Hcv protease inhibitors and uses thereof

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         one of R a  and R b  is hydrogen and the other is —OH or —OC(O)R′, or R a  and R b  are taken together to form an oxo group; 
         R′ is an optionally substituted group selected from C 1-6  aliphatic, C 3-7  cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R x  and R y  are taken together to form an optionally substituted C 3-7  membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 1  is an optionally substituted group selected from C 1-6  aliphatic or C 3-7  cycloalkyl(C 1-3  alkyl); 
         R 2  is hydrogen or an optionally substituted group selected from C 1-6  aliphatic or C 3-7  cycloalkyl; 
         R 3  is a warhead group; 
         R 4  is —NHC(O)NHR 5 , —NHC(O)OR 6 , or 
       
       
         
           
           
               
               
           
         
         R 5  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 6  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 7  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         R is hydrogen or an optionally substituted group selected from C 1-6  aliphatic, C 3-7  cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is of formula II-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound according to  claim 1 , wherein the compound is of formula II-b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound according to  claim 2 , wherein the compound is of formula III-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 2  is an optionally substituted group selected from C 1-6  aliphatic or C 3-7  cycloalkyl. 
       
     
     
         5 . The compound according to  claim 3 , wherein the compound is of formula III-b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound according to  claim 2 , wherein the compound is of formula IV-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound according to  claim 3 , wherein the compound is of formula IV-b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound according to  claim 2 , wherein the compound is of formula V-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound according to  claim 3 , wherein the compound is of formula V-b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound according to  claim 6 , wherein the compound is of formula IV-a-1 or IV-a-2: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 7 , wherein the compound is of formula IV-b-1 or IV-b-2: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 8 , wherein the compound is of formula V-a-1 or V-a-2: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 9 , wherein the compound is of formula V-b-1 or V-b-2: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of any one of  claim 1 ,  2 ,  4 ,  6 ,  8 ,  10  or  12 , wherein R 1  is n-propyl. 
     
     
         15 . The compound of any one of  claim 1 ,  3 ,  5 ,  7 ,  9 ,  11 , or  13 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of any one of  claim 1 ,  2 ,  4 ,  6 ,  8 ,  10  or  12 , wherein R 2  is cyclopropyl. 
     
     
         17 . The compound of  claim 1 , wherein R 4  is —NHC(O)OR 6 . 
     
     
         18 . The compound of any one of  claim 1 ,  2 ,  4 ,  6 ,  8 ,  10  or  12 , wherein R 5  is an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         19 . The compound of  claim 18 , wherein R 5  is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of any one of  claim 1 ,  3 ,  5 ,  7 ,  9 ,  11 , or  13 , wherein R 5  is an optionally substituted C 1-6  aliphatic group. 
     
     
         21 . The compound of  claim 20 , wherein R 5  is t-butyl. 
     
     
         22 . The compound of any one of  claim 1 ,  2 ,  4 ,  6 ,  8 ,  10  or  12 , wherein R 7  is an optionally substituted C 3-7  cycloalkyl group. 
     
     
         23 . The compound of  claim 22 , wherein R 7  is cyclohexyl. 
     
     
         24 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -L-Y, wherein:
 n is an integer from 0 to 5, inclusive; 
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and 
 each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
 
     
     
         25 . The compound according to  claim 24 , wherein n is an integer from 1 to 5, inclusive. 
     
     
         26 . The compound according to  claim 24 , wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and   Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.   
     
     
         27 . The compound according to  claim 26 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         28 . The compound according to  claims 26 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—. 
     
     
         29 . The compound according to  claim 24 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)(C═N 2 )—, —NRC(O)(C═N 2 )C(O)—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)CH═CHCH 2 O—, —NRC(O)C(═CH 2 )CH 2 —, —CH 2 NRC(O)—, —CH 2 NRC(O)CH═CH—, —CH 2 CH 2 NRC(O)—, or —CH 2 NRC(O)cyclopropylene-; wherein R is H or optionally substituted C 1-6  aliphatic; and Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         30 . The compound according to  claim 29 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-. 
     
     
         31 . The compound according to  claim 24 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         32 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -L-Y, wherein:
 n is an integer from 0 to 5, inclusive; 
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and 
 each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
 
     
     
         33 . The compound according to  claim 32 , wherein Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         34 . The compound according to  claim 33 , wherein L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 —C≡C—CH 2 —, —C≡CCH 2 O—, —CH 2 C(O)C≡C—, —C(O)C≡C—, or —CH 2 OC(═O)C≡C—. 
     
