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Title:
COMPOSITIONS AND METHODS FOR TREATING PARASITIC DISEASES
Document Type and Number:
WIPO Patent Application WO/2017/161344
Kind Code:
A1
Abstract:
Disclosed herein, inter alia, are compositions and methods for treating parasitic diseases.

Inventors:
SIBLEY LAURENCE DAVID (US)
JANETKA JAMES W (US)
RUTAGANIRA FLORENTINE (US)
SHOKAT KEVAN M (US)
Application Number:
PCT/US2017/023085
Publication Date:
September 21, 2017
Filing Date:
March 17, 2017
Export Citation:
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Assignee:
THE REGANTS OF THE UNIV OF CALIFORNIA (US)
SIBLEY LAURENCE DAVID (US)
JANETKA JAMES W (US)
International Classes:
C07D519/00; A61K31/495; A61K31/506
Foreign References:
US20100331297A12010-12-30
US20130018040A12013-01-17
US20110275651A12011-11-10
US4911920A1990-03-27
US5403841A1995-04-04
US5212162A1993-05-18
US4861760A1989-08-29
Other References:
LARSON ET AL.: "Multiple Determinants for Selective Inhibition of Apicomplexan Calcium- Dependent Protein Kinase CDPK1", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, 27 February 2012 (2012-02-27), pages 2803 - 2810, XP055421907
BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
PICKAR, DOSAGE CALCULATIONS, 1999
MACAI, ORG LETT, 2003
SMITHWATERMAN, ADV. APPL. MATH., vol. 2, 1981, pages 482
NEEDLEMANWUNSCH, J. MOL. BIOL., vol. 48, 1970, pages 443
PEARSONLIPMAN, PROC. NAT'L. ACAD. SCI. USA, vol. 85, 1988, pages 2444
AUSUBEL ET AL., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1995
HENIKOFF ET AL., PROC. NAT'L ACAD. SCI. USA, vol. 89, 1992, pages 10915 - 10919
LEI ET AL., J. BIOL. CHEM., vol. 270, no. 20, 1995, pages 11882 - 11886
RAO, J. BIOMATER SCI. POLYM. ED., vol. 7, 1995, pages 623 - 645
GAO, PHARM. RES., vol. 12, 1995, pages 857 - 863
EYLES, J. PHARM. PHARMACOL., vol. 49, 1997, pages 669 - 674
AL-MUHAMMED, J. MICROENCAPSUL., vol. 13, 1996, pages 293 - 306
CHONN, CURR. OPIN. BIOTECHNOL., vol. 6, 1995, pages 698 - 708
OSTRO, AM. J. HOSP. PHARM., vol. 46, 1989, pages 1576 - 1587
"UniProt", Database accession no. KB- Q6S4W0
"UniProtKB", Database accession no. S7UHK8
ACTA PSYCHIATR SCAND, vol. 132, no. 3, 15 April 2015 (2015-04-15), pages 161 - 79
LOURIDO SHOKATSIBLEY, J MED CHEM., vol. 56, no. 7, 11 April 2013 (2013-04-11), pages 3068 - 77
HANEFELD, U.REES, C. W.WHITE, A. J. P.WILLIAMS, D. J., J. AM. CHEM. SOC. PERKIN TRANS., vol. 1, 1996, pages 1545 - 1552
SCHENONE, S.RADI, M.MUSUMECI, F.BRULLO, C.BOTTA, M., CHEM. REV., vol. 114, 2014, pages 7189 - 7238
FORS ET AL., JACS, 2009
LOURIDO SHOKATSIBLEY, JOURNAL OF MEDICINAL CHEMISTRY, 2013
See also references of EP 3430017A4
Attorney, Agent or Firm:
TERRANOVA, Zachary, L. et al. (US)
Download PDF:
Claims:
WHAT IS CLAIMED IS: 1. A compound having the formula:

(I) wherein,

Y1 is–N= or–CH=;

R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;

L1 is–O-, -S-, or–N(R3)-;

L2 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X3 is independently halogen.

2. The compound of claim 1, wherein R1 is substituted or unsubstituted C6- C10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. 3. The compound of claim 1, wherein R2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5 to 10 membered heteroaryl, or substituted or unsubstituted C3-C8 cycloalkyl. 4. The compound of claim 1, wherein L2 is a substituted or unsubstituted C1- C5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. 5. The compound of claim 1, wherein L2 is a–

CH2-, -CH2CH2-, -CH2O-, -CH2S-, or–CH2NH-. 6. The compound of claim 1, wherein R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

7. The com ound of claim 1 havin the formula:

(I) wherein,

Ring A is C6-C10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C3- C8 cycloalkyl;

R4 is halogen, -CX4

3, -CHX4

2, -CH2X4, -OCX4

3, - OCH2X4, -OCHX4

2, -CN, -SOn4R4D, -SOv4NR4AR4B, -NHC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C( O)R4C, -C(O)-OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -N R4AOR4C, 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;

R5 is halogen, -CX5

3, -CHX5

2, -CH2X5, -OCX5

3, - OCH2X5, -OCHX5

2, -CN, -SOn5R5D, -SOv5NR5AR5B, -NHC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C( O)R5C, -C(O)-OR5C, -C(O)NR5AR5B, -OR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -N R5AOR5C, 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;

Each R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5D is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, 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; R4A and R4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5A and R5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X4, and X5 is independently–F, -Cl, -Br, or–I;

n4 and n5 are independently an integer from 0 to 4; and m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6.

8. The compound of claim 1, wherein L1 is–O-. 9. The compound of claim 1, wherein L1 is -S-. 10. The compound of claim 1, wherein L1 is–N(R3)-. 11. The compound of claim 10, wherein R3 is hydrogen. 12. The compound of claim 7, wherein Ring A is phenyl. 13. The compound of claim 7, wherein Ring A is napththyl. 14. The compound of claim 7, wherein Ring A is 5 to 10 membered heteroaryl. 15. The compound of claim 7, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, azaindolyl, benzoisoxazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. 16. The compound of claim 7, wherein Ring A is 5 to 9 membered heteroaryl. 17. The compound of claim 7, wherein Ring A is 5 to 6 membered heteroaryl. 18. The compound of claim 7, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. 19. The compound of claim 7, wherein R4 is independently–

F, -Cl, -Br, -I, -CN, -NH2, -OH, -SH, -COCH3, -COOH, -COOCH3, -CX4

3, -CHX4

2, -CH2X4, -O CX4

3, -OCHX4

2, -OCH2X4, -SCX4

3, -SCHX4

2, -SCH2X4, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -SCH3,or -SCH2CH3. 20. The compound of claim 1, wherein z4 is 2.

21. The compound of claim 1, wherein z4 is 1. 22. The compound of claim 1, wherein z4 is 0. 23. The compound of claim 1, wherein L2 is–CH2-. 24. The compound of claim 1, wherein L2 is -CH2CH2-. 25. The compound of claim 1, wherein L2 is -CH2O-. 26. The compound of claim 1, wherein L2 is -CH2S-. 27. The compound of claim 1, wherein L2 is–CH2NH-. 28. The compound of claim 7, wherein Ring B is 3 to 7 membered heterocycloalkyl. 29. The compound of claim 7, wherein Ring B is 3 to 6 membered heterocycloalkyl. 30. The compound of claim 7, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. 31. The compound of claim 7, wherein Ring B is a 6 membered heterocycloalkyl. 32. The compound of claim 7, wherein Ring B is piperidinyl or piperazinyl. 33. The compound of claim 7, wherein Ring B is a C3-C8 substituted or unsubstituted cycloalkyl. 34. The compound of claim 7, wherein Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl.

35. The compound of claim 7, wherein Ring B is substituted or unsubstituted cyclopentanyl. 36. The compound of claim 7, wherein Ring B is 5 to 10 membered heteroaryl. 37. The compound of claim 7, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. 38. The compound of claim 7, wherein Ring B is a 6 membered heteroaryl. 39. The compound of claim 7, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. 40. The compound of claim 7, wherein R5 is–

F, -Cl, -Br, -I, -CN, -NH2, -OH, -SH, -COCH3, -COOH, -COOCH3, -CX5

3, -CHX5

2, -CH2X5, -O CX5

3, -OCHX5

2, -OCH2X5, -SCX5

3, -SCHX5

2, -SCH2X5, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -SCH3, or -SCH2CH3.

41. The compound of claim 7, wherein z5 is 2. 42. The compound of claim 7, wherein z5 is 1. 43. The compound of claim 7, wherein z5 is 0. 44. The compound of claim 1, having the formula:

wherein, A1, A2, A3, A4, and A5, are each independently–C(R4)= or–N=;

R4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halogen, -CF3, -OCH3, -CN, -SO2CH3, -SO2NHR4B, -OCF3;

R5 is independently oxo, halogen, -COOH, or -C(O)NR5AR5B;

R5.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted

cycloalkyl, -C(O)NR5AR5B, , -C(N)-(substituted or unsubstituted alkyl), -C(N)- (substituted or unsubstituted cycloalkyl), -C(O)-(substituted or unsubstituted alkyl), or -C(O)- (substituted or unsubstituted cycloalkyl);

z4 and z5 are independently an integer from 0 to 2; and

R5A and R5B are independently hydrogen or substituted or unsubstituted alkyl. 45. The compound of claim 44, wherein z5 is 2. 46. The compound of claim 44, wherein R5.1 is substituted or unsubstituted cyclopropyl. 47. The compound of claim 1, wherein L2-R2 has the formula:

, wherein R23 is independently oxo,

halogen, -CX23

3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, - NHNH2, -ONH2, - NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX23

3, -OCHX23

2, 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;

R23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl; and

z2 is an integer from 0 to 9.

48. The compound of claim 1, having the formula:

. 49. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 48, or a pharmaceutically acceptable salt thereof. 50. A method of inhibiting calcium dependent protein kinase 1 activity, said method comprising: contacting the calcium dependent protein kinase 1 with an effective amount of a compound having the formula:

(I) wherein,

Y1 is–N= or–CH=;

R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L1 is–O-, -S-, or–N(R3)-;

L2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X3 is independently halogen.

51. The method of claim 50, wherein R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. 52. The method of claim 50, wherein the calcium dependent protein kinase 1 is Toxoplasmosis gondii calcium dependent protein kinase 1. 53. A method of treating an Apicomplexa infection, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

(I) wherein,

Y1 is–N= or–CH=;

R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L1 is–O-, -S-, or–N(R3)-;

L2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X3 is independently halogen. 54. The method of claim 53, wherein R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. 55. The method of claim 53, further comprising preventing reactivation of Apicomplexa bradyzoite stages that exist within tissue cysts.

56. The method of claim 53, wherein the Apicomplexa infection is in central nervous system. 57. The method of claim 53, wherein the Apicomplexa infection is in the brain and the eye. 58. The method of claim 53, wherein the Apicomplexa infection is in the brain. 59. The method of claim 53, comprising preventing chronic Apicomplexa infection. 60. The method of claim 53, comprising reducing or eliminating Apicomplexa tissue cysts present during chronic infection. 61. The method of claim 53, comprising preventing reactivation of the Apicomplexa in cysts. 62. The method of claim 53, comprising reducing Apicomplexa survival. 63. The method of claim 53, comprising reducing Apicomplexa proliferation. 64. The method of claim 53, comprising reducing Apicomplexa egress from a cell. 65. The method of claim 53, comprising reducing Apicomplexa invasion of a cell. 66. The method of claim 53, comprising reducing Apicomplexa motility. 67. The method of claim 53, comprising reducing microneme protein release. 68. The method of claim 53, wherein the Apicomplexa is Toxoplasma gondii. 69. A method of treating an Apicomplexa associated disease, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula: (I) wherein,

Y1 is–N= or–CH=;

R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L1 is–O-, -S-, or–N(R3)-;

L2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X3 is independently halogen. 70. The method of claim 69, wherein R2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. 71. The method of claim 69, wherein the disease is encephalitis. 72. The method of claim 69, wherein the disease is schizophrenia. 73. The method of claim 69, wherein the disease is toxoplasmosis. 74. The method of claim 69, wherein the disease is toxoplasmic encephalitis. 75. The method of claim 69, wherein the disease is ocular toxoplasmosis. 76. The method of claim 73, further comprising co-administering

pyrimethamine, a sulfonamide drug, or clindamycin. 77. The method of claim 76, wherein the sulfonamide drug is sulfadiazine or sulfamethoxazole.

78. The method of claim 53, wherein R1 is substituted or unsubstituted C6-C10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. 79. The method of claim 53, wherein R2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 10 membered heteroaryl. 80. The method of claim 53, wherein L2 is a bond, substituted or unsubstituted C1-C5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. 81. The method of claim 53, wherein L2 is a bond,–

CH2-, -CH2CH2-, -CH2O-, -CH2S-, or–CH2NH-. 82. The method of claim 53, wherein R3 is hydrogen, -CN, -COOH, -CX3

3, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. Th m h f l im h r in he compound has the formula:

(I) wherein,

Ring A is C6-C10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C3- C8 cycloalkyl;

R4 is halogen, -CX4

3, -CHX4

2, -CH2X4, -OCX4

3, - OCH2X4, -OCHX4

2, -CN, -SOn4R4D, -SOv4NR4AR4B, -NHC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C( O)R4C, -C(O)-OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -N R4AOR4C, 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;

R5 is halogen, -CX5

3, -CHX5

2, -CH2X5, -OCX5

3, - OCH 5A

2X5, -OCHX5

2, -CN, -SOn5R5D, -SOv5NR R5B, -NHC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C( O)R5C, -C(O)-OR5C, -C(O)NR5AR5B, -OR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -N R5AOR5C, 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;

Each R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5D is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, 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; R4A and R4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5A and R5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X4, and X5 is independently–F, -Cl, -Br, or–I;

n4 and n5 are independently an integer from 0 to 4; and

m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6.

84. The method of claim 53, wherein L1 is–O-. 85. The method of claim 53, wherein L1 is -S-. 86. The method of claim 53, wherein L1 is–N(R3)-. 87. The method of claim 86, wherein R3 is hydrogen. 88. The method of claim 83, wherein Ring A is phenyl. 89. The method of claim 83, wherein Ring A is napththyl. 90. The method of claim 83, wherein Ring A is 5 to 10 membered heteroaryl. 91. The method of claim 83, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, azaindolyl, benzoisoxazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl.

92. The method of claim 83, wherein Ring A is 5 to 9 membered heteroaryl. 93. The method of claim 83, wherein Ring A is 5 to 6 membered heteroaryl. 94. The method of claim 83, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. 95. The method of claim 83, wherein R4 is independently–

F, -Cl, -Br, -I, -CN, -NH2, -OH, -SH, -COCH3, -COOH, -COOCH3, -CX4

3, -CHX4

2, -CH2X4, -O CX4

3, -OCHX4

2, -OCH2X4, -SCX4

3, -SCHX4

2, -SCH2X4, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -SCH3,or -SCH2CH3. 96. The method of claim 53, wherein z4 is 2. 97. The method of claim 53, wherein z4 is 1. 98. The method of claim 53, wherein z4 is 0. 99. The method of claim 53, wherein L2 is a bond. 100. The method of claim 53, wherein L2 is–CH2-. 101. The method of claim 53, wherein L2 is -CH2CH2-. 102. The method of claim 53, wherein L2 is -CH2O-. 103. The method of claim 53, wherein L2 is -CH2S-. 104. The method of claim 53, wherein L2 is–CH2NH-. 105. The method of claim 83, wherein Ring B is 3 to 7 membered heterocycloalkyl. 106. The method of claim 83, wherein Ring B is 3 to 6 membered heterocycloalkyl. 107. The method of claim 83, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. 108. The method of claim 83, wherein Ring B is a 6 membered heterocycloalkyl. 109. The method of claim 83, wherein Ring B is piperidinyl or piperazinyl. 110. The method of claim 83, wherein Ring B is 5 to 10 membered heteroaryl. 111. The method of claim 83, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. 112. The method of claim 83, wherein Ring B is a C3-C8 substituted or unsubstituted cycloalkyl. 113. The method of claim 83, wherein Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl. 114. The method of claim 83, wherein Ring B is substituted or unsubstituted cyclopentanyl. 115. The method of claim 83, wherein Ring B is a 6 membered heteroaryl. 116. The method of claim 83, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. 117. The method of claim 83, wherein R5 is–

F, -Cl, -Br, -I, -CN, -NH2, -OH, -SH, -COCH3, -COOH, -COOCH3, -CX5

3, -CHX5

2, -CH2X5, -O CX5

3, -OCHX5

2, -OCH2X5, -SCX5

3, -SCHX5

2, -SCH2X5, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -SCH3, or -SCH2CH3.

