —NR x C(O)N(R) 2 ; —NR x C(O)OR x ; and —NR x C(NR x )N(R x ) 2 ; 
 when present, R 15  replaces a hydrogen atom attached to the phenyl ring and, and each occurrence of R 15  is independently selected from the group consisting of hydrogen; halogen; 
 hydroxyl; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl, C 1 -C 6  alkoxy, heteroaryl, heterocyclyl, and phenyl are optionally substituted by one, two, or three substituents independently selected from halogen; hydroxyl; phenyl; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and N(R x ) 2 ; 
 R 16  is selected from the group consisting of hydrogen; halogen; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl; 
 R 17  and R 18  are each independently selected from the group consisting of hydrogen; halogen; hydroxyl; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy; heteroaryl, heterocyclyl, and phenyl are optionally substituted by one, two, or three substituents independently selected from halogen; hydroxyl; phenyl; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and N(R x ) 2 ; provided that R 17  cannot be halogen or hydroxyl when R 17  is D to the pyrrolidine nitrogen, and R 18  cannot be halogen or hydroxyl when R 18  is D to the pyrrolidine nitrogen; or 
 R 17  and R 18 , together with the atoms to which they are attached, form C 3 -C 6  cycloalkyl or heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the C 3 -C 6  cycloalkyl and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; 
 R 9  and R 10  are independently selected, for each occurrence, from the group consisting of hydrogen; C 1 -C 6  alkyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, hydroxyl, phenyl, and heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; C 1-6  perfluoroalkyl; C 2-6 alkenyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, and hydroxyl; C 2-6 alkynyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, and hydroxyl; C 3-6 cycloalkyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6  perfluoroalkyl; halogen, oxo, and hydroxyl; phenyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl; C 1-6  perfluoroalkyl; C 1-6 alkoxy; halogen; hydroxyl; —C(O)R x ; —CO 2 (R x ); —C(O)N(R x ) 2 ; —C(NR x )N(R x ) 2 ; and —C(R x ) 3 ; 
 or R 9  and R 10 , together with the nitrogen atom to which each is attached, form a heterocyclyl including from 3 to 6 ring atoms, which is optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, halogen, oxo, and hydroxyl; wherein when R 9  and R 10  form a heterocyclyl including 6 ring atoms, the heterocyclyl optionally includes, in addition to the nitrogen atom attached to R 9  and R 10 , a second ring heteroatom selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; 
 R x  is independently selected, for each occurrence, from the group consisting of hydrogen; halogen; acyl; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl; and 
 R y  is hydrogen or C 1-3 alkyl. 
 
     
     