     
         35 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -L-Y, wherein:
 n is an integer from 0 to 5, inclusive; 
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and 
 each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
 
     
     
         36 . The compound according to  claim 35 , wherein Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         37 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -L-Y, wherein:
 n is an integer from 0 to 5, inclusive; 
 L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8  saturated or unsaturated, straight or branched, hydrocarbon chain; and 
 Y is selected from the following (i) through (xvii):
 (i) C 1-6  alkyl substituted with oxo, halogen, NO 2 , or CN; 
 (ii) C 2-6  alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or 
 (iii) C 2-6  alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or 
 (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e  groups; or 
 (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e  groups; or 
 (vi) 
 
 
       
         
           
           
               
               
           
         
       
       or
   (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e  groups; or   (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; or   (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e  groups; or   (x)   
 
       
         
           
           
               
               
           
         
       
       wherein each R e  is as defined above and described herein; or
   (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; or   (xii)   
 
       
         
           
           
               
               
           
         
       
       wherein each R and R e  is as defined above and described herein; or
   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e  groups; or   (xiv)   
 
       
         
           
           
               
               
           
         
       
       wherein each R e  is as defined above and described herein; or
   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e  groups; or   (xvi)   
 
       
         
           
           
               
               
           
         
         
           (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; 
         
         wherein: 
         each R is hydrogen or an optionally substituted group selected from C 1-6  aliphatic, C 3-7  cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
 
       
     
     
         38 . The compound according to  claim 37 , wherein L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—. 
     
     
         39 . The compound according to  claim 38 , wherein L is a covalent bond. 
     
     
         40 . The compound according to any of  claims 37 ,  38 , and  39 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R e  is independently selected from halogen. 
       
     
     
         41 . The compound according to  claim 1 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R e  is independently a suitable leaving group, NO 2 , CN, or oxo. 
       
     
     
         42 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . A composition comprising a compound according to any one of  claims 1  through  42 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         44 . The composition according to  claim 43 , in combination with an additional therapeutic agent. 
     
     
         45 . The composition according to  claim 44 , wherein the additional therapeutic agent is an antiviral agent. 
     
     
         46 . A method for inhibiting HCV protease, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound according to any of  claims 1  through  42  or a composition according to  claim 43 . 
     
     
         47 . A method for inhibiting HCV protease, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound according to any of  claims 1  through  42  or a composition according to  claim 43 . 
     
     
         48 . The method according to either of  claim 46  or  47 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly. 
     
     
         49 . The method according to any one of  claim 46 ,  47 , or  48 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys159. 
     
     
         50 . The method according to any one of  claim 46 ,  47 , or  48 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys16. 
     
     
         51 . A method for treating an HCV protease-mediated disorder in a patient, comprising the step of administering to said patient a compound according to any of  claims 1  through  42  or a composition according to  claim 43 . 
     
     
         52 . The method of  claim 51 , wherein the step of administering occurs once daily. 
     
     
         53 . The method according to  claim 51 , wherein the disorder is hepatitis C. 
     
     
         54 . A method of treating an HCV protease-mediated disorder in a patient comprising the step of irreversibly inhibiting HCV protease by covalently modifying Cys159 of HCV protease. 
     
     
         55 . A method of treating an HCV protease-mediated disorder in a patient comprising the step of irreversibly inhibiting HCV protease by covalently modifying Cys16 of HCV protease. 
     
     
         56 . A conjugate of the formula Cys159-modifier-inhibitor moiety, wherein the Cys159 is Cys159 of HCV protease. 
     
     
         57 . A conjugate of the formula Cys16-modifier-inhibitor moiety, wherein the Cys16 is Cys16 of HCV protease. 
     
     
         58 . The conjugate of  claim 56  or  57 , wherein the inhibitor moiety is of formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         one of R a  and R b  is hydrogen and the other is —OH or —OC(O)R′, or R a  and R b  are taken together to form an oxo group; 
         R′ is an optionally substituted group selected from C 1-6  aliphatic, C 3-7  cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 1  is an optionally substituted group selected from C 1-6  aliphatic or C 3-7  cycloalkyl(C 1-3  alkyl); 
         R 2  is hydrogen or an optionally substituted group selected from C 1-6  aliphatic or C 3-7  cycloalkyl; 
         R x  and R y  are taken together to form an optionally substituted C 3-7  membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 4  is —NHC(O)NHR 5 , —NHC(O)OR 6 , or 
       
       
         
           
           
               
               
           
         
         R 5  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 6  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 7  is an optionally substituted group selected from C 1-6  aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         R is hydrogen or an optionally substituted group selected from C 1-6  aliphatic, C 3-7  cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.