118. The method of claim 83, wherein z5 is 2. 119. The method of claim 83, wherein z5 is 1.

120. The method of claim 83, wherein z5 is 0.

Description:
COMPOSITIONS AND METHODS FOR TREATING PARASITIC

DISEASES CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.62/309,803, filed March 17, 2016, which is incorporated herein by reference in its entirety and for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under grant no. R01 AI094098, awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] The Apicomplexa is a large phylum containing parasites that are the causative agents for many serious human and animal diseases. Apicomplexa are unicellular spore-forming organisms that have multiple life stages. In the case of Toxoplasma gondii, infectious sporozoites contained in oocysts, which are shed from cats, and bradyzoites found in

undercooked meat, are infectious for humans. Human pathogens within the Apicomplexa include Plasmodium spp., (e.g. Plasmodium falciparum, Plasmodium vivax) Toxoplasma gondii, Babesia spp. (e.g. Babesia microti, Babesia bigemina), Cyclospora cayetanensis, Isospora belli, Sarcocystis neurona, and Cryptosporidium spp. (e.g., Cryptosporidium parvum or

Cryptosporidium hominis), which cause malaria, toxoplasmosis, babesiosis, cyclosporiasis, isosporiasis, sarcocystosis, and cryptosporidiosis respectively. Treatment and prevention of these and other Apicomplexa-associated diseases have been challenging and additional treatments are needed. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY OF THE INVENTION

[0004] In an aspect is provided a compound having the formula: (I). [0005] Y 1 is–N= or–CH=. R 1 is substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl. R 2 is 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. L 1 is–SO-, -SO 2 -,–O-, -S-,–N(R 3 )-, -B(R 6 )- (i.e. L 1 includes a boron), or substituted or

unsubstituted C 1 -C 3 alkylene. L 2 is a bond,–O-, -S-,–N(R 7 )-, -B(R 8 )- (i.e. L 2 includes a boron), substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. R 3 is hydrogen, halogen, substituted or unsubstituted alkyl,

or substituted or unsubstituted heteroalkyl; X 3 is independently halogen. R 6 is hydrogen, halogen, -

H, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, 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 7 is hydrogen, -CN, -COOH, -CX 7

3, substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 2 alkyl, unsubstituted C 1 -C 8 alkyl, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 4 alkyl, or unsubstituted C 1 -C 2 alkyl), or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 2 to 4 membered heteroalkyl, 2 to 3 membered heteroalkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted 2 to 3 membered heteroalkyl). R 8 is hydrogen, halogen, ,

H, 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. Each X 6 is independently– F, -Cl, -Br, or–I. X 7 is independently–F, -Cl, -Br, or–I. X 8 is independently–F, -Cl, -Br, or–I. [0006] In another aspect is provided a pharmaceutical composition including a

pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein. [0007] In an aspect is provided a method of treating an apicomplexan infection (e.g., Babesia spp., Plasmodium spp., Cryptosporidium parvum, Cryptosporidium hominis, Cyclospora cayetanensis, Isospora belli, Neospora caninum, Sarcocystis neurona, or Toxoplasma gondii infection), the method including administering to a subject in need thereof an effective amount of a compound described herein. [0008] In an aspect is provided a method of treating an apicomplexan associated disease, the method including administering to a subject in need thereof an effective amount of a compound described herein. [0009] In an aspect is provided a method of inhibiting calcium dependent protein kinase (CDPK) activity, the method including contacting the calcium dependent protein kinase with an effective amount of a compound described herein. [0010] In an aspect is provided a method of inhibiting Toxoplasma gondii calcium dependent protein kinase 1 (TgCDPK1) activity, the method including contacting the calcium dependent protein kinase 1 with an effective amount of a compound described herein. DETAILED DESCRIPTION

I. Definitions

[0011] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0012] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -. [0013] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. [0014] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited

by, -CH 2 CH 2 CH 2 CH 2 -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. [0015] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched non-cyclic chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g. O, N, P, Si, B, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, B, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited

to: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH- N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and–CH 2 -O-Si(CH 3 ) 3 . A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, B, or P). [0016] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,

alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'. Where“heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive.

Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0017] The terms“cycloalkyl” and“heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of“alkyl” and “heteroalkyl,” respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non- hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-1,2, dione, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. A

heterocycloalkyl moiety may include one ring heteroatom (e.g., O, N, S, Si, B, or P). A heterocycloalkyl moiety may include two optionally different ring heteroatoms (e.g., O, N, S, Si, B, or P). A heterocycloalkyl moiety may include three optionally different ring heteroatoms (e.g., O, N, S, Si, B, or P). A heterocycloalkyl moiety may include four optionally different ring heteroatoms (e.g., O, N, S, Si, B, or P). A heterocycloalkyl moiety may include five optionally different ring heteroatoms (e.g., O, N, S, Si, B, or P). A heterocycloalkyl moiety may include up to 8 optionally different ring heteroatoms (e.g., O, N, S, Si, B, or P). [0018] The terms“halo” or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C 1 -C 4 )alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0019] The term“acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0020] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4- biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of aryl and heteroaryl groups include pyridinyl,

pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl,

benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl,

pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroarylene. A heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S). A heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S). An aryl moiety may have a single ring. An aryl moiety may have two optionally different rings. An aryl moiety may have three optionally different rings. An aryl moiety may have four optionally different rings. A heteroaryl moiety may have one ring. A heteroaryl moiety may have two optionally different rings. A heteroaryl moiety may have three optionally different rings. A heteroaryl moiety may have four optionally different rings. A heteroaryl moiety may have five optionally different rings. [0021] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring

heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring

heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein. [0022] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0023] The term“alkylsulfonyl,” as used herein, means a moiety having the formula -S(O 2 )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g.,“C 1 -C 4 alkylsulfonyl”). [0024] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”,“cycloalkyl”,“het erocycloalkyl”, “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0025] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''',

-OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C( O) 2 R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NRSO 2 R', -NR'NR''R''', -ONR'R'', -NR'C=(O)NR''NR'''R'''', -CN, -NO 2 , in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like). [0026] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for

example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC (O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR' R'')=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NRSO 2 R', - NR'NR''R''', - ONR'R'',

- NR'C=(O)NR''NR'''R'''', -CN, -NO 2 , -R', -N 3 , -CH(Ph) 2 , fluoro(C 1 -C 4 )alkoxy, and fluoro(C 1 - C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0027] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0028] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure. [0029] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are

independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.

Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the

formula -(CRR') s -X'- (C''R''R''') d -, where s and d are independently -Integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0030] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), boron (B), and silicon (Si). [0031] A substituent group, as used herein, may be a group selected from the following moieties: (A) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 ,

-NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(i) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 ,

-NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(a) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 ,

-NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OC Br 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -O CH 2 F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl,

-CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 ,

-NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OC Br 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -O CH 2 F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl. [0032] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0033] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0034] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0035] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0036] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0037] The term“pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use. [0038] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. [0039] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. [0040] Provided herein are agents (e.g. compounds, drugs, therapeutic agents) that may be in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents). Additionally, prodrugs can be converted to agents (e.g. compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment. Prodrugs described herein include compounds that readily undergo chemical changes under select physiological conditions to provide agents (e.g. compounds, drugs, therapeutic agents) to a biological system (e.g. in a subject, in a cell, in the extracellular space near a cell). [0041] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0042] As used herein, the term“salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. [0043] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute

stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0044] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0045] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. [0046] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. [0047] Unless otherwise stated, structures depicted herein are also meant to include

compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention. [0048] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0049] The symbol“ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0050] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C 1 -C 20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. [0051] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. [0052] The terms“treating” or“treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, certain methods herein treat diseases associated with Apicomplexa infection (e.g., Plasmodium spp., Toxoplasma gondii, or Cryptosporidium parvum, Cryptosporidium hominis). Certain methods described herein may treat diseases associated with Apicomplexa infection (e.g., Plasmodium spp., Toxoplasma gondii, or

Cryptosporidium parvum, Cryptosporidium hominis) by inhibiting an Apicomplexa (e.g., Plasmodium spp., Toxoplasma gondii, or Cryptosporidium parvum, Cryptosporidium hominis) protein activity (e.g. CDPK1 (e.g., TgCDPK1)). Certain methods described herein may treat diseases associated with CDPK1 (e.g., TgCDPK1) activity by inhibiting CDPK1 (e.g.,

TgCDPK1) activity. For example, certain methods herein treat toxoplasmosis. For example certain methods herein treat toxoplasmosis by decreasing a symptom of toxoplasmosis.

Symptoms of toxoplasmosis would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat an infectious disease (e.g., Apicomplexa infection, Toxoplasma gondii infection, or toxoplasmosis). The term "treating" and conjugations thereof, include prevention of an injury, pathology, condition, or disease. [0053] An“effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce protein function, reduce one or more symptoms of a disease or condition). An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A therapeutically effective amount may be administered in one or more administrations. A“reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug or prodrug is an amount of a drug or prodrug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman,

Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0054] The term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease (e.g. toxoplasmosis or apicomplexan infection) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a disease associated with CDPK1 (e.g., TgCDPK1) activity may be treated with an agent (e.g. compound as described herein) effective for decreasing the level of CDPK1 (e.g., TgCDPK1) activity. For example, a disease associated with Apicomplexa infection (e.g., Plasmodium spp., Toxoplasma gondii, Cryptosporidium parvum, or Cryptosporidium hominis) may be treated with an agent (e.g. compound as described herein) effective for reducing the viability, proliferation, survival, or spread of an Apicomplexa organism (e.g., Plasmodium spp., Toxoplasma gondii, Cryptosporidium parvum, or

Cryptosporidium hominis). [0055] “Control” or“control experiment” or“standard control” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. [0056] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme. [0057] As defined herein, the term“inhibition”,“inhibit”,“inhibiting” and the like in reference to a protein-inhibitor (e.g. antagonist) interaction means negatively affecting (e.g. decreasing) the level of activity or function of the protein relative to the level of activity or function of the protein in the absence of the inhibitor. In some embodiments inhibition refers to reduction of a disease or symptoms of disease. Thus, inhibition may include, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating,

desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. [0058] As defined herein, the term“activation”,“activate”,“activating” and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g.

increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator (e.g. compound described herein). Thus, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein. [0059] The term“modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. In embodiments, a modulator is an anti- infectious disease agent. In embodiments, a modulator is a modulator of an Apicomplexa infection (e.g., Plasmodium spp., Toxoplasma gondii, Cryptosporidium parvum, or

Cryptosporidium hominis). In embodiments, a modulator is a modulator of the level of CDPK1 (e.g., TgCDPK1) activity. In embodiments, a modulator is a CDPK1 (e.g., TgCDPK1) activity inhibitor. [0060] “Chemotherapeutic” or“chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. [0061] “Patient” or“subject in need thereof” or“subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In some embodiments, a subject is human. [0062] “Disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the disease is a disease having a symptom of Apicomplexa infection (e.g., Plasmodium spp., Toxoplasma gondii, Cryptosporidium parvum, or

Cryptosporidium hominis). Cryptosporidiosis is associated with diarrheal disease especially in immunocompromised patients and young children. Symptoms include fluid loss, chronic wasting, failure to thrive and malnutrition. Acute toxoplasmosis is associated with swollen lymph nodes, muscle aches, fever, and fatigue. In those with weakened immune systems, symptoms can be more severe including headache, confusion, poor motor coordination, seizures, and impaired vision. In infants that are infected congenitally, symptoms can include intracranial calcification, chorioretinitis leading to later development of impaired vision, hydrocephalus, and neurological sequelae (seizures, delayed development of cognitive or motor skills). Chronic toxoplasmosis is associated with tissue cysts that are found in muscle and the central nervous system. Chronic toxoplasmosis has been associated with increased risk of schizophrenia, obsessive compulsive disorder, addiction, and biopolar disorder. Chronic infection also posses a risk of reactivation with loss of immunity resulting in development of toxoplasmic encephalitis, a potentially life threatening condition. Malaria is associated with high fever, shaking chills, sweating, headache, diarrhea, anemia, and seizures. Pregnancy associated malaria can lead to low birth weight and failure to thrive. Cerebral malaria can lead to coma and sudden death. In embodiments, the disease is toxoplasmosis. In some embodiments, the disease is malaria. In some embodiments, the disease is cryptosporidiosis. [0063] The term“signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components. [0064] The term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. [0065]“Nucleic acid” or“oligonucleotide” or“polynucleotide” or grammatical equivalents used herein means at least two nucleotides covalently linked together. The term“nucleic acid” includes single-, double-, or multiple-stranded DNA, RNA and analogs (derivatives) thereof. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.

[0066] A particular nucleic acid sequence also encompasses“splice variants.” Similarly, a particular protein encoded by a nucleic acid encompasses any protein encoded by a splice variant of that nucleic acid.“Splice variants,” as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different (alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate

polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition.

[0067] Nucleic acid is“operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally,“operably linked” means that the DNA sequences being linked are near each other, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0068] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% ,94%, 95%, 96%, 97%, 98%, 99% or higher identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 10 amino acids or 20 nucleotides in length, or more preferably over a region that is 10-50 amino acids or 20-50 nucleotides in length. As used herein, percent (%) amino acid sequence identity is defined as the percentage of amino acids in a candidate sequence that are identical to the amino acids in a reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods.

[0069] For sequence comparisons, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0070] A“comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 10 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well- known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds.1995 supplement)).

[0071] Twenty amino acids are commonly found in proteins. Those amino acids can be grouped into nine classes or groups based on the chemical properties of their side chains. Substitution of one amino acid residue for another within the same class or group is referred to herein as a “conservative” substitution. Conservative amino acid substitutions can frequently be made in a protein without significantly altering the conformation or function of the protein. Substitution of one amino acid residue for another from a different class or group is referred to herein as a“non- conservative” substitution. In contrast, non-conservative amino acid substitutions tend to modify conformation and function of a protein.

Example of amino acid classification

Small/Aliphatic residues: Gly, Ala, Val, Leu, Ile

Cyclic Imino Acid: Pro

Hydroxyl-containing Residues: Ser, Thr

Acidic Residues: Asp, Glu

Amide Residues: Asn, Gln

Basic Residues: Lys, Arg

Imidazole Residue: His

Aromatic Residues: Phe, Tyr, Trp

Sulfur-containing Residues: Met, Cys [0072] In some embodiments, the conservative amino acid substitution comprises substituting any of glycine (G), alanine (A), isoleucine (I), valine (V), and leucine (L) for any other of these aliphatic amino acids; serine (S) for threonine (T) and vice versa; aspartic acid (D) for glutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) and vice versa; lysine (K) for arginine (R) and vice versa; phenylalanine (F), tyrosine (Y) and tryptophan (W) for any other of these aromatic amino acids; and methionine (M) for cysteine (C) and vice versa. Other substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three- dimensional structure of the protein. For example, glycine (G) and alanine (A) can frequently be interchangeable, as can alanine (A) and valine (V). Methionine (M), which is relatively hydrophobic, can frequently be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are frequently

interchangeable in locations in which the significant feature of the amino acid residue is its charge and the differing pKs of these two amino acid residues are not significant. Still other changes can be considered“conservative” in particular environments (see, e.g.,

BIOCHEMISTRY at pp.13-15, 2nd ed. Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat’l Acad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995)

270(20):11882-11886).

[0073]“Polypeptide,”“peptide,” and“protein” are used herein interchangeably and mean any peptide-linked chain of amino acids, regardless of length or post-translational modification. As noted below, the polypeptides described herein can be, e.g., wild-type proteins, biologically- active fragments of the wild-type proteins, or variants of the wild- type proteins or fragments. Variants, in accordance with the disclosure, can contain amino acid substitutions, deletions, or insertions. The substitutions can be conservative or non-conservative.

[0074] Following expression, the proteins can be isolated. The term“purified” or“isolated” as applied to any of the proteins described herein refers to a polypeptide that has been separated or purified from components (e.g., proteins or other naturally-occurring biological or organic molecules) which naturally accompany it, e.g., other proteins, lipids, and nucleic acid in a cell expressing the proteins. Typically, a polypeptide is purified when it constitutes at least 60 (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the total protein in a sample.

[0075] An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to a residue when the selected residue occupies the same essential spatial or other structural relationship as a specified residue relative the rest of the protein. [0076] “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0077] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0078] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, anti-neurodegenerative disease agent, anti- inflammatory disease agent). The compound of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation, to increase degradation of a prodrug and release of the drug, detectable agent). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos.4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623- 645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857- 863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles. [0079] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of cancer or neurodegenerative disease). Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein. [0080] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g. symptoms of toxoplasmosis or an apicomplexa infection), kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention.

Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art. [0081] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0082] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. [0083] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. [0084] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0085] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent. [0086] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. [0087] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for cancer such as radiation or surgery. [0088] The term“calcium-dependent protein kinase” or“CDPK” refers to the calcium- dependent protein kinase of an Apicomplexa species. Included in the term“calcium-dependent protein kinase” or“CDPK” are the wildtype, natural variants, and mutant forms of the protein. In embodiments,“calcium-dependent protein kinase” or“CDPK” refers to the protein associated with UniProt KB-P62343, UniProt S7UHK8, UniProt KB S7UHK8_TOXGO, UniProt KB- Q6S4W0, UniProt KB-S8EXE8, or UniProtKB-S8EQY1. In embodiments, the reference numbers immediately above refer to the protein, and associated nucleic acids, known as of the date of filing of this application. In embodiments, the CDPK is CDPK1, CPKD2, or CDPK6. [0089] The term“calcium-dependent protein kinase 1” or“CDPK1” refers to the calcium- dependent protein kinase of Apicomplexa. In embodiments,“calcium-dependent protein kinase 1” or“CDPK1” or refers to the Toxoplasma gondii protein (TgCDPK1). Included in the term “calcium-dependent protein kinase 1” or“CDPK1” are the wildtype, natural variants, and mutant forms of the protein. In embodiments,“calcium-dependent protein kinase 1” or“CDPK1” refers to the protein associated with UniProt S7UHK8 and/or UniProtKB S7UHK8_TOXGO. In embodiments, the reference numbers immediately above refer to the protein, and associated nucleic acids, known as of the date of filing of this application. In embodiments, the CDPK1 is a CDPK1 protein from Pasmodium falciparum (e.g., UniProt KB-P62343). In embodiments, the CDPK1 is a CDPK1 protein from Cryptosporidium parvum (e.g., UniProt KB- Q6S4W0). In embodiments, the CDPK1 is a CDPK1 protein from Toxoplasma gondii (e.g., UniProt S7UHK8, or S7UHK8_TOXGO). [0090] As used herein, the term“infectious disease” refers to a disease or condition related to the presence of an organism (the agent or infectious agent) within or contacting the subject or patient. Examples include a bacterium, protozoa, protist, fungus, virus, or other microorganism. A“protist infectious disease” is an infectious disease wherein the organism is a protist. The terms“parasitic infectious disease,”“parasitic disease,” and“parasite infectious disease” are interchangeable and refer to a disease caused by an infectious agent that is a parasite, such as a protist or protozoa. In embodiments, a parasitic infectious disease is caused by an Apicomplexa (e.g., Babesia, Plasmodium spp., Cryptosporidium parvum, Cryptosporidium hominis,

Cyclospora cayetanensis, Isospora belli, Neospora caninum, Sarcocystis neurona, or Toxoplasma gondii). Examples of parasitic infectious diseases include babesiosis, malaria, neosporosis, cryptosporidiosis, cyclosporiasis, isosporiasis, neosporosis, sarcocystosis, and toxoplasmosis. In embodiments, the infectious agent is Toxoplasma gondii and the infectious disease is

toxoplasmosis. [0091] The term“Apicomplexa infection” as used herein is used in accordance with its plain ordinary meaning and refers to a disease or condition related to the presence of an Apicomplexa organism (the agent or infectious agent) within or contacting the subject or patient. Apicomplexa organism are eukaryotic organism (e.g., parasite or protist) which may be characterized according to cytoskeletal structures such as an apical complex or structures during their life cycle (e.g., the tachyzoites, bradyzoites, oocysts, sporocysts, sporozoites, or enteroepithelial) stage.

[0092] Non-limiting examples of apicomplexan genera include Babesia (e.g., Babesia bigemina, Babesia bovis, Babesia caballi, Babesia canis, Babesia cati, Babesia crassa, Babesia divergens, Babesia duncani, Babesia felis, Babesia gibsoni, Babesia herpailuri, Babesia jakimovi, Babesia major, Babesia microti, Babesia motasi, Babesia ovate, Babesia ovis, Babesia pantherae, or Babesia sp. 'north carolina dog' ), Plasmodium (e.g., Plasmodium accipiteris, Plasmodium achiotense, Plasmodium achromaticum, Plasmodium acuminatum, Plasmodium adleri, Plasmodium adunyinkai, Plasmodium aegyptensis, Plasmodium aeuminatum,

Plasmodium agamae, Plasmodium alaudae, Plasmodium alloelongatum, Plasmodium anasum, Plasmodium anomaluri, Plasmodium arachniformis, Plasmodium ashfordi, Plasmodium atheruri, Plasmodium audaciosum, Plasmodium auffenbergi, Plasmodium aurulentum,

Plasmodium australis, Plasmodium attenuatum, Plasmodium azurophilum, Plasmodium billbrayi, Plasmodium billcollinsi, Plasmodium balli, Plasmodium bambusicolai, Plasmodium basilisci, Plasmodium beaucournui, Plasmodium beebei, Plasmodium beltrani, Plasmodium berghei, Plasmodium bertii, Plasmodium bigueti, Plasmodium bioccai, Plasmodium biziurae, Plasmodium blacklocki, Plasmodium booliati, Plasmodium bouillize, Plasmodium bowiei, Plasmodium brodeni, Plasmodium brasilianum, Plasmodium brumpti, Plasmodium brygooi, Plasmodium bubalis, Plasmodium bucki, Plasmodium buteonis, Plasmodium caloti, Plasmodium capistrani, Plasmodium carmelinoi, Plasmodium cathemerium, Plasmodium caucasica, Plasmodium cephalophi, Plasmodium cercopitheci, Plasmodium chabaudi, Plasmodium chiricahuae, Plasmodium circularis, Plasmodium circumflexum, Plasmodium clelandi,

Plasmodium cnemaspi, Plasmodium cnemidophori, Plasmodium coatneyi, Plasmodium coggeshalli, Plasmodium coluzzii, Plasmodium colombiense, Plasmodium columbae,

Plasmodium cordyli, Plasmodium corradettii, Plasmodium coturnixi, Plasmodium coulangesi, Plasmodium cuculus, Plasmodium cyclopsi, Plasmodium cynomolgi bastianelli, Plasmodium cynomolgi ceylonensis, Plasmodium cynomolgi cynomolgi, Plasmodium dherteae, Plasmodium diminutivum, Plasmodium diploglossi, Plasmodium dissanaikei, Plasmodium dominicana, Plasmodium dorsti, Plasmodium draconis, Plasmodium durae, Plasmodium egerniae,

Plasmodium elongatum, Plasmodium eylesi, Plasmodium fairchildi, Plasmodium falciparum, Plasmodium fallax, Plasmodium fieldi, Plasmodium fischeri, Plasmodium foleyi, Plasmodium formosanum, Plasmodium forresteri, Plasmodium floridense, Plasmodium fragile, Plasmodium gaboni, Plasmodium gabaldoni, Plasmodium garnhami, Plasmodium gallinaceum, Plasmodium gemini, Plasmodium georgesi, Plasmodium ghadiriani, Plasmodium giganteum, Plasmodium giovannolai, Plasmodium ginsburgi, Plasmodium girardi, Plasmodium globularis, Plasmodium gloriai, Plasmodium gologoense, Plasmodium golvani, Plasmodium gonatodi, Plasmodium gonderi, Plasmodium gracilis, Plasmodium griffithsi, Plasmodium guangdong, Plasmodium gundersi, Plasmodium guyannense, Plasmodium heischi, Plasmodium hegneri, Plasmodium hermani, Plasmodium heroni, Plasmodium heteronucleare, Plasmodium hexamerium,

Plasmodium hispaniolae, Plasmodium hoionucleophilum, Plasmodium holaspi, Plasmodium holti, Plasmodium homocircumflexum, Plasmodium homopolare, Plasmodium huffi, Plasmodium hydrochaeri, Plasmodium hylobati, Plasmodium incertae, Plasmodium icipeensis, Plasmodium iguanae, Plasmodium inopinatum, Plasmodium inui, Plasmodium japonicum, Plasmodium jeanriouxi, Plasmodium jefferyi, Plasmodium jiangi, Plasmodium josephinae, Plasmodium joyeuxi, Plasmodium juxtanucleare, Plasmodium kachelibaensis, Plasmodium kadogoi,

Plasmodium kaninii, Plasmodium kempi, Plasmodium kentropyxi, Plasmodium knowlesi knowlesi, Plasmodium knowlesi edesoni, Plasmodium koreafense, Plasmodium kyaii,

Plasmodium lacertiliae, Plasmodium lagopi, Plasmodium lainsoni, Plasmodium landauae, Plasmodium lemuris, Plasmodium lenoblei, Plasmodium lepidoptiformis, Plasmodium lionatum, Plasmodium lophurae, Plasmodium loveridgei, Plasmodium lucens, Plasmodium lutzi,

Plasmodium lygosomae,Plasmodium mabuiae, Plasmodium mackerrasae, Plasmodium mackiei, Plasmodium maculilabre, Plasmodium maior, Plasmodium majus, Plasmodium malagasi, Plasmodium malariae, Plasmodium multivacuolaris, Plasmodium marginatum, Plasmodium matutinum, Plasmodium megaglobularis, Plasmodium megalotrypa, Plasmodium melanoleuca, Plasmodium melanipherum, Plasmodium merulae, Plasmodium mexicanum, Plasmodium michikoa, Plasmodium minasense, Plasmodium minuoviride, Plasmodium modestum,

Plasmodium mohammedi, Plasmodium morulum, Plasmodium multiformis, Plasmodium narayani, Plasmodium necatrix, Plasmodium neusticuri, Plasmodium nucleophilium,

Plasmodium octamerium, Plasmodium odhiamboi, Plasmodium odocoilei, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, Plasmodium pachysomum, Plasmodium paddae,

Plasmodium papernai, Plasmodium parahexamerium, Plasmodium paranucleophilum,

Plasmodium parvulum, Plasmodium pedioecetii, Plasmodium pelaezi, Plasmodium

percygarnhami, Plasmodium pessoai, Plasmodium petersi, Plasmodium pifanoi, Plasmodium pinotti, Plasmodium pitheci, Plasmodium pitmani, Plasmodium polare, Plasmodium

polymorphum, Plasmodium pulmophilium, Plasmodium pythonias, Plasmodium quelea,

Plasmodium reichenowi, Plasmodium relictum, Plasmodium reniai, Plasmodium rhadinurum, Plasmodium rhodaini, Plasmodium robinsoni, Plasmodium rousetti, Plasmodium rousseloti, Plasmodium rouxi, Plasmodium sandoshami, Plasmodium sapaaensis, Plasmodium sasai, Plasmodium saurocaudatum, Plasmodium schwetzi, Plasmodium sergentorum, Plasmodium scelopori, Plasmodium scorzai, Plasmodium semiovale, Plasmodium semnopitheci, Plasmodium silvaticum, Plasmodium simium, Plasmodium simplex, Plasmodium smirnovi, Plasmodium snounoui, Plasmodium stellatum, Plasmodium stuthionis, Plasmodium tanzaniae, Plasmodium tenue, Plasmodium tejerai, Plasmodium telfordi, Plasmodium tomodoni, Plasmodium torrealbai, Plasmodium toucani, Plasmodium traguli, Plasmodium tranieri, Plasmodium tribolonti, Plasmodium tropiduri, Plasmodium tumbayaensis, Plasmodium tyrio, Plasmodium uilenbergi, Plasmodium uluguruense, Plasmodium uncinatum, Plasmodium unalis, Plasmodium

uzungwiense, Plasmodium watteni, Plasmodium wenyoni, Plasmodium vacuolatum, Plasmodium valkiunasi, Plasmodium vastator, Plasmodium vaughani, Plasmodium vautieri, Plasmodium venkataramiahii, Plasmodium vinckei, Plasmodium vivax, Plasmodium volans, Plasmodium voltaicum, Plasmodium wenyoni, Plasmodium yoelii, Plasmodium youngi, or Plasmodium zonuriae), Cryptosporidium (e.g., Cryptosporidium andersoni, Cryptosporidium bailey,

Cryptosporidium bovis, Cryptosporidium cervine, Cryptosporidium canis, Cryptosporidium cuniculus, Cryptosporidium ducismarci, Cryptosporidium fayeri, Cryptosporidium felis, Cryptosporidium fragile, Cryptosporidium galli, Cryptosporidium hominis, Cryptosporidium marcopodum, Cryptosporidium meleagridis, Cryptosporidium molnari, Cryptosporidium muris, Cryptosporidium parvum, Cryptosporidium ryanae, Cryptosporidium saurophilum,

Cryptosporidium serpentis, Cryptosporidium suis, Cryptosporidium ubiquitum, Cryptosporidium wrairi, or Cryptosporidium xiaoi), Cyclospora (e.g., Cyclospora cayetanensis), Isospora belli (e.g., Iaspora almaataensis, Iaspora anseris, Iaspora ashmoonensis, Iaspora bahiensis, Iaspora belli, Iaspora bigemina, Iaspora bronchocelae, Iaspora buteonis, Iaspora buteonis, Iaspora canis, Iaspora felis, Iaspora hammondi, Iaspora heydorni, Iaspora hominis, Iaspora mandari, Iaspora mejiro, Iaspora neorivolta, Iaspora ohioensis, Iaspora peromysci, Iaspora rara, Iaspora ratti, Iaspora rivolta, Iaspora suis, Iaspora thibetana,or Iaspora wallacei), Neospora (e.g., Neospora caninum or Neospora hughesi) or Toxoplasma gondii. In embodiments, the apicomplexan is an apicomplexan species found in humans. In embodiments, the apicomplexan is an apicomplexan species found in mammals. In embodiments, the apicomplexan is disease causing apicomplexan species in mammals. [0093] As used herein the abbreviation“sp.” for species means at least one species (e.g., 1, 2, 3, 4, 5, or more species) of the indicated genus. The abbreviation“spp.” for species means 2 or more species (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the indicated genus. In embodiments, methods and compositions provided herein comprise a single species within an indicated genus or indicated genera, or 2 or more (e.g., a plurality comprising more than 2) species within an indicated genus or indicated genera. In embodiments, 1, 2, 3, 4, 5, or more or all of the indicated species is or are isolated.

II. Compositions

[0094] In an aspect is provided a compound having the formula: (I). [0095] Y 1 is–N= or–CH=. R 1 is substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl. R 2 is 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. L 1 is–SO-, -SO 2 -,–O-, -S-,–N(R 3 )-, -B(R 6 )- (i.e. L 1 includes a boron), or substituted or unsubstituted C 1 -C 3 alkylene (e.g., C 1 -C 2 alkylene, C 2 -C 3 alkylene, n-propylene, isopropylene, ethylene, or methylene). L 2 is a bond,–O-, -S-,–N(R 7 )-, -B(R 8 )- (i.e. L 2 includes a boron), substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. R 3 is hydrogen, halogen, -SO 2 CH 3 , -CN, -COOH, -COCH 3 , -CX3

3, -CHX3

2, -CH 2 X 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; X 3 is independently halogen. R 6 is hydrogen, halogen, -CX 6

3, -CHX6

2, -CH 2 X 6 , -OCX 6

3, - OCH 2 X 6 , -OCHX 6

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)O H, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, 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 7 is hydrogen, -CN, -COOH, -CX 7

3, substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 2 alkyl, unsubstituted C 1 -C 8 alkyl, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 4 alkyl, or unsubstituted C 1 -C 2 alkyl), or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 2 to 4 membered heteroalkyl, 2 to 3 membered heteroalkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted 2 to 3 membered heteroalkyl). R 8 is hydrogen, halogen, -CX 8

3,

-CHX 8

2, -CH 2 X 8 , -OCX 8

3, -OCH 2 X 8 , -OCHX 8

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)OH, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHO H, 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. Each X 6 is independently– F, -Cl, -Br, or–I. Each X 7 is independently–F, -Cl, -Br, or–I. Each X 8 is independently– F, -Cl, -Br, or–I. [0096] In embodiments, R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In embodiments, R 2 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, L 1 is–O-, -S-, or–N(R 3 )-. In embodiments, L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, R 3 is hydrogen, -CN, -COOH, -CF 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0097] In embodiments, Y 1 is–N=. In embodiments, Y 1 is–CH=. [0098] In embodiments, R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl. [0099] In embodiments, R 1 is substituted or unsubstituted aryl. In embodiments, R 1 is substituted aryl. In embodiments, R 1 is unsubstituted aryl. In embodiments, R 1 is substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 1 is substituted C 6 -C 10 aryl. In embodiments, R 1 is unsubstituted C 6 -C 10 aryl. In embodiments, R 1 is substituted or unsubstituted C 10 aryl. In embodiments, R 1 is substituted C 10 aryl. In embodiments, R 1 is unsubstituted C 10 aryl. In embodiments, R 1 is substituted or unsubstituted phenyl. In embodiments, R 1 is substituted phenyl. In embodiments, R 1 is unsubstituted phenyl. [0100] In embodiments, R 1 is substituted or unsubstituted heteroaryl. In embodiments, R 1 is substituted heteroaryl. In embodiments, R 1 is unsubstituted heteroaryl. In embodiments, R 1 is substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 1 is substituted 5 to 10 membered heteroaryl. In embodiments, R 1 is unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 1 is substituted 5 to 9 membered heteroaryl. In embodiments, R 1 is unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 1 is substituted 5 to 6 membered heteroaryl. In embodiments, R 1 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 5 membered heteroaryl. In embodiments, R 1 is substituted 5 membered heteroaryl. In embodiments, R 1 is unsubstituted 5 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 1 is substituted 6 membered heteroaryl. In embodiments, R 1 is unsubstituted 6 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 9 membered heteroaryl. In embodiments, R 1 is substituted 9 membered heteroaryl. In embodiments, R 1 is unsubstituted 9 membered heteroaryl. In embodiments, R 1 is substituted or unsubstituted 10 membered heteroaryl. In embodiments, R 1 is substituted 10 membered heteroaryl. In embodiments, R 1 is unsubstituted 10 membered heteroaryl. [0101] In embodiments, R 1 is substituted or unsubstituted phenyl. In embodiments, R 1 is substituted or unsubstituted napththyl. In embodiments, R 1 is substituted or unsubstituted benzofuranyl. In embodiments, R 1 is substituted or unsubstituted isobenzofuranyl. In embodiments, R 1 is substituted or unsubstituted indolyl. In embodiments, R 1 is substituted or unsubstituted isoindolyl. In embodiments, R 1 is substituted or unsubstituted benzothienyl. In embodiments, R 1 is substituted or unsubstituted benzo[c]thienyl. In embodiments, R 1 is substituted or unsubstituted benzimidazolyl. In embodiments, R 1 is substituted or unsubstituted benzoisoxazolyl. In embodiments, R 1 is substituted or unsubstituted azaindolyl. In

