Bicyclic pyrazolo protein kinase modulators

Abstract

The present invention provides novel bicyclic pyrazolo kinase modulators and methods of using the novel bicyclic pyrazolo kinase modulators to treat diseases mediated by kinase activity.

1 - 26 . (canceled) 
     
     
         27 . A method of modulating the activity of a protein kinase comprising contacting said protein kinase with a compound of claim  1 . 
     
     
         28 . A method of modulating the activity of a protein tyrosine kinase comprising contacting said protein tyrosine kinase with a compound of claim  1 . 
     
     
         29 . A method of modulating the activity of a receptor tyrosine kinase comprising contacting said receptor tyrosine kinase with a compound of claim  1 . 
     
     
         30 . A method of modulating the activity of a protein kinase comprising contacting said protein kinase with a compound of one of claims  1 . 
     
     
         31 . A method for treating cancer in a human patient in need of such treatment, said method comprising administering to the patient a therapeutically effective amount of a compound of claim  1 . 
     
     
         32 . (canceled) 
     
     
         33 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X is —O—, 
         L 1  is —C(Z)—, or —SO 2 —, 
         wherein Z is ═O, ═S, or ═NR 11 , 
         wherein R 11  is hydrogen, —OH, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         R 1  is hydrogen, —CF 3 , amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR 12 , or —NR 13 R 14 , wherein 
         R 12 , R 13 , and R 14  are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, 
         R 13  and R 14  are optionally joined to from a ring with the nitrogen to which they are attached, wherein said ring is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 2  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, 
         wherein R 2  is attached to the remainder of the molecule via a carbon atom to form a carbon-carbon bond, or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The compound of  claim 33 , wherein
 L 1  is —C(Z)—, wherein Z is ═O.   
     
     
         35 . The compound of  claim 33 , wherein
 R 2  is substituted or unsubstituted C 1 -C 20  alkyl, substituted or unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.   
     
     
         36 . The compound of  claim 33 , wherein
 R 2  is substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 7  cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.   
     
     
         37 . The compound of  claim 33 , wherein R 2  is
 (1) unsubstituted C 1 -C 10  alkyl;   (2) unsubstituted 2 to 10 membered heteroalkyl;   (3) unsubstituted C 3 -C 7  cycloalkyl;   (4) unsubstituted 3 to 7 membered heterocycloalkyl;   (5) unsubstituted aryl;   (6) unsubstituted heteroaryl;   (7) substituted C 1 -C 10  alkyl;   (8) substituted 2 to 10 membered heteroalkyl;   (9) substituted C 3 -C 7  cycloalkyl;   (10) substituted 3 to 7 membered heterocycloalkyl;   (11) substituted aryl; or   (12) substituted heteroaryl;   wherein   (7), (8), (9), or (10) is substituted with an oxo, —OH, —CF 3 , —COOH, halogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 21 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 -substituted or unsubstituted heteroaryl, -L 22 -C(O)R 3 , -L 22 -OR 4 , -L 22 -NR 4 R 5 , OR 4 , or -L 22 -S(O) m R 6 ,   (11) or (12) is substituted with an —OH, —CF 3 , —COOH, halogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 2 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, R 22 -substituted or unsubstituted heteroaryl, -L 22 -C(O)R 3 , -L 22 -OR 4 , -L 22 -NR 4 R 5 , or -L 22 S(O) m R 6 ,   R 3  is hydrogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 2 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, R 22 -substituted or unsubstituted heteroaryl, —OR 31 , or —NR 32 R 33 , wherein   R 31 , R 32 , and R 33  are independently hydrogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 21 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 -substituted or unsubstituted heteroaryl,   R 4  and R 5  are independently hydrogen, —CF 3 , R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 21 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, R 22 -substituted or unsubstituted heteroaryl, or —C(O)R 41 , wherein   R 41  is hydrogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 21 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 -substituted or unsubstituted heteroaryl,   R 6  is hydrogen, R 21 -substituted or unsubstituted C 1 -C 10  alkyl, R 21 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 -substituted or unsubstituted heteroaryl,   L 22  is a bond, unsubstituted C 1 -C 10  alkylene or unsubstituted heteroalkylene, m is 0, 1, or 2,   R 21  is oxo, —OH, —COOH, —CF 3 , amino, halogen, R 23 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 23 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 23 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 24 -substituted or unsubstituted aryl, or R 24 -substituted or unsubstituted heteroaryl,   R 22  is —OH, —COOH, amino, halogen, —CF 3 , R 23 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 23 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 23 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 24 -substituted or unsubstituted aryl, or R 24 -substituted or unsubstituted heteroaryl,   R 23  is oxo, —OH, —COOH, amino, halogen, —CF 3 , unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and   R 24  is —OH, —COOH, amino, halogen, —CF 3 , unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.   
     
