Ion channel modulators and methods of use

Abstract

In general, the invention relates to novel 4-phenylpyrimidine compounds useful as ion channel modulators. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and/or calcium channels for the treatment of pain.

What is claimed is: 
     
         1 . A method of modulating a sodium ion channel comprising the step of contacting said sodium ion channel with a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 Each X is defined by —Z A R 6 , wherein each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A , —NR A NR A CO—, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —; 
 Each R 6  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R A  is independently hydrogen, an optionally substituted C 1-8  aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R A  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each n is 1-4; 
 Each R 1  and R 2  is defined by —Z B R 7 , wherein each Z B  is independently a bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR B —, —CONR B NR B —, CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B , —NR B NR B CO—, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —; 
 Each R 7  is independently R B , halo, —OH, —NHC(NH)NH 2 , —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R B  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R B  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each R 3  and R 4  is defined by —Z C R 8 , wherein each —Z C  is independently a bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C , —NR C NR C CO—, —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; 
 Each R 8  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R C  is independently hydrogen, or an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R C  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents; and 
 Each Y is hydrogen or unsubstituted C 1-3  alkyl. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C 1-8  aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         3 . The method of  claim 2 , wherein R 1  is an optionally substituted —C 1-3  aliphatic-aryl. 
     
     
         4 . The method of  claim 3 , wherein R 1  is a phenylmethyl, phenylethyl, or phenylpropyl, in which the aliphatic and phenyl portion are each optionally substituted with 1-3 substituents independently selected from halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, and heteroaryl. 
     
     
         5 . The method of  claim 2 , wherein R 1  is an optionally substituted aliphatic. 
     
     
         6 . The method of  claim 5 , wherein R 1  is isopropyl. 
     
     
         7 . The method of  claim 2 , wherein R 1  is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic. 
     
     
         8 . The method of  claim 2 , wherein R 1  is an optionally substituted aryl or an optionally substituted heteroaryl. 
     
     
         9 . The method of  claim 2 , wherein R 2  is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic. 
     
     
         10 . The method of  claim 9 , wherein R 1  is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic. 
     
     
         11 . The method of  claim 1 , wherein R 1 , R 2 , and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocyclic or bicyclic ring including 1-3 heteroatoms. 
     
     
         12 . The method of  claim 11 , wherein R 1 , R 2 , and the nitrogen atom to which they are attached form a morpholinyl, piperadinyl, piperazinyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, thiomorpholinyl, or 3,4-dihydro-benzo[b][1,4]oxazine, each of which is optionally substituted with 1-3 substituents selected from alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C 1-5  aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl. 
     
     
         13 . The method of  claim 1 , wherein, R 3 , R 4  and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicyclic heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S. 
     
     
         14 . The method of  claim 13 , wherein R 3 , R 4  and the nitrogen atom to which they are attached form a morpholinyl, thiomorpholinyl, piperadinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, a fully saturated or partially unsaturated bicyclic heterocycloaliphatic having 1-3 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1-3 of alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C 1-5  aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl. 
     
     
         15 . The method of  claim 1 , wherein R 3  is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C 1-8  aliphatic. 
     
     
         16 . The method of  claim 16 , wherein R 3  is an optionally substituted aryl. 
     
     
         17 . The method of  claim 16 , wherein R 3  is an optionally substituted aliphatic. 
     
     
         18 . The method of  claim 16 , wherein R 3  is an optionally substituted heteroaryl. 
     
     
         19 . The method of  claim 1 , wherein X is o-halo. 
     