embodiments, R 1 is substituted or unsubstituted pyrrolopyridinyl. In embodiments, R 1 is substituted or unsubstituted purinyl. In embodiments, R 1 is substituted or unsubstituted indazolyl. In embodiments, R 1 is substituted or unsubstituted benzoxazolyl. In embodiments, R 1 is substituted or unsubstituted benzisoxazolyl. In embodiments, R 1 is substituted or

unsubstituted benzothiazolyl. In embodiments, R 1 is substituted or unsubstituted quinolinyl. In embodiments, R 1 is substituted or unsubstituted isoquinolinyl. In embodiments, R 1 is substituted or unsubstituted quinoxalinyl. In embodiments, R 1 is substituted or unsubstituted quinazolinyl. In embodiments, R 1 is substituted or unsubstituted cinnolinyl. In embodiments, R 1 is substituted or unsubstituted or phthalazinyl. In embodiments, R 1 is substituted or unsubstituted furanyl. In embodiments, R 1 is substituted or unsubstituted pyrrolyl. In embodiments, R 1 is substituted or unsubstituted thienyl. In embodiments, R 1 is substituted or unsubstituted imidazolyl. In embodiments, R 1 is substituted or unsubstituted pyrazolyl. In embodiments, R 1 is substituted or unsubstituted oxazolyl. In embodiments, R 1 is substituted or unsubstituted isoxazolyl. In embodiments, R 1 is substituted or unsubstituted thiazolyl. In embodiments, R 1 is substituted or unsubstituted isothiazolyl. In embodiments, R 1 is substituted or unsubstituted triazolyl. In embodiments, R 1 is substituted or unsubstituted oxadiazolyl. In embodiments, R 1 is substituted or unsubstituted thiadiazolyl. In embodiments, R 1 is substituted or unsubstituted tetrazolyl. In embodiments, R 1 is substituted or unsubstituted pyridinyl. In embodiments, R 1 is substituted or unsubstituted pyrazinyl. In embodiments, R 1 is substituted or unsubstituted pyrimidinyl. In embodiments, R 1 is substituted or unsubstituted pyridazinyl. In embodiments, R 1 is substituted or unsubstituted triazinyl. [0102] In embodiments, R 1 is substituted phenyl. In embodiments, R 1 is substituted napththyl. In embodiments, R 1 is substituted benzofuranyl. In embodiments, R 1 is substituted

isobenzofuranyl. In embodiments, R 1 is substituted indolyl. In embodiments, R 1 is substituted isoindolyl. In embodiments, R 1 is substituted benzothienyl. In embodiments, R 1 is substituted benzo[c]thienyl. In embodiments, R 1 is substituted benzimidazolyl. In embodiments, R 1 is substituted azaindolyl. In embodiments, R 1 is substituted benzoisoxazolyl. In embodiments, R 1 is substituted pyrrolopyridinyl. In embodiments, R 1 is substituted purinyl. In embodiments, R 1 is substituted indazolyl. In embodiments, R 1 is substituted benzoxazolyl. In embodiments, R 1 is substituted benzisoxazolyl. In embodiments, R 1 is substituted benzothiazolyl. In embodiments, R 1 is substituted quinolinyl. In embodiments, R 1 is substituted isoquinolinyl. In embodiments, R 1 is substituted quinoxalinyl. In embodiments, R 1 is substituted quinazolinyl. In embodiments, R 1 is substituted cinnolinyl. In embodiments, R 1 is substituted or phthalazinyl. In embodiments, R 1 is substituted furanyl. In embodiments, R 1 is substituted pyrrolyl. In embodiments, R 1 is substituted thienyl. In embodiments, R 1 is substituted imidazolyl. In embodiments, R 1 is substituted pyrazolyl. In embodiments, R 1 is substituted oxazolyl. In embodiments, R 1 is substituted isoxazolyl. In embodiments, R 1 is substituted thiazolyl. In embodiments, R 1 is substituted isothiazolyl. In embodiments, R 1 is substituted triazolyl. In embodiments, R 1 is substituted oxadiazolyl. In embodiments, R 1 is substituted thiadiazolyl. In embodiments, R 1 is substituted tetrazolyl. In embodiments, R 1 is substituted pyridinyl. In embodiments, R 1 is substituted pyrazinyl. In embodiments, R 1 is substituted pyrimidinyl. In embodiments, R 1 is substituted pyridazinyl. In embodiments, R 1 is substituted triazinyl. [0103] In embodiments, R 1 is unsubstituted phenyl. In embodiments, R 1 is unsubstituted napththyl. In embodiments, R 1 is unsubstituted benzofuranyl. In embodiments, R 1 is unsubstituted isobenzofuranyl. In embodiments, R 1 is unsubstituted indolyl. In embodiments, R 1 is unsubstituted isoindolyl. In embodiments, R 1 is unsubstituted benzothienyl. In

embodiments, R 1 is unsubstituted benzo[c]thienyl. In embodiments, R 1 is unsubstituted benzimidazolyl. In embodiments, R 1 is unsubstituted azaindolyl. In embodiments, R 1 is unsubstituted benzoisoxazolyl. In embodiments, R 1 is unsubstituted pyrrolopyridinyl. In embodiments, R 1 is unsubstituted purinyl. In embodiments, R 1 is unsubstituted indazolyl. In embodiments, R 1 is unsubstituted benzoxazolyl. In embodiments, R 1 is unsubstituted

benzisoxazolyl. In embodiments, R 1 is unsubstituted benzothiazolyl. In embodiments, R 1 is unsubstituted quinolinyl. In embodiments, R 1 is unsubstituted isoquinolinyl. In embodiments, R 1 is unsubstituted quinoxalinyl. In embodiments, R 1 is unsubstituted quinazolinyl. In embodiments, R 1 is unsubstituted cinnolinyl. In embodiments, R 1 is unsubstituted or

phthalazinyl. In embodiments, R 1 is unsubstituted furanyl. In embodiments, R 1 is unsubstituted pyrrolyl. In embodiments, R 1 is unsubstituted thienyl. In embodiments, R 1 is unsubstituted imidazolyl. In embodiments, R 1 is unsubstituted pyrazolyl. In embodiments, R 1 is unsubstituted oxazolyl. In embodiments, R 1 is unsubstituted isoxazolyl. In embodiments, R 1 is unsubstituted thiazolyl. In embodiments, R 1 is unsubstituted isothiazolyl. In embodiments, R 1 is unsubstituted triazolyl. In embodiments, R 1 is unsubstituted oxadiazolyl. In embodiments, R 1 is unsubstituted thiadiazolyl. In embodiments, R 1 is unsubstituted tetrazolyl. In embodiments, R 1 is

unsubstituted pyridinyl. In embodiments, R 1 is unsubstituted pyrazinyl. In embodiments, R 1 is unsubstituted pyrimidinyl. In embodiments, R 1 is unsubstituted pyridazinyl. In embodiments, R 1 is unsubstituted triazinyl. [0104] In embodiments, R 1 is R 20 -substituted or unsubstituted aryl or R 20 -substituted or unsubstituted heteroaryl. In embodiments, R 1 is R 20 -substituted or unsubstituted phenyl or R 20 - substituted or unsubstituted 5 to 6 membered heteroaryl. [0105] R 20 is independently halogen, -CX 20

3, -CHX20

2, -CH 2 X 20 , -OCH 2 X 20 , -OCX 20

3, -OCHX 20

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 21 -substituted or unsubstituted alkyl, R 21 -substituted or unsubstituted heteroalkyl, R 21 - substituted or unsubstituted cycloalkyl, R 21 -substituted or unsubstituted heterocycloalkyl, R 21 - substituted or unsubstituted aryl, or R 21 -substituted or unsubstituted heteroaryl. X 20 is halogen. In embodiments, X 20 is F. [0106] In embodiments, R 20 is independently

halogen, -CX 20

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H,

-SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 20

3, -OCHX20

2, R 21 -substituted or unsubstituted C 1 -C 8 alkyl, R 21 - substituted or unsubstituted 2 to 8 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 21 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 21 -substituted or unsubstituted phenyl, or R 21 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 20 is– F,-Cl, -Br, or–I. In embodiments, R 20 is independently halogen, unsubstituted C 1 -C 3 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 20 is independently halogen, unsubstituted methyl, or -OCH 3 . In embodiments, R 20 is -Br. In embodiments, R 20 is -Cl. In embodiments, R 20 is -F. In embodiments, R 20 is -OCH 3 . In embodiments, R 20 is -CH 3 . In embodiments, R 20 is -CF 3 . [0107] R 21 is independently oxo, halogen, -CX 21

3, -CHX21

2, -CH 2 X 21 , -OCH 2 X 21 , -OCX 21

3, -OCHX 21

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H,

-NHC(O)OH, -NHOH, R 22 -substituted or unsubstituted alkyl, R 22 -substituted or unsubstituted heteroalkyl, R 22 -substituted or unsubstituted cycloalkyl, R 22 -substituted or unsubstituted heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 -substituted or unsubstituted heteroaryl. In embodiments, R 21 is independently oxo,

halogen, -CX 21

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 21

3, -OCHX21

2, R 22 -substituted or unsubstituted C 1 -C 8 alkyl, R 22 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 22 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 22 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 22 -substituted or

unsubstituted phenyl, or R 22 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 21 is– F, -Cl, -Br, or–I. [0108] R 22 is independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0109] In embodiments, R 22 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 22 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0110] In embodiments R 2 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments R 2 is hydrogen.

[0111] In embodiments, R 2 is substituted or unsubstituted alkyl. In embodiments, R 2 is substituted alkyl. In embodiments, R 2 is unsubstituted alkyl. In embodiments, R 2 is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted C 1 -C 8 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is substituted C 1 -C 4 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is R 23 -substituted or unsubstituted alkyl. In embodiments, R 2 is R 23 - substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl. In embodiments, R 2 is unsubstituted pentyl. [0112] In embodiments, R 2 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 2 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0113] In embodiments, R 2 is R 23 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 2 is R 23 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 2 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0114] In embodiments, R 2 is substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 2 is substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 2 is substituted or unsubstituted cycloheptanyl. In embodiments, R 2 is substituted or unsubstituted cyclohexanyl. In embodiments, R 2 is substituted or unsubstituted cyclopentanyl. In embodiments, R 2 is substituted or unsubstituted cyclooctanyl. [0115] In embodiments, R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 2 is substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 2 is substituted or unsubstituted C 5 -C 6 cycloalkyl. In embodiments, R 2 is substituted C 3 -C 8 cycloalkyl. In embodiments, R 2 is substituted C 3 -C 6 cycloalkyl. In embodiments, R 2 is substituted C 5 -C 6 cycloalkyl. In embodiments, R 2 is unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 2 is unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 2 is unsubstituted C 5 -C 6 cycloalkyl. [0116] In embodiments, R 2 is R 23 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 2 is R 23 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R2 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 2 is R 23 -substituted or unsubstituted cyclooctanyl. In embodiments, R 2 is R 23 - substituted or unsubstituted cycloheptanyl. In embodiments, R 2 is R 23 -substituted or

unsubstituted cyclohexanyl. In embodiments, R 2 is R 23 -substituted or unsubstituted

cyclopentanyl. In embodiments, R 2 is R 23 -substituted cyclooctanyl. In embodiments, R 2 is R 23 - substituted cycloheptanyl. In embodiments, R 2 is R 23 -substituted cyclohexanyl. In embodiments, R 2 is R 23 -substituted cyclopentanyl. In embodiments, R 2 is unsubstituted cyclooctanyl. In embodiments, R 2 is unsubstituted cycloheptanyl. In embodiments, R 2 is unsubstituted

cyclohexanyl. In embodiments, R 2 is unsubstituted cyclopentanyl. In embodiments, R 2 is R 23 - substituted cycloheptanyl. In embodiments, R 2 is R 23 -substituted cyclohexanyl. In embodiments, R 2 is R 23 -substituted cyclopentanyl. [0117] In embodiments, R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted heterocycloalkyl. In embodiments, R 2 is substituted heterocycloalkyl. In embodiments, R 2 is unsubstituted heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R 2 is substituted 3 to 7 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 3 to 7 membered

heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 2 is substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 3 to 5 membered heterocycloalkyl. In embodiments, R 2 is substituted 3 to 5 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 3 to 5 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R 2 is substituted 5 to 6 membered

heterocycloalkyl. In embodiments, R 2 is unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 3 membered heterocycloalkyl. In embodiments, R 2 is substituted 3 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 3 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 2 is substituted 4 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 4 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 5 membered heterocycloalkyl. In embodiments, R 2 is substituted 5 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 5 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 6 membered heterocycloalkyl. In

embodiments, R 2 is substituted 6 membered heterocycloalkyl. In embodiments, R 2 is

unsubstituted 6 membered heterocycloalkyl. In embodiments, R 2 is substituted or unsubstituted 7 membered heterocycloalkyl. In embodiments, R 2 is substituted 7 membered heterocycloalkyl. In embodiments, R 2 is unsubstituted 7 membered heterocycloalkyl. [0118] In embodiments, R 2 is substituted or unsubstituted heteroaryl. In embodiments, R 2 is substituted heteroaryl. In embodiments, R 2 is unsubstituted heteroaryl. In embodiments, R 2 is substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 2 is substituted 5 to 10 membered heteroaryl. In embodiments, R 2 is unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 2 is substituted 5 to 9 membered heteroaryl. In embodiments, R 2 is unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 2 is substituted 5 to 6 membered heteroaryl. In embodiments, R 2 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 5 membered heteroaryl. In embodiments, R 2 is substituted 5 membered heteroaryl. In embodiments, R 2 is unsubstituted 5 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 2 is substituted 6 membered heteroaryl. In embodiments, R 2 is unsubstituted 6 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 9 membered heteroaryl. In embodiments, R 2 is substituted 9 membered heteroaryl. In embodiments, R 2 is unsubstituted 9 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted 10 membered heteroaryl. In embodiments, R 2 is substituted 10 membered heteroaryl. In embodiments, R 2 is unsubstituted 10 membered heteroaryl. [0119] In embodiments, R 2 is substituted or unsubstituted aziridinyl. In embodiments, R 2 is substituted or unsubstituted azirinyl. In embodiments, R 2 is substituted or unsubstituted diaziridinyl. In embodiments, R 2 is substituted or unsubstituted diazirinyl. In embodiments, R 2 is substituted or unsubstituted oxaziridinyl. In embodiments, R 2 is substituted or unsubstituted azetidinyl. In embodiments, R 2 is substituted or unsubstituted azetyl. In embodiments, R 2 is substituted or unsubstituted diazetidinyl. In embodiments, R 2 is substituted or unsubstituted diazetyl. In embodiments, R 2 is substituted or unsubstituted pyrrolidinyl. In embodiments, R 2 is substituted or unsubstituted pyrazolidinyl. In embodiments, R 2 is substituted or unsubstituted oxazolidinyl. In embodiments, R 2 is substituted or unsubstituted isoxazolidinyl. In

embodiments, R 2 is substituted or unsubstituted thiazolidinyl. In embodiments, R 2 is substituted or unsubstituted isothiazolidinyl. In embodiments, R 2 is substituted or unsubstituted furazanyl. In embodiments, R 2 is substituted or unsubstituted dithiazolyl. In embodiments, R 2 is substituted or unsubstituted piperidinyl. In embodiments, R 2 is substituted or unsubstituted piperazinyl. In embodiments, R 2 is substituted or unsubstituted morpholinyl. In embodiments, R 2 is substituted or unsubstituted thiomorpholinyl. [0120] In embodiments, R 2 is substituted aziridinyl. In embodiments, R 2 is substituted azirinyl. In embodiments, R 2 is substituted diaziridinyl. In embodiments, R 2 is substituted diazirinyl. In embodiments, R 2 is substituted oxaziridinyl. In embodiments, R 2 is substituted azetidinyl. In embodiments, R 2 is substituted azetyl. In embodiments, R 2 is substituted diazetidinyl. In embodiments, R 2 is substituted diazetyl. In embodiments, R 2 is substituted pyrrolidinyl. In embodiments, R 2 is substituted pyrazolidinyl. In embodiments, R 2 is substituted oxazolidinyl. In embodiments, R 2 is substituted isoxazolidinyl. In embodiments, R 2 is substituted thiazolidinyl. In embodiments, R 2 is substituted isothiazolidinyl. In embodiments, R 2 is substituted furazanyl. In embodiments, R 2 is substituted dithiazolyl. In embodiments, R 2 is substituted piperidinyl. In embodiments, R 2 is substituted piperazinyl. In embodiments, R 2 is substituted morpholinyl. In embodiments, R 2 is substituted thiomorpholinyl. [0121] In embodiments, R 2 is unsubstituted aziridinyl. In embodiments, R 2 is unsubstituted azirinyl. In embodiments, R 2 is unsubstituted diaziridinyl. In embodiments, R 2 is unsubstituted diazirinyl. In embodiments, R 2 is unsubstituted oxaziridinyl. In embodiments, R 2 is