         3 . A compound having formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R is —C(R 1 )(R 11 )(R 2 ); 
 R 1  is —C(R 3 )(R 31 )(R 4 ); 
 each of R 1  and R 2  is independently selected from the group consisting of: 
 hydrogen; 
 halogen; 
 C 1-6 alkyl, optionally substituted by one, two or three substituents independently selected from the group consisting of halogen; hydroxyl; C 1-6 alkoxy; phenyl; N(R x ) 2 ; C 3 -C 6  cycloalkyl; 
 heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the phenyl, cycloakyl, heteroaryl, and heterocyclyl are each optionally substituted with one, two, or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 C 1-6  perfluoroalkyl; 
 C 2-6 alkenyl; 
 C 2-6 alkynyl; 
 C 3-6 cycloalkyl optionally substituted by one, two or three independently selected C 1-3 alkyl; 
 phenyl optionally substituted with one, two, or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 —OR x ; 
 —C(O)R x ; 
 —CO 2 (R x ); 
 —C(O)N(R x ) 2 ; 
 —C(NR x )N(R x ) 2 ; 
 —OC(O)R x ; 
 —OCO 2 R x ; 
 —OC(O)N(R x ) 2 ; 
 —N(R x ) 2 ; 
 —NR x C(O)R x ; 
 —NR x C(O)N(R x ) 2 ; 
 —NR x C(O)OR x ; and 
 —NR x C(NR x )N(R x ) 2 ; or 
 R 1  and R 2  together with the carbon atom to which each is attached form a ring selected from the group consisting of (i) phenyl and (ii) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; phenyl, and N(R x ) 2 ; 
 each of R 3  and R 4  is independently selected from the group consisting of: 
 hydrogen; 
 halogen; 
 C 1-6 alkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen; hydroxyl; C 1-6 alkoxy; phenyl; N(R x ) 2 ; C 3 -C 6  cycloalkyl; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the phenyl, cycloakyl, heteroaryl, and heterocyclyl are each optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 C 1-6  perfluoroalkyl; 
 C 2-6 alkenyl; 
 C 2-6 alkynyl; 
 C 3-6 cycloalkyl optionally substituted with one, two or three independently selected C 1-3 alkyl; 
 phenyl optionally substituted with one, two, or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; and N(R x ) 2 ; 
 —OR x ; 
 —C(O)R x ; 
 —CO 2 (R x ); 
 —C(O)N(R x ) 2 ; 
 —C(NR x )N(R x ) 2 ; 
 —OC(O)R x ; 
 —OCO 2 R x ; 
 —OC(O)N(R x ) 2 ; 
 —N(R x ) 2 ; 
 —NR x C(O)R x ; 
 —NR x C(O)N(R x ) 2 ; 
 —NR x C(O)OR x ; and 
 —NR x C(NR x )N(R x ) 2 ; or 
 R 3  and R 4  together with the carbon atom to which each is attached form a ring selected from the group consisting of (i) phenyl and (ii) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; phenyl, and N(R x ) 2 ; 
 each of R 11  and R 31  is, independently, hydrogen, C 1 -C 6  alkyl, or C 1-6  perfluoroalkyl; or 
 R 1  is absent when R 1  and R 2  together form phenyl or heteroaryl; 
 R 31  is absent when R 3  and R 4  together form phenyl or heteroaryl; 
 each of R a , R b , R c , and R d  is independently selected from the group consisting of hydrogen; halogen; hydroxyl; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl, C 1 -C 6  alkoxy, heteroaryl, heterocyclyl, and phenyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; 
 each of R e  and R g  is independently selected from the group consisting of hydrogen; acyl; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl; 
 R f  is selected from the group consisting of hydrogen; halogen; acyl; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl; 
 R h  is hydrogen or C 1-3 alkyl; 
 R 1  is selected from the group consisting of hydrogen; halogen; cyano, CH 3 , and CF 3 ; 
 R 21  is selected from the group consisting of hydrogen; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; C 2 -C 6  acyloxy, heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy, heteroaryl, heterocyclyl, and phenyl are each optionally and independently substituted by one, two or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl, phenyl, and N(R x ) 2 ; 
 each of R 22  and R 23  is independently selected from the group consisting of hydrogen; halogen; hydroxyl; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; C 2 -C 6  acyloxy, heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy, heteroaryl, heterocyclyl, and phenyl are each optionally and independently substituted by one, two or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; phenyl, and N(R x ) 2 ; or 
 R 21  and R 22 , together with the carbon atoms to which each is attached, form a ring selected from the group consisting of (i) 3-6 membered heterocyclyl wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; (ii) C 3 -C 6  cycloalkyl; (iii) phenyl; and (iv) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; wherein each of (i)-(iv) is optionally substituted by one, two, or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; phenyl, and N(R x ) 2 ; and R 23  is as defined above; or 
 R 22  and R 23 , together with the carbon atoms to which each is attached, form a ring selected from the group consisting of (i) 3-6 membered heterocyclyl wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; (ii) C 3 -C 6  cycloalkyl; (iii) phenyl; and (iv) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; wherein each of (i)-(iv) is optionally substituted by one, two, or three substituents that are independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6  alkyl, C 1-6  perfluoroalkyl; phenyl, and N(R x ) 2 ; and R 21  is as defined above; 
 each occurrence of R 9  and R 10  is independently selected from the group consisting of hydrogen; C 1 -C 6  alkyl, optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, oxo, and hydroxyl; C 1-6  perfluoroalkyl; C 2-6 alkenyl, optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, oxo, and hydroxyl; C 2-6 alkynyl, optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, oxo, and hydroxyl; C 3-6 cycloalkyl, optionally substituted by one, two, or three substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6  perfluoroalkyl; halogen, oxo, and hydroxyl; and phenyl, optionally substituted by one, two, or three substituents each independently selected from the group consisting of C 1-6 alkyl; C 1-6  perfluoroalkyl; C 1-6 alkoxy; halogen; hydroxyl; —C(O)R x ; —CO 2 (R x ); —C(O)N(R) 2 ; —C(NR x )N(R x ) 2 ; and —C(R x ) 3 ; 
 or R 9  and R 10 , together with the nitrogen atom to which each is attached, form heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; which is optionally substituted by one, two, or three substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6  perfluoroalkyl; halogen, oxo, and hydroxyl; wherein when R 9  and R 10  form a heterocyclyl including 6 ring atoms, the heterocyclyl optionally includes, in addition to the nitrogen atom attached to R 9  and R 10 , a second ring heteroatom selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and 
 R x  is independently selected, for each occurrence, from the group consisting of hydrogen; halogen; acyl; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl. 
 
     
     
         4 - 31 . (canceled) 
     
     
         32 . The compound of any one of  claim 3 , wherein each of R a , R b , R c , R d , R e , and R f  is hydrogen. 
     
     
         33 . The compound of any one of  claim 3 , wherein each occurrence of R 9  and R 10  is hydrogen. 
     