     
         38 . The compound of  claim 37 , wherein
 if R 21  or R 22  is substituted or unsubstituted heterocycloalkyl, the heterocycloalkyl is hydantoinyl, dioxolanyl, dioxanyl, trioxanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholino, piperidinyl, or piperazinyl.   
     
     
         39 . The compound of  claim 37 , wherein
 if R 21  or R 22  is substituted or unsubstituted heteroaryl, then the heteroaryl is pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrazyl, pyrimidyl, pyridazinyl, thiazolyl, isothioazolyl, triazolyl, thienyl, triazinyl, or thiadiazolyl.   
     
     
         40 . The compound of  claim 37 , wherein
 R 2  is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.   
     
     
         41 . The compound of  claim 37 , wherein
 R 2  is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.   
     
     
         42 . The compound of  claim 40 , wherein the R 2  is substituted with a(n)
 (1) unsubstituted C 1 -C 10  alkyl,   (2) unsubstituted 2 to 10 membered heteroalkyl,   (3) unsubstituted C 3 -C 7  cycloalkyl,   (4) unsubstituted 3 to 7 membered heterocycloalkyl,   (5) unsubstituted aryl,   (6) unsubstituted heteroaryl,   (7) halogen,   (8) —OH,   (9) amino,   (10) —CF 3 ,   (11) 3 to 7 membered heterocycloalkyl substituted with unsubstituted C 1 -C 10  alkyl, or   (12) C 1 -C 10  alkyl substituted with an unsubstituted aryl.   
     
     
         43 . The compound of  claim 40 , wherein the R 2  is substituted with a
 (1) halogen,   (2) -L 22 -C(O)R 3 ,   (3) -L 22 -OR 4 ,   (4) -L 22 -NR 4 R 5 , or   (5) -L 22 -S(O) m R 6 .   
     
     
         44 . The compound of  claim 40 , wherein the R 2  substituent is
 (1) -L 22 -C(O)R 3 , wherein   R 3  is hydrogen, unsubstituted C 1 -C 10  alkyl, —OR 31 , —NR 32 R 33 , wherein   R 31 , R 32 , and R 33  are independently hydrogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted C 3 -C 7  cycloalkyl, and   L 22  is unsubstituted C 1 -C 10  alkylene,   (2) -L 22 -OR 4 , wherein   R 4  is hydrogen, —CF 3 , —CHF 2 , unsubstituted C 1 -C 10  alkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted C 1 -C 10  cycloalkylalkyl, or —C(O)R 41 , wherein   R 41  is hydrogen, or unsubstituted C 1 -C 10  alkyl,   (3) -L 22 -NR 4 R 5 , wherein   R 4  and R 5  are independently hydrogen, unsubstituted C 1 -C 10  alkyl, or —C(O)R 41 , wherein   R 41  is independently hydrogen, or unsubstituted C 1 -C 10  alkyl, or   (4) L 22 S(O) m R 6 , wherein   R 7  is hydrogen or unsubstituted C 1 -C 10  alkyl.   
     