unsubstituted azetidinyl. In embodiments, R 2 is unsubstituted azetyl. In embodiments, R 2 is unsubstituted diazetidinyl. In embodiments, R 2 is unsubstituted diazetyl. In embodiments, R 2 is unsubstituted pyrrolidinyl. In embodiments, R 2 is unsubstituted pyrazolidinyl. In embodiments, R 2 is unsubstituted oxazolidinyl. In embodiments, R 2 is unsubstituted isoxazolidinyl. In embodiments, R 2 is unsubstituted thiazolidinyl. In embodiments, R 2 is unsubstituted

isothiazolidinyl. In embodiments, R 2 is unsubstituted furazanyl. In embodiments, R 2 is unsubstituted dithiazolyl. In embodiments, R 2 is unsubstituted piperidinyl. In embodiments, R 2 is unsubstituted piperazinyl. In embodiments, R 2 is unsubstituted morpholinyl. In embodiments, R 2 is unsubstituted thiomorpholinyl. [0122] In embodiments, R 2 is substituted or unsubstituted piperidinyl. In embodiments, R 2 is substituted or unsubstituted piperazinyl. In embodiments, R 2 is substituted or unsubstituted benzofuranyl. In embodiments, R 2 is substituted or unsubstituted isobenzofuranyl. In embodiments, R 2 is substituted or unsubstituted indolyl. In embodiments, R 2 is substituted or unsubstituted isoindolyl. In embodiments, R 2 is substituted or unsubstituted benzothienyl. In embodiments, R 2 is substituted or unsubstituted benzo[c]thienyl. In embodiments, R 2 is substituted or unsubstituted benzimidazolyl. In embodiments, R 2 is substituted or unsubstituted azaindolyl. In embodiments, R 2 is substituted or unsubstituted benzoisoxazolyl. In

embodiments, R 2 is substituted or unsubstituted pyrrolopyridinyl. In embodiments, R 2 is substituted or unsubstituted purinyl. In embodiments, R 2 is substituted or unsubstituted indazolyl. In embodiments, R 2 is substituted or unsubstituted benzoxazolyl. In embodiments, R 2 is substituted or unsubstituted benzisoxazolyl. In embodiments, R 2 is substituted or

unsubstituted benzothiazolyl. In embodiments, R 2 is substituted or unsubstituted quinolinyl. In embodiments, R 2 is substituted or unsubstituted isoquinolinyl. In embodiments, R 2 is substituted or unsubstituted quinoxalinyl. In embodiments, R 2 is substituted or unsubstituted quinazolinyl. In embodiments, R 2 is substituted or unsubstituted cinnolinyl. In embodiments, R 2 is substituted or unsubstituted phthalazinyl. In embodiments, R 2 is substituted or unsubstituted furanyl. In embodiments, R 2 is substituted or unsubstituted pyrrolyl. In embodiments, R 2 is substituted or unsubstituted thienyl. In embodiments, R 2 is substituted or unsubstituted imidazolyl. In embodiments, R 2 is substituted or unsubstituted pyrazolyl. In embodiments, R 2 is substituted or unsubstituted oxazolyl. In embodiments, R 2 is substituted or unsubstituted isoxazolyl. In embodiments, R 2 is substituted or unsubstituted thiazolyl. In embodiments, R 2 is substituted or unsubstituted isothiazolyl. In embodiments, R 2 is substituted or unsubstituted triazolyl. In embodiments, R 2 is substituted or unsubstituted oxadiazolyl. In embodiments, R 2 is substituted or unsubstituted thiadiazolyl. In embodiments, R 2 is substituted or unsubstituted tetrazolyl. In embodiments, R 2 is substituted or unsubstituted pyridinyl. In embodiments, R 2 is substituted or unsubstituted pyrazinyl. In embodiments, R 2 is substituted or unsubstituted pyrimidinyl. In embodiments, R 2 is substituted or unsubstituted pyridazinyl. In embodiments, R 2 is substituted or unsubstituted triazinyl. In embodiments, R 2 is substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 2 is substituted or unsubstituted pyridinyl. In embodiments, R 2 is substituted or unsubstituted pyrazinyl. In embodiments, R 2 is substituted or unsubstituted pyrimidinyl. In embodiments, R 2 is substituted or unsubstituted pyridazinyl. [0123] In embodiments, R 2 is substituted piperidinyl. In embodiments, R 2 is substituted piperazinyl. In embodiments, R 2 is substituted benzofuranyl. In embodiments, R 2 is substituted isobenzofuranyl. In embodiments, R 2 is substituted indolyl. In embodiments, R 2 is substituted isoindolyl. In embodiments, R 2 is substituted benzothienyl. In embodiments, R 2 is substituted benzo[c]thienyl. In embodiments, R 2 is substituted benzimidazolyl. In embodiments, R 2 is substituted azaindolyl. In embodiments, R 2 is substituted benzoisoxazolyl. In embodiments, R 2 is substituted pyrrolopyridinyl. In embodiments, R 2 is substituted purinyl. In embodiments, R 2 is substituted indazolyl. In embodiments, R 2 is substituted benzoxazolyl. In embodiments, R 2 is substituted benzisoxazolyl. In embodiments, R 2 is substituted benzothiazolyl. In embodiments, R 2 is substituted quinolinyl. In embodiments, R 2 is substituted isoquinolinyl. In embodiments, R 2 is substituted quinoxalinyl. In embodiments, R 2 is substituted quinazolinyl. In embodiments, R 2 is substituted cinnolinyl. In embodiments, R 2 is substituted phthalazinyl. In embodiments, R 2 is substituted furanyl. In embodiments, R 2 is substituted pyrrolyl. In embodiments, R 2 is substituted thienyl. In embodiments, R 2 is substituted imidazolyl. In embodiments, R 2 is substituted pyrazolyl. In embodiments, R 2 is substituted oxazolyl. In embodiments, R 2 is substituted isoxazolyl. In embodiments, R 2 is substituted thiazolyl. In embodiments, R 2 is substituted isothiazolyl. In embodiments, R 2 is substituted triazolyl. In embodiments, R 2 is substituted oxadiazolyl. In embodiments, R 2 is substituted thiadiazolyl. In embodiments, R 2 is substituted tetrazolyl. In embodiments, R 2 is substituted pyridinyl. In embodiments, R 2 is substituted pyrazinyl. In embodiments, R 2 is substituted pyrimidinyl. In embodiments, R 2 is substituted pyridazinyl. In embodiments, R 2 is substituted triazinyl. In embodiments, R 2 is substituted 6 membered heteroaryl. In embodiments, R 2 is substituted pyridinyl. In

embodiments, R 2 is substituted pyrazinyl. In embodiments, R 2 is substituted pyrimidinyl. In embodiments, R 2 is substituted pyridazinyl. [0124] In embodiments, R 2 is unsubstituted piperidinyl. In embodiments, R 2 is unsubstituted piperazinyl. In embodiments, R 2 is unsubstituted benzofuranyl. In embodiments, R 2 is unsubstituted isobenzofuranyl. In embodiments, R 2 is unsubstituted indolyl. In embodiments, R 2 is unsubstituted isoindolyl. In embodiments, R 2 is unsubstituted benzothienyl. In

embodiments, R 2 is unsubstituted benzo[c]thienyl. In embodiments, R 2 is unsubstituted benzimidazolyl. In embodiments, R 2 is unsubstituted azaindolyl. In embodiments, R 2 is unsubstituted benzoisoxazolyl. In embodiments, R 2 is unsubstituted pyrrolopyridinyl. In embodiments, R 2 is unsubstituted purinyl. In embodiments, R 2 is unsubstituted indazolyl. In embodiments, R 2 is unsubstituted benzoxazolyl. In embodiments, R 2 is unsubstituted

benzisoxazolyl. In embodiments, R 2 is unsubstituted benzothiazolyl. In embodiments, R 2 is unsubstituted quinolinyl. In embodiments, R 2 is unsubstituted isoquinolinyl. In embodiments, R 2 is unsubstituted quinoxalinyl. In embodiments, R 2 is unsubstituted quinazolinyl. In embodiments, R 2 is unsubstituted cinnolinyl. In embodiments, R 2 is unsubstituted phthalazinyl. In embodiments, R 2 is unsubstituted furanyl. In embodiments, R 2 is unsubstituted pyrrolyl. In embodiments, R 2 is unsubstituted thienyl. In embodiments, R 2 is unsubstituted imidazolyl. In embodiments, R 2 is unsubstituted pyrazolyl. In embodiments, R 2 is unsubstituted oxazolyl. In embodiments, R 2 is unsubstituted isoxazolyl. In embodiments, R 2 is unsubstituted thiazolyl. In embodiments, R 2 is unsubstituted isothiazolyl. In embodiments, R 2 is unsubstituted triazolyl. In embodiments, R 2 is unsubstituted oxadiazolyl. In embodiments, R 2 is unsubstituted thiadiazolyl. In embodiments, R 2 is unsubstituted tetrazolyl. In embodiments, R 2 is unsubstituted pyridinyl. In embodiments, R 2 is unsubstituted pyrazinyl. In embodiments, R 2 is unsubstituted pyrimidinyl. In embodiments, R 2 is unsubstituted pyridazinyl. In embodiments, R 2 is unsubstituted triazinyl. In embodiments, R 2 is unsubstituted 6 membered heteroaryl. In embodiments, R 2 is

unsubstituted pyridinyl. In embodiments, R 2 is unsubstituted pyrazinyl. In embodiments, R 2 is unsubstituted pyrimidinyl. In embodiments, R 2 is unsubstituted pyridazinyl. [0125] In embodiments, R 2 is -CX 2

3, -CHX2

2, or -CH 2 X 2 . In embodiments, R 2 is -CF 3 , -CHF 2 , or -CH 2 F. In embodiments, R 2 is substituted cyclopropyl In embodiments, R 2 is R 23 -substituted cyclopropyl. In embodiments, R 2 is unsubstituted cyclopropyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is -CF 3 . In embodiments, R 2 is -CHF 2. In

embodiments, R 2 is -CH 2 F. X 2 is a halogen. In embodiments, X 2 is F. [0126] In embodiments, L 2 -R 2 is unsubstituted isopropyl. In embodiments, -L 2 -R 2 is unsubstituted tert-butyl. In embodiments, -L 2 -R 2 is hydrogen. In embodiments, -L 2 -R 2 is

,

[0128] In embodiments, -L 2 -R 2 is wherein X 23 is a halogen; z2 is an

integer from 0 to 15. In embodiments, z2 is 2.In embodiments, -L 2 -R 2 is

wherein X 23 is a halogen; z2 is an integer from 0 to 13. In embodiments, z2 is 2. In

embodiments, wherein X 23 is a halogen; z2 is an integer from 0 to 11.

In embodiments, z2 is 2. In embodiments, -L 2 -R 2 is wherein X 23 is a halogen; z2

is an integer from 0 to 9. In embodiments, z2 is 2. [0129] In embodiments, L 2 -R 2 is , wherein X 23 is a halo en z2 is an integer

from 0 to 9. In embodiments, z2 is 2. In embodiments, , wherein R 23 is as described herein z2 is an inte er from 0 to 9. In embodiments, z2 is 2. In

embodiments, L 2 -R 2 is , wherein X 23 is as des ri h r in z2 i an integer

from 0 to 8. In embodiments, z2 is 2. In embodiments, L 2 -R 2 is , wherein R 23 is as described herein z2 is an inte er from 0 to 8. In embodiments, z2 is 2. In

embodiments, L 2 -R 2 is as described herein; z2 is an integer

from 0 to 8. In embodi , wherein R 23 is as described herein; z2 is an integer from 0 to 8. In embodiments, z2 is 2. In embodiments, X 23 is F.

[0130] In embodiments, L 2 -R 2 is , wherein R 23.1 is R 23 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 23 substituent; and wherein R 23 is as described herein and z2 is an integer from 0 to 9. In embodiments, z2 is 2. In embodiments, R 23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)- (substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl. In embodiments, R 23 is–OH, oxo, -F, or -COOH.

[0131] In embodiments, L 2 -R 2 is , wherein R 23.1 is R 23 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 23 substituent; and wherein R 23 is as described herein and z2 is an integer from 0 to 9. In embodiments, z2 is 2. In embodiments, R 23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)- (substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl. In embodiments, R 23 is–OH, oxo, -F, or -COOH.

[0132] In embodiments, L 2 -R 2 is , wherein R 23.1 is R 23 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 23 substituent; and wherein R 23 is as described herein and z2 is an integer from 0 to 9. In embodiments, z2 is 2. In embodiments, R 23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)- (substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl. In embodiments, R 23 is–OH, oxo, -F, or -COOH.

[0133] In embodiments, L 2 -R 2 is , wherein R 23.1 is R 23 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 23 substituent; and wherein R 23 is as described herein and z2 is an integer from 0 to 9. In embodiments, z2 is 2. In embodiments, R 23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)- (substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl. In embodiments, R 23 is–OH, oxo, -F, or -COOH. [0134] In embodiments, R 23 is independently oxo. In embodiments, R 23 is independently halogen. In embodiments, R 23 is independently -F. In embodiments, R 23 is independently -Cl. In embodiments, R 23 is independently–COOH. In embodiments, R 23 is independently - C(O)NR 23A R 23B . [0135] In embodiments, R 23.1 is hydrogen. In embodiments, R 23.1 is substituted or unsubstituted alkyl. In embodiments, R 23.1 is independently substituted or unsubstituted alkyl. In

embodiments, R 23.1 is R 24 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 - C 4 alkyl). In embodiments, R 23.1 is R 24 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 23.1 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 23.1 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 23.1 is R 24 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 23.1 is R 24 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 23.1 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R23.1 is unsubstituted cyclopropyl. [0136] In embodiments, R 23.1 is R 24 -substituted cyclopropyl. In embodiments, R 23.1 is -

C(O)NH 2 . In embodiments, R 23.1 is -C(O)NR 23A R 23B , . In embodiments, R 23.1 is . In

embodiments, R 23.1 is . In embodiments, R 23.1 is . In embodiments, R 23.1 . [0137] In embodiments, R 23.1 is -C(N)-(substituted or unsubstituted alkyl). In embodiments, R 23.1 is -C(N)-( substituted or unsubstituted C 1 -C 8 alkyl). In embodiments, R 23.1 is -C(N)- (substituted or unsubstituted C 1 -C 6 alkyl). In embodiments, R 23.1 is -C(N)-(substituted or unsubstituted C 1 -C 4 alkyl). In embodiments, R 23.1 is -C(N)-(R 24 -substituted or unsubstituted alkyl). In embodiments, R 23.1 is -C(N)-(unsubstituted alkyl). In embodiments, R 23.1 is -C(N)-(R 24 - substituted alkyl). [0138] In embodiments, R 23.1 is -C(N)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 23.1 is -C(N)-(substituted or unsubstituted C 3 -C 8 cycloalkyl). In embodiments, R 23.1 is -C(N)-(substituted or unsubstituted C 3 -C 6 cycloalkyl). In embodiments, R 23.1 is -C(N)- (substituted or unsubstituted C 5 -C 6 cycloalkyl). In embodiments, R 23.1 is -C(N)-(R 24 -substituted or unsubstituted cycloalkyl). In embodiments, R 23.1 is -C(N)-(unsubstituted cycloalkyl). In embodiments, R 23.1 is -C(N)-(R 24 -substituted cycloalkyl). [0139] In embodiments, R 23.1 is -C(O)-(substituted or unsubstituted alkyl). In embodiments, R 23.1 is -C(O)-(substituted or unsubstituted C 1 -C 8 alkyl). In embodiments, R 23.1 is -C(O)- (substituted or unsubstituted C 1 -C 6 alkyl). In embodiments, R 23.1 is -C(O)-(substituted or unsubstituted C 1 -C 4 alkyl). In embodiments, R 23.1 is -C(O)-(R 24 -substituted or unsubstituted alkyl). In embodiments, R 23.1 is -C(O)-(unsubstituted alkyl). In embodiments, R 23.1 is -C(O)- (R 24 -substituted alkyl). [0140] In embodiments, R 23.1 is -C(O)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 23.1 is -C(O)-(substituted or unsubstituted C 3 -C 8 cycloalkyl). In embodiments, R 23.1 is -C(O)-(substituted or unsubstituted C 3 -C 6 cycloalkyl). In embodiments, R 23.1 is -C(O)- (substituted or unsubstituted C 5 -C 6 cycloalkyl). In embodiments, R 23.1 is -C(O)-(R 24 -substituted or unsubstituted cycloalkyl). In embodiments, R 23.1 is -C(O)-(unsubstituted cycloalkyl). In embodiments, R 23.1 is -C(O)-(R 24 -substituted cycloalkyl). [0141] In embodiments, z4 and z5 are independently an integer from 0 to 2. In embodiments z4 is 0. In embodiments z4 is 1. In embodiments z4 is 2. In embodiments z5 is 0. In

embodiments z5 is 1. In embodiments z5 is 2.