     
         34 . The compound of any one of  claim 3 , wherein R 1  is hydrogen. 
     
     
         35 . The compound of any one of  claim 3 , wherein R g  is hydrogen. 
     
     
         36 . The compound of any one of  claim 3 , wherein R g  is CH 3 . 
     
     
         37 . The compound of any one of  claim 3 , wherein R h  is hydrogen. 
     
     
         38 . The compound of any one of  claim 3 , wherein R h  is CH 3 . 
     
     
         39 . A compound having formula (IV): 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, thereof, 
       wherein:
 R is selected from the group consisting of C 1-6 alkyl; C 1-6  perfluoroalkyl; C 3-6 cycloalkyl; phenyl; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; —OR x ; —C(O)R x ; —CO 2 (R x ); —C(O)N(R x ) 2 ; —C(NR x )N(R x ) 2 ; —OC(O)R x ; —OCO 2 R x ; —OC(O)N(R x ) 2 ; —N(R x ) 2 ; —NR x C(O)R x ; —NR x C(O)N(R x ) 2 ; —NR x C(O)OR x ; and —NR x C(NR x )N(R) 2 ; wherein C 1-6 alkyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and N(R x ) 2 ; 
 R 5  and R 6  are independently selected from the group consisting of hydrogen; C 1 -C 6  alkyl, optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, and N(R x ) 2 ; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; and -Q-Ar, wherein Q is a bond or C 1 -C 6  alkylene, optionally substituted by one, two, or three independently selected halogens, and Ar is selected from the group consisting of phenyl and heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S, wherein phenyl and heteroaryl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; or 
 R 5  and R 6 , together with the atoms to which they are attached, form a C 3 -C 6  cycloalkyl or heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the C 3 -C 6  cycloalkyl and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; 
 R 55  is H, or R 55  and R 5 , together with the atoms to which they are attached, form a C 3 -C 6  cycloalkyl or heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the C 3 -C 6  cycloalkyl and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; 
 R 7  and R 78  are each independently selected from the group consisting of hydrogen; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; heteroaryl; heterocyclyl; phenyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S, and N(R x ) 2 ; 
 R 8  is selected from the group consisting of hydrogen; halogen; hydroxyl; C 1 -C 6  alkyl; C 1-6  perfluoroalkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and phenyl; wherein C 1 -C 6  alkyl; C 1 -C 6  alkoxy; C 3 -C 6  cycloalkoxy; heteroaryl; heterocyclyl; and phenyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; or 
 R 7  and R 8 , together with the atoms to which they are attached, form C 3 -C 6  cycloalkyl or heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; wherein the C 3 -C 6  cycloalkyl and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, phenyl, and N(R x ) 2 ; 
 R 9  and R 10  are independently selected, for each occurrence, from the group consisting of hydrogen; C 1 -C 6  alkyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, hydroxyl, phenyl, and heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; C 1-6  perfluoroalkyl; C 2-6 alkenyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, and hydroxyl; C 2-6 alkynyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, oxo, and hydroxyl; C 3-6 cycloalkyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6  perfluoroalkyl; halogen, oxo, and hydroxyl; phenyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl; C 1-6  perfluoroalkyl; C 1-6 alkoxy; halogen; hydroxyl; —C(O)R x ; —CO 2 (R x ); —C(O)N(R) 2 ; —C(NR x )N(R x ) 2 ; and —C(R x ) 3 ; 
 or R 9  and R 10 , together with the nitrogen atom to which each is attached, form a heterocyclyl including from 3 to 6 ring atoms, which is optionally substituted by one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, halogen, oxo, and hydroxyl; wherein when R 9  and R 10  form a heterocyclyl including 6 ring atoms, the heterocyclyl optionally includes, in addition to the nitrogen atom attached to R 9  and R 10 , a second ring heteroatom selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; 
 R x  is independently selected, for each occurrence, from the group consisting of hydrogen; halogen; acyl; C 1-6 alkyl; C 1-6  perfluoroalkyl; and phenyl; and 
 R y  is C 1-3 alkyl. 
 
     
     
         40 . The compound of  claim 39 , wherein R is C 1-6 alkyl. 
     
     
         41 . The compound of  claim 40 , wherein R y  is CH 3 . 
     
     
         42 . The compound of any one of  claim 41 , wherein R 3  is —OH. 
     
     
         43 . The compound of any one of  claim 42 , wherein R 4  is C 1 -C 6  alkyl. 
     
     
         44 . The compound of any one of  claim 42 , wherein R 4  is CH 3 . 
     
     
         45 . The compound of any one of  claim 44 , wherein R 5 , R 6 , R 7 , R 8 , R 55 , and R 8  are hydrogen. 
     
     
         46 - 98 . (canceled)