     
         45 . The compound of  claim 37 , wherein
 if R 2  is substituted or unsubstituted aryl, then the aryl is phenyl, benz[cd]indol-2(1H)-one-yl, oxindolyl, indazolinonyl, benzoimidazolyl, indolyl, benzodioxanyl, cournarinyl, chromonyl, benzopyrazyl, naphthyl, quinolyl, or isoquinolyl;   if R 2  is substituted or unsubstituted heteroaryl, then the heteroaryl is pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazyl, pyridazinyl, thiazolyl, isothioazolyl, triazolyl, thienyl, triazinyl, thiadiazolyl, or   if R 2  is substituted or unsubstituted heterocycloalkyl, then the heterocycloalkyl is hydantoinyl, dioxolanyl, dioxanyl, trioxanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholino, piperidinyl, or piperazinyl.   
     
     
         46 . The compound of  claim 37 , wherein
 if (11) or (12) is substituted with a R 21 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, then the heterocycloalkyl is dioxolanyl, dioxanyl, trioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholino, piperidinyl, or piperazinyl; or   if (11) or (12) is substituted with a R 22 -substituted or unsubstituted heteroaryl, then the heteroaryl is pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrazyl, pyrimidyl, pyridazinyl, thiazolyl, isothioazolyl, triazolyl, or thienyl, triazinyl, or thiadiazolyl.   
     
     
         47 . The compound of  claim 33 , wherein
 R 1  is hydrogen, amino, substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 7  cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.   
     
     
         48 . The compound of  claim 33 , wherein R 1  is
 (1) —CF 3 ;   (2) unsubstituted C 1 -C 10  alkyl;   (3) unsubstituted 2 to 10 membered heteroalkyl;   (4) unsubstituted C 3 -C 7  cycloalkyl;   (5) unsubstituted 3 to 7 membered heterocycloalkyl;   (6) unsubstituted aryl;   (7) unsubstituted heteroaryl;   (8) substituted C 1 -C 10  alkyl;   (9) substituted 2 to 10 membered heteroalkyl;   (10) substituted C 3 -C 7  cycloalkyl;   (11) substituted 3 to 7 membered heterocycloalkyl;   (12) substituted aryl; or   (13) substituted heteroaryl;   wherein   (8), (9), (10) or (11) is substituted with an oxo, —OH, —CF 3 , —COOH, halogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl, -L 11 -C(O)R 100 , -L 11 -OR 104 , -L 11 -NR 104 R 105 , or -L 11 -S(O) q R 107 ,   (12) or (13) is substituted with an —OH, —CF 3 . —COOH, halogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R16-substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl, -L 11 -C(O)R 100 , -L 11 -OR 104 , -L 11 -NR 104 R 105 , or -L 11 -S(O) q —R 107 ,   R 100  is hydrogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl, —OR 101 , or —NR 102 R 103 , wherein   R 101 , R 102 , R 103  are independently hydrogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, or R 16 -substituted or unsubstituted heteroaryl,   R 104  and R 105  are independently hydrogen, —CF 3 , R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl, or —C(O)R 106 , wherein   R 106  is independently hydrogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, or R 16 -substituted or unsubstituted heteroaryl,   R 107  is hydrogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 15 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 16 -substituted or unsubstituted aryl, or R 16 -substituted or unsubstituted heteroaryl,   L 11  is a bond, unsubstituted C 1 -C 10  alkylene, or unsubstituted heteroalkylene, q is 0, 1, or 2,   R 15  is oxo, —OH, —COOH, —CF 3 , halogen, R 17 -substituted or unsubstituted C 1 -C 10  alkyl,   R 17 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 17 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 17 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 18 -substituted or unsubstituted aryl, or R 18 -substituted or unsubstituted heteroaryl,   R 16  is —OH, —COOH, —CF 3 , halogen, R 17 -substituted or unsubstituted C 1 -C 10  alkyl, R 17 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 17 -substituted or unsubstituted C 3 -C 7  cycloalkyl, R 17 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 18 -substituted or unsubstituted aryl, or R 18 -substituted or unsubstituted heteroaryl,   R 17  is oxo, —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl, and   R 18  is —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.   
     
     
         49 . The compound of  claim 48 , wherein
 if R 15  or R 16  is substituted or unsubstituted heterocycloalkyl, the heterocycloalkyl is hydantoinyl, dioxolanyl, dioxanyl, trioxanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholino, piperidinyl, or piperazinyl.   
     