[0142] In embodiments, L 2 -R 2 is , wherein R 23 is as described herein; z2 is an integer from 0 to 9. In embodiments z2 is 2. [0143] In embodiments, L 2 -R 2 is wherein R 35 is as described herein. In

embodiments, L 2 -R 2 is . In

embodiments, are each independently R 35 at a fixed position (e.g., non-floating as shown in the formula described herein and ma inde endently be any R 35 substituent. In embodiments, L 2 -R 2 is

wherein R 35.3 and R 35.4 are each independently R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35

substituent. In embodiments, L , wherein R 35.1 and R 35.4 are each independently R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, R 35.1 is halogen. In embodiments, R 35.1 is F. [0144] In embodiments , , wherein R 35 is as described herein. In

embodiments, In embodimen

embodiments, L 2 -R 2 is wherein R 35.1 , R 35.2 , R 35.3 , and R 35.4 are each independently R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, L 2 -R 2 is

, wherein R 35.1 and R 35.4 are each independently R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, R 35.1 is halogen. In embodiments, R 35.1 is F. In embodiments, L -R is , wherein R 35 is as described herein. In embodiments, L 2 -R 2 is

. In embodiments,

[0145] In embodiments, R 2 is R 23 -substituted or unsubstituted heterocycloalkyl or R 23 - substituted or unsubstituted heteroaryl. In embodiments, R 2 is R 23 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 23 -substituted or unsubstituted 5 to 6 membered heteroaryl. [0146] R 23 is independently oxo, halogen, -CX 23

3, -CHX23

2, -CH 2 X 23 , -OCH 2 X 23 , -OCX 23

3, -OCHX 23

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 ,

23

-substituted or unsubstituted alkyl, R 24 -substituted or

unsubstituted heteroalkyl, R 24 -substituted or unsubstituted cycloalkyl, R 24 -substituted or unsubstituted heterocycloalkyl, R 24 -substituted or unsubstituted aryl, or R 24 -substituted or unsubstituted heteroaryl. In embodiments, R 23 is a halogen. In embodiments, R 23 is R 24 - substituted or unsubstituted alkyl. X 23 is halogen. In embodiments, X 23 is F. In embodiments, R 23 is unsubstituted alkyl. In embodiments, R 23 is -F. In embodiments, R 23 is a–Cl. In embodiments, R 23 is -CX 23

3. In embodiments, R 23 is -CHX 23

2. In embodiments,

In embodiments . In embodiments 3 . In embodiments

or -OCHX 23

2. [0147] In embodiments, R 23 is independently oxo,

halogen, , , , , , , , , , , , N N , ON , N C(O)N N , N C(O)N , N SO , N C(O) , N C(O)O ,

-substituted or unsubstituted C 1 -C 8 alkyl, R 24 -substituted or unsubstituted 2 to 8

membered heteroalkyl, R 24 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 24 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 24 -substituted or unsubstituted phenyl, or R 24 - substituted or unsubstituted 5 to 6 membered heteroary

embodiment , , , , , ,

-OCHX 23

2. In embodiments, , , , , ,

-OCHF 2 . In embodiments, R 23 is unsubstituted cyclopropyl. In embodiments, R 23 is

unsubstituted methyl. In embodiments In embodiments,

embodiments F. In embodiments, In embodiments,

embodiments, 23

[0148] R 24 is independently oxo, halogen

-NHOH, R 25 -substituted or unsubstituted alkyl, R 25 -substituted or unsubstituted heteroalkyl, R 25 - substituted or unsubstituted cycloalkyl, R 25 -substituted or unsubstituted heterocycloalkyl, R 25 - substituted or unsubstituted aryl, or R 25 -substituted or unsubstituted heteroaryl. In embodiments, R 24 is independently oxo,

halogen, -NHOH, -OCX 24

3, -OCHX24

2, R 25 -substituted or unsubstituted C 1 -C 8 alkyl, R 25 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 25 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 25 -substituted or unsubstituted 3 to 68membered heterocycloalkyl, R 25 -substituted or unsubstituted phenyl, or R 25 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 24 is– F, -Cl, -Br, or–I. [0149] R 25 is independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0150] In embodiments, R 25 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 25 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0151] In embodiments, R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R 3 is

hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is hydrogen. In embodiments, R 3 is hydrogen, -SO 2 CH 3 , -CN, -COCH 3 , -CX3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0152] In embodiments, R 3 is hydrogen. In embodiments, R 3 is -CX 3

3. In embodiments, R 3 is -CHX 3

2. In embodiments, R 3 is -CH 2 X 3 . In embodiments, R 3 is -CN. In embodiments, R 3 is -COOH. In embodiments, R 3 is substituted or unsubstituted alkyl. In embodiments, R 3 is substituted or unsubstituted heteroalkyl. In embodiments, R 3 is substituted alkyl. In

embodiments, R 3 is substituted heteroalkyl. In embodiments, R 3 is unsubstituted alkyl. In embodiments, R 3 is unsubstituted heteroalkyl. In embodiments, R 3 is substituted or

unsubstituted C 1 -C 8 alkyl. In embodiments, R 3 is substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 3 is substituted C 1 -C 8 alkyl. In embodiments, R 3 is substituted 2 to 8 membered heteroalkyl. In embodiments, R 3 is unsubstituted C 1 -C 8 alkyl. In embodiments, R 3 is unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 3 is substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 3 is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is substituted C 1 -C 4 alkyl. In embodiments, R 3 is substituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 3 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted tert-butyl. [0153] In embodiments, R 3 is hydrogen, -CN, -COOH, -CX 3

3, R 26 -substituted or unsubstituted alkyl or R 26 -substituted or unsubstituted heteroalkyl. In embodiments, R 3 is

hydrogen, -CN, -COOH, -CX 3

3, R 26 -substituted or unsubstituted C 1 -C 8 alkyl or R 26 -substituted or unsubstituted 2 to 8 membered heteroalkyl. X 3 is–F, -Cl, -Br, or–I. In embodiments, R 3 is independently hydrogen. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted ethyl. [0154] R 26 is independently oxo, halogen, -CX 26

3, -CHX26

2, -CH 2 X 26 , -OCH 2 X 26 , -OCX 26

3, -OCHX 26

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, -OCX 26

3, -OCHX26

2, R 27 -substituted or unsubstituted alkyl, R 27 -substituted or unsubstituted heteroalkyl, R 27 -substituted or unsubstituted cycloalkyl, R 27 -substituted or unsubstituted heterocycloalkyl, R 27 -substituted or unsubstituted aryl, or R 27 -substituted or unsubstituted heteroaryl. In embodiments, R 26 is independently oxo,

halogen, -CX 26

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 26

3, -OCHX26

2, R 27 -substituted or unsubstituted C 1 -C 8 alkyl, R 27 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 27 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 27 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 27 -substituted or

unsubstituted phenyl, or R 27 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 26 is– F,-Cl, -Br, or–I. [0155] R 27 is independently oxo, halogen, -CX 27

3, -CHX27

2, -CH 2 X 27 , -OCH 2 X 27 , -OCX 27

3, -OCHX 27

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, -OCX 27

3, -OCHX27

2, R 28 -substituted or unsubstituted alkyl, R 28 -substituted or unsubstituted heteroalkyl, R 28 -substituted or unsubstituted cycloalkyl, R 28 -substituted or unsubstituted heterocycloalkyl, R 28 -substituted or unsubstituted aryl, or R 28 -substituted or unsubstituted heteroaryl. In embodiments, R 27 is independently oxo,

halogen, -CX 27

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 27

3, -OCHX27

2, R 28 -substituted or unsubstituted C 1 -C 8 alkyl, R 28 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 28 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 28 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 28 -substituted or

unsubstituted phenyl, or R 28 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 27 is– F, -Cl, -Br, or–I. [0156] R 28 is independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0157] In embodiments, R 28 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 28 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0158] In embodiments, X 3 is independently halogen. In embodiments, X 3 is independently– F. In embodiments, X 3 is independently–Cl. In embodiments, X 3 is independently–Br. In embodiments, X 3 is independently–I. [0159] In embodiments, L 1 is–O-. In embodiments, L 1 is -S-. In embodiments, L 1 is–N(R 3 )-. In embodiments, L 1 is–SO-. In embodiments, L 1 is -SO 2 -. In embodiments, L 1 is–N(H)-. In embodiments, L 1 is–SO-, -SO 2 -,–O-, -S-,–N(R 3 )-, -B(R 6 )- (i.e. L 1 includes a boron), or R 6 - substituted or unsubstituted C 1 -C 3 alkylene. In embodiments, L 1 is R 6 -substituted or

unsubstituted C 1 -C 3 alkylene. In embodiments, L 1 is R 6 -substituted C 1 -C 3 alkylene. In embodiments, L 1 is unsubstituted C 1 -C 3 alkylene. In embodiments, L 1 is unsubstituted methylene. In embodiments, L 1 is–O-, -S-,–N(R 3 )-, or substituted or unsubstituted C 1 -C 3 alkylene. [0160] In embodiments, L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L 2 is a bond. In embodiments, L 2 is substituted or unsubstituted alkylene. In embodiments, L 2 is substituted or unsubstituted heteroalkylene. In embodiments, L 2 is a bond, -N(R 7 )-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L 2 is a bond,–O-, -S-,–N(R 7 )-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0161] In embodiments, L 2 is a bond, substituted or unsubstituted C 1 -C 5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. In embodiments, L 2 is a bond,– CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, or–CH 2 NH-. In embodiments, L 2 is a bond. In

embodiments, L 2 is–CH 2 -. In embodiments, L 2 is -CH 2 CH 2 -. In embodiments, L 2 is -CH 2 O-. In embodiments, L 2 is -CH 2 S-. In embodiments, L 2 is–CH 2 NH-. [0162] In embodiments, L 2 is a substituted or unsubstituted alkylene. In embodiments, L 2 is a substituted or unsubstituted heteroalkylene. In embodiments, L 2 is a substituted alkylene. In embodiments, L 2 is a substituted heteroalkylene. In embodiments, L 2 is a unsubstituted alkylene. In embodiments, L 2 is a unsubstituted heteroalkylene. In embodiments, L 2 is a substituted or unsubstituted C 1 -C 8 alkylene. In embodiments, L 2 is a substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is a substituted C 1 -C 8 alkylene. In embodiments, L 2 is a substituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is a unsubstituted C 1 -C 8 alkylene. In embodiments, L 2 is a unsubstituted 2 to 8 membered heteroalkylene. In

embodiments, L 2 is a substituted or unsubstituted C 1 -C 4 alkylene. In embodiments, L 2 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is a substituted C 1 -C 4 alkylene. In embodiments, L 2 is a substituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is a unsubstituted C 1 -C 4 alkylene. In embodiments, L 2 is a unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is a unsubstituted methylene. In embodiments, L 2 is a unsubstituted ethylene. In embodiments, L 2 is a substituted C 2 -C 8 alkylene. In embodiments, L 2 is a unsubstituted C 2 -C 8 alkylene. In embodiments, L 2 is a substituted C 3 -C 8 alkylene. In embodiments, L 2 is a unsubstituted C 3 -C 8 alkylene. In embodiments, L 2 is a substituted C 4 -C 8 alkylene. In embodiments, L 2 is an unsubstituted C 4 -C 8 alkylene. In embodiments, L 2 is a substituted C 2 -C 3 alkylene. In embodiments, L 2 is an unsubstituted C 2 -C 3 alkylene. [0163] In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted alkylene or R 35 - substituted or unsubstituted heteroalkylene. In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted C 1 -C 8 alkylene or R 35 -substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted C 1 -C 4 alkylene or R 35 -substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted C 1 -C 3 alkylene or R 35 -substituted or unsubstituted 2 to 3 membered

heteroalkylene. In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted C 1 -C 2 alkylene or R 35 -substituted or unsubstituted 2 membered heteroalkylene. In embodiments, L 2 is R 35 - substituted or unsubstituted alkylene or R 35 -substituted or unsubstituted heteroalkylene. In embodiments, L 2 is R 35 -substituted or unsubstituted C 1 -C 8 alkylene or R 35 -substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is R 35 -substituted or unsubstituted C 1 -C 4 alkylene or R 35 -substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is a bond, R 35 -substituted or unsubstituted C 1 -C 3 alkylene or R 35 -substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 2 is R 35 -substituted or unsubstituted C 1 -C 2 alkylene or R 35 -substituted or unsubstituted 2 membered heteroalkylene. [0164] R 35 is independently oxo,

halogen, -CX 35

3, -CHX35

2, -CH 2 X 35 , -OCH 2 X 35 , -OCX 35

3, -OCHX35

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 36 -substituted or unsubstituted alkyl, R 36 -substituted or unsubstituted heteroalkyl, R 36 -substituted or unsubstituted cycloalkyl, R 36 -substituted or unsubstituted heterocycloalkyl, R 36 -substituted or unsubstituted aryl, or R 36 - substituted or unsubstituted heteroaryl. In embodiments, R 35 is independently oxo,

halogen, -CX 35

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 35

3, -OCHX35

2, R 36 -substituted or unsubstituted C 1 -C 8 alkyl, R 36 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 36 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 36 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 36 -substituted or

unsubstituted phenyl, or R 36 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 35 is– F,-Cl, -Br, or–I. In embodiments, R 35 is -CX 35

3, -CHX35

2, -CH 2 X 35 , -OCH 2 X 35 , -OCX 35

3, or -OCHX 35

2. In embodiments, R 35 is -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , or

-OCHF 2 . In embodiments, R 35 is unsubstituted cyclopropyl. In embodiments, R 35 is

unsubstituted methyl. In embodiments, R 35 is -CF 3 . In embodiments, R 35 is -CHF 2. In

embodiments, R 35 is -CH 2 F. In embodiments, R 35 is -OCH 2 F. In embodiments, R 35 is -OCF 3 . In embodiments, R 35 is -OCHF 2 . In embodiments, R 35 is halogen. In embodiments, R 35 is F. In embodiments, R 35 is–OH. [0165] R 36 is independently oxo, halogen, -CX 36

3, -CHX36

2, -CH 2 X 36 , -OCH 2 X 36 , -OCX 36

3, -OCHX 36

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 37 -substituted or unsubstituted alkyl, R 37 -substituted or unsubstituted heteroalkyl, R 37 - substituted or unsubstituted cycloalkyl, R 37 -substituted or unsubstituted heterocycloalkyl, R 37 - substituted or unsubstituted aryl, or R 37 -substituted or unsubstituted heteroaryl. In embodiments, R 36 is independently oxo, halogen, -CX 36

3, -CHX36

2, -CH 2 X 36 , -OCH 2 X 36 , -OCX 36

3,

-OCHX 36

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 37 -substituted or unsubstituted C 1 -C 8 alkyl, R 37 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 37 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 37 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 37 -substituted or unsubstituted phenyl, or R 37 - substituted or unsubstituted 5 to 6 membered heteroaryl. X 36 is–F, -Cl, -Br, or–I. [0166] R 37 is independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0167] In embodiments, R 37 is independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 37 is independently oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0168] In embodiments, R 6 is halogen, -CX 6

3, -CHX6

2, -CH 2 X 6 , -OCX 6

3, - OCH 2 X 6 , -OCHX 6

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)O H, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, 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. In embodiments, R 6 is -CX 6

3, -CHX6

2, -CH 2 X 6 , -OCX 6

3, - OCH 2 X 6 , -OCHX 6

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)O H, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, 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. In embodiments, R 6 is hydrogen. [0169] In embodiments, R 6 is halogen, -CX 6

3, -CHX6

2, -CH 2 X 6 , -OCX 6

3, - OCH 2 X 6 , -OCHX 6

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)O H, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 26 -substituted or unsubstituted alkyl, R 26 -substituted or unsubstituted heteroalkyl, R 26 -substituted or unsubstituted cycloalkyl, R 26 -substituted or unsubstituted heterocycloalkyl, R 26 -substituted or unsubstituted aryl, or R 26 -substituted or unsubstituted heteroaryl. [0170] In embodiments, R 7 is -CN, -COOH, -CX 7

3, substituted or unsubstituted alkyl (e.g., C 1 - C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 2 alkyl, unsubstituted C 1 -C 8 alkyl, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 4 alkyl, or unsubstituted C 1 -C 2 alkyl), or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 2 to 4 membered heteroalkyl, 2 to 3 membered heteroalkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted 2 to 3 membered heteroalkyl). In embodiments, R 7 is -CN, -COOH, -CX 7

3, R 35 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 2 alkyl, unsubstituted C 1 -C 8 alkyl, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 4 alkyl, or unsubstituted C 1 -C 2 alkyl), or R 35 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 2 to 4 membered heteroalkyl, 2 to 3 membered heteroalkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted 2 to 3 membered heteroalkyl). [0171] In embodiments, R 7 is -CN, -CX 7

3, substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 2 alkyl, unsubstituted C 1 -C 8 alkyl, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 4 alkyl, or unsubstituted C 1 -C 2 alkyl), or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 2 to 4 membered heteroalkyl, 2 to 3 membered heteroalkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted 2 to 3 membered heteroalkyl). [0172] In embodiments, R 8 is halogen, -CX 8