     
         20 . A method of modulating a calcium or sodium ion channel comprising the step of contacting said calcium or sodium ion channel with a compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts thereof, wherein:
 Each X is defined by —Z A R 6 , wherein each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A , —NR A NR A CO—, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, NR A SO 2 —, or —NR A SO 2 NR A —; 
 Each R 6  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R A  is independently hydrogen, an optionally substituted C 1-8  aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R A  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each n is 1-4; 
 Each R 1  and R 2  is defined by —Z B R 7 , wherein each Z B  is independently a bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B , —NR B NR B CO—, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —; 
 Each R 7  is independently R B , halo, —OH, —NHC(NH)NH 2 , —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R B  is an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R B  are taken together with the atoms) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each R 3  and R 4  is defined by —Z C R 8 , wherein each Z C  is independently bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C , —NR C NR C CO—, —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; 
 Each R 8  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and 
 Each R C  is independently hydrogen, or an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R C  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocycle or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents. 
 
     
     
         21 . The method of  claim 20 , wherein R 1  is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C 1-8  aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         22 . The method of  claim 21 , wherein R 1  is an optionally substituted —C 1-3  aliphatic-aryl. 
     
     
         23 . The method of  claim 21 , wherein R 1  is an optionally substituted aliphatic. 
     
     
         24 . The method of  claim 23 , wherein R 1  is isopropyl. 
     
     
         25 . The method of  claim 21 , wherein R 1  is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic. 
     
     
         26 . The method of  claim 21 , wherein R 1  is an optionally substituted aryl or an optionally substituted heteroaryl. 
     
     
         27 . The method of  claim 21 , wherein R 2  is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic. 
     
     
         28 . The method of  claim 27 , wherein R 1  is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic. 
     
     
         29 . The method of  claim 20 , wherein R 1 , R 2 , and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocyclic or bicyclic ring including 1-3 heteroatoms. 
     
     
         30 . The method of  claim 20 , wherein, R 3 , R 4  and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicyclic heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S. 
     
     
         31 . The method of  claim 20 , wherein R 3  is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C 1-8  aliphatic. 
     
     
         32 . A method of modulating a sodium or calcium ion channel comprising the step of contacting said sodium ion channel with a compound selected from compound numbers 1-351 in Table 1. 
     
     
         33 . A compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Each X is defined by —Z A R 6 , wherein each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A , —NR A NR A CO—, —NR A CO—, —S—, —SO—, —SO 2 —, NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —; 
 Each R 6  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 Each R A  is independently hydrogen, an optionally substituted C 1-8  aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R A  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each n is 1-4; 
 Each R 1  and R 2  is defined by —Z B R 7 , wherein each Z B  is independently a bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B , —NR B NR B CO—, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —, or —NR B SO 2 NR B ; 
 Each R 7  is independently R B , halo, —OH, —NHC(NH)NH 2 , —NH 2 , —NO 2 , —CN, —CF 1 , or —OCF 3 ; 
 Each R B  is an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R B  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Each R 3  and R 4  is defined by —Z C R 8 , wherein each Z C  is independently a bond or an optionally substituted straight or branched C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C , —NR C NR C CO—, —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; 
 Each R 8  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and 
 Each R C  is independently hydrogen, or an optionally substituted C 1-8  aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0.5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R C  are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents, 
 Provided that:
 when R 1  is alkyl, R 2  is not 3,5-bis-trifluoromethyl-phenyl-alkyl; 
 when R 1  and R 2  together form pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with —CH 3  or —CH 2 CH 3 , then X is not m-methyl, o-halo, p-aryl, or p-cyano; 
 when R 1  or R 2  are aliphatic or alkoxyalkyl, then X is not m-methyl, o-halo, p-aryl, or p-cyano; and 
 when R 1  is phenylmethyl optionally substituted with 1-2 —CH 3  groups or cycloaliphatic, and R 2  is unsubstituted methyl, ethyl, or isopropyl, then 
 (1) R 3  together with R 4  form pyrrolidinyl, morpholinyl, piperidinyl optionally substituted with aliphatic, aminocarbonyl, or alkylcarbonyl, or one of R 3  or R 4  is phenylmethyl, methylfuranyl, or methoxypropyl; and 
 (2) X is not m-methyl, p-aryl, o-halo or p-cyano. 
 