     
         50 . The compound of  claim 48 , wherein
 if R 15  or R 16  is substituted or unsubstituted heteroaryl, the heteroaryl is pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrazyl, pyrimidyl, pyridazinyl, thiazolyl, isothioazolyl, triazolyl, or thienyl, triazinyl, or thiadiazolyl.   
     
     
         51 . The compound of  claim 48 , wherein
 R 15  is oxo, —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl, and   R 16  is —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.   
     
     
         52 . The compound of  claim 33 , wherein R 1  is
 (1) unsubstituted C 1 -C 10  alkyl;   (2) unsubstituted 2 to 10 membered heteroalkyl;   (3) unsubstituted C 3 -C 7  cycloalkyl;   (4) unsubstituted 3 to 7 membered heterocycloalkyl;   (5) substituted C 1 -C 10  alkyl;   (6) substituted 2 to 10 membered heteroalkyl;   (7) substituted C 3 -C 7  cycloalkyl;   (8) substituted 3 to 7 membered heterocycloalkyl;   (9) substituted phenyl; or   (10) substituted heteroaryl;   wherein (5), (6), (7), or (8) is substituted with an oxo, —OH, —CF 3 . —COOH, halogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, or R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl, and   wherein (9) or (10) is substituted with an —OH, —CF 3 . —COOH, halogen, R 15 -substituted or unsubstituted C 1 -C 10  alkyl, or R 15 -substituted or unsubstituted 2 to 10 membered heteroalkyl.   
     
     
         53 . The compound of  claim 52 , wherein R 15  is oxo, —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted 2 to 10 membered heteroalkyl. 
     
     
         54 . The compound of  claim 33 , wherein R 1  is
 (1) unsubstituted C 1 -C 10  alkyl,   (2) unsubstituted 2 to 10 membered heteroalkyl,   (3) unsubstituted C 3 -C 7  cycloalkyl,   (4) unsubstituted 3 to 7 membered heterocycloalkyl;   (5) C 1 -C 10  alkyl substituted with an oxo, —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;   (6) 2 to 10 membered heteroalkyl substituted with an oxo, —OH, —CF 3 , —COOH, halogen, unsubstituted C 1 -C 10  alkyl, 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;   (7) C 3 -C 7  cycloalkyl substituted with —OH, —CF 3 , —COOH, halogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted 2 to 10 membered heteroalkyl;   (8) 3 to 7 membered heterocycloalkyl substituted with —OH, —CF 3 , —COOH, halogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted 2 to 10 membered heteroalkyl;   (9) phenyl substituted with —OH, —CF 3 , —COOH, halogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted 2 to 10 membered heteroalkyl; or   (10) heteroaryl substituted with —OH, —CF 3 , —COOH, halogen, unsubstituted C 1 -C 10  alkyl, or unsubstituted 2 to 10 membered heteroalkyl.   
     
     
         55 . The compound of  claim 48 , wherein if R 1  is a substituted or unsubstituted heteroaryl, the heteroaryl is pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazyl, pyridazinyl, thiazolyl, isothioazolyl, triazolyl, thienyl, triazinyl, or thiadiazolyl. 
     
     
         56 . The compound of  claim 48 , wherein if R 1  is a substituted or unsubstituted heterocycloalkyl, then the heterocycloalkyl is hydantoinyl, dioxolanyl, dioxanyl, trioxanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholino, piperidinyl, or piperazinyl. 
     
     
         57 . The compound of  claim 48 , wherein the R 1  is substituted with a
 (1) halogen,   (2) -L 11 -C(O)R 100 ,   (3) -L 11 -OR 104 ,   (4) -L 11 -OR 104 ,   (5) -L 11 -S(O) q R 107 .   
     
     
         58 . The compound of  claim 57 , wherein
 R 15  is oxo, —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl, and   R 16  is —OH, —COOH, —CF 3 , halogen, unsubstituted C 1 -C 10  alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 7  cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.   
     
     
         59 . A pharmaceutical composition comprising a compound of  claim 33  in admixture with a pharmaceutically acceptable excipient.