3,

-CHX 8

2, -CH 2 X 8 , -OCX 8

3, -OCH 2 X 8 , -OCHX 8

2, -CN, -SH, -SO 2 NH 2 , -NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)OH, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHO H, 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. In embodiments, R 8 is

halogen, -CX 8

3, -CHX8

2, -CH 2 X 8 , -OCX 8

3, -OCH 2 X 8 , -OCHX 8

2, -CN, -SH, -SO 2 NH 2 ,

-NHC(O)NH 2 , -N(O), -N(O) 2 , -NH 2 , -C(O)H, -C(O)OH, -C(O)NH 2 , -OH, -NHSO 2 H, -NHC(O) H, -NHC(O)OH, -NHOH, R 35 -substituted or unsubstituted alkyl, R 35 -substituted or unsubstituted heteroalkyl, R 35 -substituted or unsubstituted cycloalkyl, R 35 -substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted heteroaryl. [0173] Each X 6 is independently–F, -Cl, -Br, or–I. Each X 7 is independently–F, -Cl, -Br, or –I. Each X 8 is independently–F, -Cl, -Br, or–I. [0174] In embodiments, the compound has the formula:

[0175] (II), wherein L 1 , L 2 , and Y 1 are as described herein. It is understood that when R 1 is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl it may be written as Ring A and all substitutions of R 1 may be assumed by

substitutions to Ring A. For example, when R 1 is R 20 -substituted aryl or R 20 -substituted heteroaryl, it may be written as R 4 -substituted Ring A. It is understood that when R 2 is a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, it may be written as Ring B and all substitutions of R 2 may be assumed by substitutions to Ring B. For example, when R 2 is R 23 -substituted aryl or R 23 -substituted heteroaryl, it may be written as R 5 - substituted Ring B. [0176] Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl. Ring B is 3 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C 3 -C 8 cycloalkyl. R 4 is halogen, -CX 4

3, - CHX 4

2, -CH 2 X 4 , -OCX 4

3, -OCH 2 X 4 , -OCHX 4

2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B ,

-NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)-OR 4C , -C(O)NR 4A R 4B , -OR 4D , -NR 4A S O 2 R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -NR 4A OR 4C , 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. Two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 5 is halogen, -CX 5

3, -CHX5 2, - CH 2 X 5 , -OCX 5

3, -OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)-OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A SO 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -NR 5A OR 5C , 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. Two adjacent R 5 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Each R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X 4 , and X 5 is independently–F, -Cl, -Br, or–I. The symbols n4 and n5 are independently an integer from 0 to 4. The symbols m4, m5, v4, and v5 are independently an integer from 1 to 2. The symbol z4 is an integer from 0 to 9. The symbol z5 is an integer from 0 to 6. [0177] In embodiments, Ring A is phenyl. In embodiments, Ring A is napththyl. In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments, Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, azaindolyl, benzoisoxazolyl, pyrrolopyridinyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl,

benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. In embodiments, Ring A is 5 to 9 membered heteroaryl. In embodiments, Ring A is 5 to 6 membered heteroaryl. In embodiments, Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. [0178] In embodiments, Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl. In

embodiments, Ring A is C 6 -C 10 aryl or 5 to 9 membered heteroaryl. In embodiments, Ring A is phenyl or 5 to 6 membered heteroaryl. In embodiments, Ring A is aryl. In embodiments, Ring A is C 6 -C 10 aryl. In embodiments, Ring A is C 10 aryl. In embodiments, Ring A is phenyl. [0179] In embodiments, Ring A is heteroaryl. In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments, Ring A is 5 to 9 membered heteroaryl. In embodiments, Ring A is 5 to 6 membered heteroaryl. In embodiments, Ring A is 5 membered heteroaryl. In

embodiments, Ring A is 6 membered heteroaryl. In embodiments, Ring A is 9 membered heteroaryl. In embodiments, Ring A is 10 membered heteroaryl. [0180] In embodiments, Ring A is phenyl. In embodiments, Ring A is napththyl. In embodiments, Ring A is benzofuranyl. In embodiments, Ring A is isobenzofuranyl. In embodiments, Ring A is indolyl. In embodiments, Ring A is isoindolyl. In embodiments, Ring A is benzothienyl. In embodiments, Ring A is benzo[c]thienyl. In embodiments, Ring A is benzimidazolyl. In embodiments, Ring A is azaindolyl. In embodiments, Ring A is

benzoisoxazolyl. In embodiments, Ring A is pyrrolopyridinyl. In embodiments, Ring A is purinyl. In embodiments, Ring A is indazolyl. In embodiments, Ring A is benzoxazolyl. In embodiments, Ring A is benzisoxazolyl. In embodiments, Ring A is benzothiazolyl. In embodiments, Ring A is quinolinyl. In embodiments, Ring A is isoquinolinyl. In embodiments, Ring A is quinoxalinyl. In embodiments, Ring A is quinazolinyl. In embodiments, Ring A is cinnolinyl. In embodiments, Ring A is or phthalazinyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is thienyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is isothiazolyl. In embodiments, Ring A is triazolyl. In embodiments, Ring A is oxadiazolyl. In embodiments, Ring A is thiadiazolyl. In embodiments, Ring A is tetrazolyl. In embodiments, Ring A is pyridinyl. In embodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyrimidinyl. In embodiments, Ring A is pyridazinyl. In embodiments, Ring A is triazinyl.

[0181] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

. In embodiments, (Ring

A)-(R 4 ) z4 is . In

embodimen ) z4 is

. In embodiments, (Ring A)- (R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

,

ng - z4 s . n emo mens, ng - z4 s . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is , ( . In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments,

(Ring A)-(R ) z4 is .

[0182] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)- (R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

. In embodiments, (Ring A)-(R 4 ) z4 is .

ing A)- iments, . In embodiments, (Ring A)-(R 4 ) z4 . In embodiments, (Ring A)-(R 4 ) z4 is ing . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments,

(Ring A)-(R ) z4 is . [0184] In embodiments, (Ring . In embodiments, (Ring A)- (R 4 ) z4 is . In

embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments Ring )( ) , ( g )(

In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In

embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

. In embodiments, (Ring

A)-(R 4 ) z4 is .

[0185] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)- (R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is , ( . In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring .

[0186] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)- (R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is , ( . In embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring .

[0187] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)- (R 4 ) z4 is , ( g . In embodiments, (Ring A)-(R 4 ) z4 In embodiments, (Ring A)-(R 4 ) z4 is diments, (Ring . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is , ( . In

embodiments, (Ring A)-(R 4 ) z4 is In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, . In embodiments, (Ring A)- . In

embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is g . In embodiments, (Ring is ments,

[0189] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.3 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

In embodiments, (Ring A)-(R 4 ) z4 is , wherein R 4.1 and R 4.2 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is In

. In embodiments, (Ring A)-(R 4 ) z4 is

each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4

substituent. In embodiments, (Ring A)-(R 4 ) z4 is wherein R 4.2 and R 4.3 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.2 and R 4.4 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

[0190] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.2 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.5 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4

substituent In embodiments, (Ring A)-(R 4 ) z4 is wherein R 4.2 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent.

[0191] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is , wherein R 4.1 and R 4.3 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

In embodiments, (Ring A)-(R 4 ) z4 is , wherein R 4.1 and R 4.2 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may

independently be any R 4 substitu , (Ring A)-(R 4 ) z4 is . In

embodiments, (Ring A)-(R 4 ) z4 is wherein R 4.1 and R 4.5 are each

independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein)

and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.2 and R 4.3 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent.

[0192] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.1 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.1 and R 4.3 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

In embodiments, (Ring A)-(R 4 ) z4 is , wherein R 4.1 and R 4.2 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may

independently be any R 4 substitu

embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.2 and R 4.3 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is wherein R 4.2 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent.

[0193] In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.1 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. In embodiments, (Ring A)-(R 4 ) z4 is

wherein R 4.1 and R 4.2 are each independently R 4 at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4 substituent.

In embodiments, (Ring A)-(R 4 ) z4 is . In embodiments, (Ring A)-(R 4 ) z4 is

, wherein R 4.1 and R 4.5 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4

substituent. In embodiments, (Ring A)-(R 4 ) z4 is , wherein R 4.2 and R 4.4 are each independently R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. [0194] In embodiments, R 4 is independently hydrogen. In embodiments, R 4 is independently halogen. In embodiments, R 4 is independently -CX 4

3. In embodiments, R 4 is independently - CHX 4

2. In embodiments, R 4 is independently -CH 2 X 4 . In embodiments, R 4 is

independently -OCX 4

3. In embodiments, R 4 is independently -OCH 2 X 4 . In embodiments, R 4 is independently -OCHX 4

2. In embodiments, R 4 is independently -CN. In embodiments, R 4 is independently -SO n4 R 4D . In embodiments, R 4 is independently -SO v4 NR 4A R 4B . In embodiments, R 4 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4 is independently -N(O) m4 . In embodiments, R 4 is independently -NR 4A R 4B . In embodiments, R 4 is independently -C(O)R 4C . In embodiments, R 4 is independently -C(O)-OR 4C . In embodiments, R 4 is

independently -C(O)NR 4A R 4B . In embodiments, R 4 is independently -OR 4D . In embodiments, R 4 is independently -NR 4A SO 2 R 4D . In embodiments, R 4 is independently -NR 4A C(O)R 4C . In embodiments, R 4 is independently -NR 4A C(O)OR 4C . In embodiments, R 4 is

independently -NR 4A OR 4C . In embodiments, R 4 is independently -OH. In embodiments, R 4 is independently -NH 2 . In embodiments, R 4 is independently -COOH. In embodiments, R 4 is independently -CONH 2 . In embodiments, R 4 is independently -NO 2 . In embodiments, R 4 is independently–SH. In embodiments, R 4 is independently halogen, unsubstituted C 1 -C 3 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independently halogen, unsubstituted methyl, or -OCH 3 . In embodiments, R 4 is independently -Br. In embodiments, R 4 is independently -Cl. In embodiments, R 4 is independently -F. In embodiments, R 4 is

independently -OCH 3 . In embodiments, R 4 is independently -CH 3 . In embodiments, R 4 is independently -CF 3 . [0195] In embodiments, R 4 is independently substituted or unsubstituted alkyl. In

embodiments, R 4 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4 is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 4 is independently substituted or unsubstituted aryl. In embodiments, R 4 is independently substituted or unsubstituted heteroaryl. In embodiments, R 4 is independently substituted alkyl. In embodiments, R 4 is independently substituted heteroalkyl. In embodiments, R 4 is independently substituted cycloalkyl. In embodiments, R 4 is independently, substituted heterocycloalkyl. In embodiments, R 4 is independently substituted aryl. In embodiments, R 4 is independently substituted heteroaryl. In embodiments, R 4 is independently unsubstituted alkyl. In embodiments, R 4 is independently unsubstituted heteroalkyl. In embodiments, R 4 is independently unsubstituted cycloalkyl. In embodiments, R 4 is independently, unsubstituted heterocycloalkyl. In embodiments, R 4 is independently unsubstituted aryl. In embodiments, R 4 is independently unsubstituted heteroaryl. In embodiments, R 4 is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4 is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4 is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4 is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 4 is

independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4 is independently substituted C 1 -C 8 alkyl. In embodiments, R 4 is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 4 is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is independently, substituted 3 to 8 membered heterocycloalkyl. In

embodiments, R 4 is independently substituted C 6 -C 10 aryl. In embodiments, R 4 is independently substituted 5 to 10 membered heteroaryl. In embodiments, R 4 is independently unsubstituted C 1 - C 8 alkyl. In embodiments, R 4 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4 is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 4 is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4 is independently substituted or unsubstituted C 1 - C 4 alkyl. In embodiments, R 4 is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4 is independently, substituted or unsubstituted 3 to 6 membered

heterocycloalkyl. In embodiments, R 4 is independently substituted or unsubstituted phenyl. In embodiments, R 4 is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4 is independently substituted C 1 -C 4 alkyl. In embodiments, R 4 is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 4 is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4 is independently substituted phenyl. In embodiments, R 4 is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 4 is independently unsubstituted C 1 - C 4 alkyl. In embodiments, R 4 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4 is independently unsubstituted phenyl. In embodiments, R 4 is independently unsubstituted 5 to 6 membered heteroaryl. [0196] In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0197] In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted heterocycloalkyl. In

embodiments, two adjacent R 4 substituents may be joined to form a substituted aryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted

heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted aryl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted heteroaryl. [0198] In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted C 6 -C 10 aryl. In embodiments, two adjacent R4 substituents may be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted 5 to 10 membered heteroaryl. [0199] In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted phenyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted phenyl. In embodiments, two adjacent R 4 substituents may be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted phenyl. In embodiments, two adjacent R 4 substituents may be joined to form an unsubstituted 5 to 6 membered heteroaryl. [0200] In embodiments, R 4A is independently hydrogen. In embodiments, R 4A is

independently -CX 4A

3. In embodiments, R 4A is independently -CHX 4A

2. In embodiments, R 4A is independently -CH 2 X 4A . In embodiments, R 4A is independently -CN. In embodiments, R 4A is independently -COOH. In embodiments, R 4A is independently -CONH 2 . In embodiments, R 4A is independently substituted or unsubstituted alkyl. In embodiments, R 4A is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4A is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4A is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 4A is independently substituted or unsubstituted aryl. In embodiments, R 4A is independently substituted or unsubstituted heteroaryl. In embodiments, R 4A is independently substituted alkyl. In embodiments, R 4A is independently substituted

heteroalkyl. In embodiments, R 4A is independently substituted cycloalkyl. In embodiments, R 4A is independently, substituted heterocycloalkyl. In embodiments, R 4A is independently substituted aryl. In embodiments, R 4A is independently substituted heteroaryl. In embodiments, R 4A is independently unsubstituted alkyl. In embodiments, R 4A is independently unsubstituted heteroalkyl. In embodiments, R 4A is independently unsubstituted cycloalkyl. In embodiments, R 4A is independently, unsubstituted heterocycloalkyl. In embodiments, R 4A is independently unsubstituted aryl. In embodiments, R 4A is independently unsubstituted heteroaryl. In embodiments, R 4A is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4A is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4A is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4A is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 4A is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4A is independently substituted C 1 -C 8 alkyl. In embodiments, R 4A is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 4A is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 4A is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A is independently substituted C 6 -C 10 aryl. In embodiments, R 4A is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 4A is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 4A is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4A is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4A is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 4A is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4A is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 4A is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4A is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4A is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A is independently substituted or unsubstituted phenyl. In embodiments, R 4A is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4A is independently substituted C 1 - C 4 alkyl. In embodiments, R 4A is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 4A is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 4A is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A is independently substituted phenyl. In embodiments, R 4A is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 4A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4A is independently unsubstituted 2 to 4 membered heteroalkyl. In

embodiments, R 4A is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4A is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A is independently unsubstituted phenyl. In embodiments, R 4A is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4A is independently unsubstituted methyl. In embodiments, R 4A is independently unsubstituted ethyl. In embodiments, R 4A is independently unsubstituted propyl. In embodiments, R 4A is independently unsubstituted isopropyl. In embodiments, R 4A is independently unsubstituted tert-butyl. [0201] In embodiments, R 4B is independently hydrogen. In embodiments, R 4B is

independently -CX 4B

3. In embodiments, R 4B is independently -CHX 4B

2. In embodiments, R 4B is independently -CH 2 X 4B . In embodiments, R 4B is independently -CN. In embodiments, R 4B is independently -COOH. In embodiments, R 4B is independently -CONH 2 . In embodiments, R 4B is independently substituted or unsubstituted alkyl. In embodiments, R 4B is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4B is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4B is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 4B is independently substituted or unsubstituted aryl. In embodiments, R 4B is independently substituted or unsubstituted heteroaryl. In embodiments, R 4B is independently substituted alkyl. In embodiments, R 4B is independently substituted

heteroalkyl. In embodiments, R 4B is independently substituted cycloalkyl. In embodiments, R 4B is independently, substituted heterocycloalkyl. In embodiments, R 4B is independently substituted aryl. In embodiments, R 4B is independently substituted heteroaryl. In embodiments, R 4B is independently unsubstituted alkyl. In embodiments, R 4B is independently unsubstituted heteroalkyl. In embodiments, R 4B is independently unsubstituted cycloalkyl. In embodiments, R 4B is independently, unsubstituted heterocycloalkyl. In embodiments, R 4B is independently unsubstituted aryl. In embodiments, R 4B is independently unsubstituted heteroaryl. In embodiments, R 4B is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4B is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4B is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4B is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4B is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 4B is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4B is independently substituted C 1 -C 8 alkyl. In embodiments, R 4B is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 4B is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 4B is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4B is independently substituted C 6 -C 10 aryl. In embodiments, R 4B is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 4B is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 4B is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4B is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4B is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4B is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 4B is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4B is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 4B is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4B is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4B is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4B is independently substituted or unsubstituted phenyl. In embodiments, R 4B is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4B is independently substituted C 1 - C 4 alkyl. In embodiments, R 4B is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 4B is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 4B is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4B is independently substituted phenyl. In embodiments, R 4B is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 4B is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4B is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4B is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4B is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4B is independently unsubstituted phenyl. In embodiments, R 4B is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4B is independently unsubstituted methyl. In embodiments, R 4B is independently unsubstituted ethyl. In embodiments, R 4B is independently unsubstituted propyl. In embodiments, R 4B is independently unsubstituted isopropyl. In embodiments, R 4B is independently unsubstituted tert-butyl. [0202] In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or