 
     
     
         34 . The compound of  claim 33 , wherein R 1  is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C 1-8  aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         35 . The compound of  claim 34 , wherein R 1  is an optionally substituted —C 1-3  aliphatic-aryl. 
     
     
         36 . The compound of  claim 35 , wherein R 1  is a phenylmethyl, phenylethyl, or phenylpropyl, in which the aliphatic and phenyl portion are each optionally substituted with 1-3 substituents independently selected from halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, and heteroaryl. 
     
     
         37 . The compound of  claim 35 , wherein R 1  is a naphthylmethyl, naphthylethyl, naphthylpropyl, indenylmethyl, indenylethyl, or indenylpropyl, in which the aliphatic and the bicyclic aryl group are each optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, heteroaryl, or combinations thereof. 
     
     
         38 . The compound of  claim 35 , wherein the aryl portion is an optionally substituted 2,3-dihydrobenzo[b][1,4]dioxinyl or an optionally substituted benzo[d][1,3]dioxolyl. 
     
     
         39 . The compound of  claim 34 , wherein R 1  is an optionally substituted 2,3-dihydrobenzofurylalkyl, an optionally substituted indolinylalkyl, an optionally substituted 2,3-dihydrobenzo[b][1,4]dioxinylalkyl, an optionally substituted benzo[d][1,3]dioxolylalkyl, an optionally substituted pyridinylalkyl, an optionally substituted isoindolinylalkyl, or an optionally substituted quinolinylalkyl. 
     
     
         40 . The compound of  claim 34 , wherein R 1  is methyl, ethyl, propyl, butyl, or isopropyl, each of which is optionally substituted with 1-2 substituents independently selected from halo, cyano, hydroxy, or optionally substituted aryl, aryloxy, alkylamino, heteroaryl, cycloaliphatic, or heterocycloaliphatic. 
     
     
         41 . The compound of  claim 40 , wherein R 1  is isopropyl. 
     
     
         42 . The compound of  claim 34 , wherein R 1  is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic. 
     
     
         43 . The compound of  claim 42 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.1]heptyl, each of which is optionally substituted with 1-2 halo, hydroxy, aryl, heteroaryl, or combinations thereof. 
     
     
         44 . The compound of  claim 34 , wherein R 1  is an optionally substituted aryl or an optionally substituted heteroaryl. 
     
     
         45 . The compound of  claim 34 , wherein R 1  is phenyl, indenyl, dihydroindenyl, naphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl, each of which is optionally substituted with 1-2 halo, hydroxy, cyano, or optionally substituted aliphatic, alkoxy, aryl, heteroaryl; or combinations thereof. 
     
     
         46 . The compound of  claim 34 , wherein R 2  is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic. 
     
     
         47 . The compound of  claim 46 , wherein R 1  is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic. 
     
     
         48 . The compound of  claim 33 , wherein R 1  and R 2  are each independently selected from hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 33 , wherein R 1 , R 2 , and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocycle or bicyclic ring including 1-3 heteroatoms. 
     
     
         50 . The compound of  claim 49 , wherein R 1 , R 2 , and the nitrogen atom to which they are attached form a morpholinyl, piperadinyl, piperazinyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, thiomorpholinyl, or 3,4-dihydro-benzo[b][1,4]oxazine, each of which is optionally substituted with 1-3 substituents selected from, alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C 1-5  aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl. 
     
     
         51 . The compound of  claim 33 , wherein R 1 , R 2  the nitrogen atom to which they are attached form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 33 , wherein, R 3 , R 4  and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicycle heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S. 
     
     
         53 . The compound of  claim 52 , wherein R 3 , R 4  and the nitrogen atom to which they are attached form a morpholinyl, thiomorpholinyl, piperadinyl, piperizinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, a fully saturated or partially unsaturated bicycle heterocycloaliphatic having 1-3 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1-3 of alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C 1-5  aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl. 
     
     
         54 . The compound of  claim 33 , wherein R 3  is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C 1-8  aliphatic. 
     
     
         55 . The compound of  claim 54 , wherein R 3  is phenyl, naphthyl or indenyl each optionally substituted with 1-3 of halo, cyano, hydroxy, alkoxy, alkoxycarbonyl, an optionally substituted C 1-6  aliphatic, aminocarbonyl, alkylaminocarbonyl, aryl, and heteroaryl. 
     
     
         56 . The compound of  claim 54 , wherein R 3  is alkyl optionally substituted with 1-2 of halo, cyano, —C(O)OH, hydroxy, cycloaliphatic, heterocycloaliphatic, optionally substituted aryl, alkoxy, haloalkylaryl, bicycloaliphatic, aryloxy, haloaryl, alkylamino, heteroaryl, cycloaliphatic, and heterocycloaliphaticpropyl. 
     
     
         57 . The compound of  claim 54 , wherein R 3  is an optionally substituted alkenyl. 
     
     
         58 . The compound of  claim 54 , wherein R 3  is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoindolinyl. 
     
     
         59 . The compound of  claim 54 , wherein R 3  is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[22.1]heptyl. 
     
     
         60 . The compound of  claim 33 , wherein X is o-halo. 
     
     
         61 . The compound of  claim 33 , wherein R 3  and R 4  are each independently selected from hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         62 . The compound of  claim 33 , wherein R 3 , R 4  the nitrogen atom to which they are attached form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from: 
       
         
           
           
               
               
           
         
       
     
     
         63 . The compound of  claim 33 , wherein R 1 , R 2 , R 3  and R 4  are each independently selected from hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         64 . The compound of  claim 33 , wherein R 1 , R 2  and the nitrogen atom to which they are attached, or R 3 , R 4  and the nitrogen atom to which they are attached, form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from: 
       
         
           
           
               
               
           
         
       
     
     
         65 . The compound of  claim 33 , wherein
 Each R 3  or R 4  is heterocycloaliphatic, bicycloaryl, bicycloheteroaliphatic, bicycloheteroaryl, heterocycloalkenyl, cycloaliphatic, alkenyl, 5-membered heterocycloaliphatic, heteroaralkyl, or bicycloaralkyl, each of which is optionally substituted;
 One of R 3  and R 4  is hydrogen; 
 R 3  or R 4  is alkyl substituted with cycloaliphatic, heteroaryl, heterocycloaliphatic, cyano, alkoxycarbonyl, carboxy, guanidinylalkyl, bicycloaryl, halo, or alkoxy; or 
 R 3  together with R 4  form a ring system selected from thiomorpholinyl, bicycloheteroaryl, bicyclic heterocycloaliphatic, 5-membered heterocycloaliphatic, and 6-membered heterocycloalkenyl; 
   Provided that:
 when R 1  and R 2  together form pyrrolidinyl, morpholinyl, piperidinyl, each optionally substituted with —CH 3  or —CH 2 CH 3 , then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; 
 when R 1  and R 2  are aliphatic or alkoxyalkyl, then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; and 
   when R 1  is phenylmethyl optionally substituted with 1-2 —CH 3  groups or cycloaliphatic, and R 2  is one selected from unsubstituted methyl, ethyl, and isopropyl, then R 3  together with R 4  form pyrrolidinyl, morpholinyl, piperidinyl optionally substituted with aliphatic, or aminocarbonyl, or alkylcarbonyl, or R 3  or R 4  is phenylmethyl, methylfuranyl, or methoxypropyl, and X is not o-halo or p-cyano.   
     
     
         66 . A compound selected from compound numbers 1-207 from Table 2. 
     
     
         67 . A pharmaceutical composition, comprising a compound as in any of  claims 32 - 66  and a pharmaceutically acceptable carrier.