unsubstituted heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or

unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 5 to 6 membered heteroaryl. [0203] In embodiments, R 4C is independently hydrogen. In embodiments, R 4C is

independently -CX 4C

3. In embodiments, R 4C is independently -CHX 4C

2. In embodiments, R 4C is independently -CH 2 X 4C . In embodiments, R 4C is independently -CN. In embodiments, R 4C is independently -COOH. In embodiments, R 4C is independently -CONH 2 . In embodiments, R 4C is independently substituted or unsubstituted alkyl. In embodiments, R 4C is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4C is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4C is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 4C is independently substituted or unsubstituted aryl. In embodiments, R 4C is independently substituted or unsubstituted heteroaryl. In embodiments, R 4C is independently substituted alkyl. In embodiments, R 4C is independently substituted

heteroalkyl. In embodiments, R 4C is independently substituted cycloalkyl. In embodiments, R 4C is independently, substituted heterocycloalkyl. In embodiments, R 4C is independently substituted aryl. In embodiments, R 4C is independently substituted heteroaryl. In embodiments, R 4C is independently unsubstituted alkyl. In embodiments, R 4C is independently unsubstituted heteroalkyl. In embodiments, R 4C is independently unsubstituted cycloalkyl. In embodiments, R 4C is independently, unsubstituted heterocycloalkyl. In embodiments, R 4C is independently unsubstituted aryl. In embodiments, R 4C is independently unsubstituted heteroaryl. In embodiments, R 4C is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4C is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4C is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4C is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4C is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 4C is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4C is independently substituted C 1 -C 8 alkyl. In embodiments, R 4C is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 4C is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 4C is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4C is independently substituted C 6 -C 10 aryl. In embodiments, R 4C is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 4C is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 4C is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4C is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4C is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4C is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 4C is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4C is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 4C is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4C is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4C is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4C is independently substituted or unsubstituted phenyl. In embodiments, R 4C is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4C is independently substituted C 1 - C 4 alkyl. In embodiments, R 4C is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 4C is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 4C is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4C is independently substituted phenyl. In embodiments, R 4C is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 4C is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4C is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4C is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4C is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4C is independently unsubstituted phenyl. In embodiments, R 4C is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4C is independently unsubstituted methyl. In embodiments, R 4C is independently unsubstituted ethyl. In embodiments, R 4C is independently unsubstituted propyl. In embodiments, R 4C is independently unsubstituted isopropyl. In embodiments, R 4C is independently unsubstituted tert-butyl. [0204] In embodiments, R 4D is independently hydrogen. In embodiments, R 4D is

independently -CX 4D

3. In embodiments, R 4D is independently -CHX 4D

2. In embodiments, R 4D is independently -CH 2 X 4D . In embodiments, R 4D is independently -CN. In embodiments, R 4D is independently -COOH. In embodiments, R 4D is independently -CONH 2 . In embodiments, R 4D is independently substituted or unsubstituted alkyl. In embodiments, R 4D is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4D is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4D is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 4D is independently substituted or unsubstituted aryl. In embodiments, R 4D is independently substituted or unsubstituted heteroaryl. In embodiments, R 4D is independently substituted alkyl. In embodiments, R 4D is independently substituted

heteroalkyl. In embodiments, R 4D is independently substituted cycloalkyl. In embodiments, R 4D is independently, substituted heterocycloalkyl. In embodiments, R 4D is independently substituted aryl. In embodiments, R 4D is independently substituted heteroaryl. In embodiments, R 4D is independently unsubstituted alkyl. In embodiments, R 4D is independently unsubstituted heteroalkyl. In embodiments, R 4D is independently unsubstituted cycloalkyl. In embodiments, R 4D is independently, unsubstituted heterocycloalkyl. In embodiments, R 4D is independently unsubstituted aryl. In embodiments, R 4D is independently unsubstituted heteroaryl. In embodiments, R 4D is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4D is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4D is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4D is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4D is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 4D is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4D is independently substituted C 1 -C 8 alkyl. In embodiments, R 4D is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 4D is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 4D is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4D is independently substituted C 6 -C 10 aryl. In embodiments, R 4D is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 4D is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 4D is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 4D is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4D is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4D is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 4D is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 4D is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 4D is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4D is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4D is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4D is independently substituted or unsubstituted phenyl. In embodiments, R 4D is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4D is independently substituted C 1 - C 4 alkyl. In embodiments, R 4D is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 4D is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 4D is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4D is independently substituted phenyl. In embodiments, R 4D is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 4D is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4D is independently unsubstituted 2 to 4 membered heteroalkyl. In

embodiments, R 4D is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 4D is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 4D is independently unsubstituted phenyl. In embodiments, R 4D is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 4D is independently unsubstituted methyl. In embodiments, R 4D is independently unsubstituted ethyl. In embodiments, R 4D is independently unsubstituted propyl. In embodiments, R 4D is independently unsubstituted isopropyl. In embodiments, R 4D is independently unsubstituted tert-butyl. [0205] In embodiments, R 4 is independently hydrogen,

halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCX 4

3, -OCH 2 X 4 , -OCHX 4

2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -NR 4A S O 2 R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -NR 4A OR 4C , R 29 -substituted or unsubstituted alkyl, R 29 -substituted or unsubstituted heteroalkyl, R 29 -substituted or unsubstituted cycloalkyl, R 29 - substituted or unsubstituted heterocycloalkyl, R 29 -substituted or unsubstituted aryl, or R 29 - substituted or unsubstituted heteroaryl. In embodiments, R 4 is independently

halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCH 2 X 4 , -OCX 4

3, -OCHX4

2, -CN, -OH, -NH 2 , -COOH, -CO NH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX4

3, -OCHX4

2, R 29 - substituted or unsubstituted alkyl, R 29 -substituted or unsubstituted heteroalkyl, R 29 -substituted or unsubstituted cycloalkyl, R 29 -substituted or unsubstituted heterocycloalkyl, R 29 -substituted or unsubstituted aryl, or R 29 -substituted or unsubstituted heteroaryl. In embodiments, R 4 is independently

halogen, -CX 4

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 4

3, -OCHX4

2, R 29 -substituted or unsubstituted C 1 -C 8 alkyl, R 29 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 29 -substituted or unsubstituted phenyl, or R 29 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 4 is– F,-Cl, -Br, or–I. In embodiments, R 4 is independently hydrogen. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently halogen. In embodiments, R 4 is independently -Cl. In embodiments, R 4 is independently -Br. In embodiments, R 4 is independently -F. In

embodiments, R 4 is independently -OCH 3 . In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently -CF 3 . [0206] In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted cycloalkyl, R 29 -substituted or unsubstituted heterocycloalkyl, R 29 -substituted or unsubstituted aryl, or R 29 -substituted or unsubstituted heteroaryl. [0207] In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted aryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 - substituted cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted aryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted heteroaryl. [0208] In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted C 6 -C 10 aryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted 5 to 10 membered heteroaryl. [0209] In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted phenyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R4 substituents may be joined to form an R 29 -substituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted phenyl. In embodiments, two adjacent R 4 substituents may be joined to form an R 29 -substituted 5 to 6 membered heteroaryl. [0210] R 29 is independently oxo, halogen, -CX 29

3, -CHX29

2, -CH 2 X 29 , -OCH 2 X 29 , -OCX 29

3, -OCHX 29

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 30 -substituted or unsubstituted alkyl, R 30 -substituted or unsubstituted heteroalkyl, R 30 - substituted or unsubstituted cycloalkyl, R 30 -substituted or unsubstituted heterocycloalkyl, R 30 - substituted or unsubstituted aryl, or R 30 -substituted or unsubstituted heteroaryl. In embodiments, R 29 is independently oxo,

halogen, -CX 29

3, -CHX29

2, -CH 2 X 29 , -OCH 2 X 29 , -OCX 29

3, -OCHX29

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30 -substituted or unsubstituted C 1 -C 8 alkyl, R 30 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 30 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30 -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 30 -substituted or unsubstituted phenyl, or R 30 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 29 is–F,-Cl, -Br, or–I. [0211] R 30 is independently oxo, halogen, -CX 30

3, -CHX30

2, -CH 2 X 30 , -OCH 2 X 30 , -OCX 30

3, -OCHX 30

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 31 -substituted or unsubstituted alkyl, R 31 -substituted or unsubstituted heteroalkyl, R 31 - substituted or unsubstituted cycloalkyl, R 31 -substituted or unsubstituted heterocycloalkyl, R 31 - substituted or unsubstituted aryl, or R 31 -substituted or unsubstituted heteroaryl. In embodiments, R 30 is independently oxo, halogen, -CX 30

3, -CHX30

2, -CH 2 X 30 , -OCH 2 X 30 , -OCX 30

3,

-OCHX 30

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 31 -substituted or unsubstituted C 1 -C 8 alkyl, R 31 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 31 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 31 -substituted or unsubstituted phenyl, or R 31 - substituted or unsubstituted 5 to 6 membered heteroaryl. X 30 is–F, -Cl, -Br, or–I. [0212] In embodiments, R 4A is independently

hydrogen, -CX 4A

3, -CN, -COOH, -CONH 2 , -CHX4A

2, -CH 2 X 4A , R 29A -substituted or unsubstituted alkyl, R 29A -substituted or unsubstituted heteroalkyl, R 29A -substituted or unsubstituted cycloalkyl, R 29A -substituted or unsubstituted heterocycloalkyl, R 29A -substituted or unsubstituted aryl, or R 29A -substituted or unsubstituted heteroaryl. In embodiments, R 4A is independently

hydrogen, -CX 4A

3, -CN, -COOH, -CONH 2 , -CHX4A

2, -CH 2 X 4A , R 29A -substituted or unsubstituted C 1 -C 8 alkyl, R 29A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29A -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 29A -substituted or unsubstituted phenyl, or R 29A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 4A is–F, -Cl, -Br, or–I. In embodiments, R 4A is independently hydrogen. In embodiments, R 4A is independently unsubstituted methyl. In embodiments, R 4A is independently unsubstituted ethyl. [0213] In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29A -substituted or unsubstituted heterocycloalkyl or R 29A - substituted or unsubstituted heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29A -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 29A -substituted or unsubstituted 5 to 6 membered heteroaryl. [0214] R 29A is independently oxo,

halogen, -CX 29A

3, -CHX29A

2, -CH 2 X 29A , -OCH 2 X 29A , -OCX 29A

3, -OCHX29A

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30A -substituted or unsubstituted alkyl, R 30A -substituted or unsubstituted heteroalkyl, R 30A -substituted or unsubstituted cycloalkyl, R 30A -substituted or unsubstituted heterocycloalkyl, R 30A -substituted or unsubstituted aryl, or R 30A -substituted or unsubstituted heteroaryl. In embodiments, R 29A is independently oxo, halogen, -CX 29A

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 29A

3, -OCHX29A

2, R 30A -substituted or unsubstituted C 1 -C 8 alkyl, R 30A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 30A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30A -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 30A -substituted or unsubstituted phenyl, or R 30A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 29A is –F, -Cl, -Br, or–I. [0215] R 30A is independently oxo,

halogen, -CX 30A

3, -CHX30A

2, -CH 2 X 30A , -OCH 2 X 30A , -OCX 30A

3,

-OCHX 30A

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 30A

3, -OCHX30A

2, R 31A -substituted or unsubstituted alkyl, R 31A -substituted or unsubstituted heteroalkyl, R 31A -substituted or unsubstituted cycloalkyl, R 31A -substituted or unsubstituted heterocycloalkyl, R 31A -substituted or unsubstituted aryl, or R 31A -substituted or unsubstituted heteroaryl. In embodiments, R 30A is independently oxo,

halogen, -CX 30A

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 30A

3, -OCHX30A

2, R 31A -substituted or unsubstituted C 1 -C 8 alkyl, R 31A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 31A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31A -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 31A -substituted or unsubstituted phenyl, or R 31A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 30A is –F,-Cl, -Br, or–I. [0216] In embodiments, R 4B is independently

hydrogen, -CX 29B

3, -CHX29B

2, -CH 2 X 29B , -OCH 2 X 29B , -OCX 29B

3, -OCHX29B

2, -CN, -COOH, -CO NH 2 , -CHX4B

2, -CH 2 X 4B , R 29B -substituted or unsubstituted alkyl, R 29B -substituted or unsubstituted heteroalkyl, R 29B -substituted or unsubstituted cycloalkyl, R 29B -substituted or unsubstituted heterocycloalkyl, R 29B -substituted or unsubstituted aryl, or R 29B -substituted or unsubstituted heteroaryl. In embodiments, R 4B is independently

hydrogen, -CX 4B

3, -CN, -COOH, -CONH 2 , -CHX4B

2, -CH 2 X 4B , R 29B -substituted or unsubstituted C 1 -C 8 alkyl, R 29B -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29B -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 29B -substituted or unsubstituted phenyl, or R 29B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 4B is–F, -Cl, -Br, or–I. In embodiments, R 4B is independently hydrogen. In embodiments, R 4B is independently unsubstituted methyl. In embodiments, R 4B is independently unsubstituted ethyl. [0217] In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29B -substituted or unsubstituted heterocycloalkyl or R 29B - substituted or unsubstituted heteroaryl. In embodiments, R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29B -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 29B -substituted or unsubstituted 5 to 6 membered heteroaryl. [0218] R 29B is independently oxo,

halogen, -CX 29B

3, -CHX29B

2, -CH 2 X 29B , -OCH 2 X 29B , -OCX 29B

3,

-OCHX 29B

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30B -substituted or unsubstituted alkyl, R 30B -substituted or unsubstituted heteroalkyl, R 30B -substituted or unsubstituted cycloalkyl, R 30B -substituted or unsubstituted heterocycloalkyl, R 30B -substituted or unsubstituted aryl, or R 30B -substituted or unsubstituted heteroaryl. In embodiments, R 29B is independently oxo,

halogen, -CX 29B

3, -CHX29B

2, -CH 2 X 29B , -OCH 2 X 29B , -OCX 29B

3, -OCHX29B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30B -substituted or unsubstituted -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 30B -substituted or unsubstituted phenyl, or R 30B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 29B is–F, -Cl, -Br, or–I. [0219] R 30B is independently oxo,

halogen, -CX 30B

3, -CHX30B

2, -CH 2 X 30B , -OCH 2 X 30B , -OCX 30B

3, -OCHX30B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31B -substituted or unsubstituted alkyl, R 31B -substituted or unsubstituted heteroalkyl, R 31B -substituted or unsubstituted cycloalkyl, R 31B -substituted or unsubstituted heterocycloalkyl, R 31B -substituted or unsubstituted aryl, or R 31B -substituted or unsubstituted heteroaryl. In embodiments, R 30B is independently oxo, halogen, -CX 30B

3, -CHX30B

2, -CH 2 X 30B , -OCH 2 X 30B , -OCX 30B

3, -OCHX30B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31B -substituted or unsubstituted -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 31B -substituted or unsubstituted phenyl, or R 31B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 30B is–F,-Cl, -Br, or–I. [0220] In embodiments, R 4C is independently

hydrogen, -CX 4C

3, -CN, -COOH, -CONH 2 , -CHX4C

2, -CH 2 X 4C , R 29C -substituted or unsubstituted alkyl, R 29C -substituted or unsubstituted heteroalkyl, R 29C -substituted or unsubstituted cycloalkyl, R 29C -substituted or unsubstituted heterocycloalkyl, R 29C -substituted or unsubstituted aryl, or R 29C -substituted or unsubstituted heteroaryl. In embodiments, R 4C is independently

hydrogen, -CX 4C

3, -CN, -COOH, -CONH 2 , -CHX4C

2, -CH 2 X 4C , R 29C -substituted or unsubstituted C 1 -C 8 alkyl, R 29C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29C -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29C -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 29C -substituted or unsubstituted phenyl, or R 29C -substituted or unsubstituted 5 to 6 membered heteroaryl. X 4C is–F, -Cl, -Br, or–I. In embodiments, R 4C is independently hydrogen. In embodiments, R 4C is independently unsubstituted methyl. In embodiments, R 4C is independently unsubstituted ethyl. [0221] R 29C is independently oxo,

halogen, -CX 29C

3, -CHX29C

2, -CH 2 X 29C , -OCH 2 X 29C , -OCX 29C

3, -OCHX29C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30C -substituted or unsubstituted alkyl, R 30C -substituted or unsubstituted heteroalkyl, R 30C -substituted or unsubstituted cycloalkyl, R 30C -substituted or unsubstituted heterocycloalkyl, R 30C -substituted or unsubstituted aryl, or R 30C -substituted or unsubstituted heteroaryl. In embodiments, R 29C is independently oxo, halogen, -CX 29C

3, -CHX29C

2, -CH 2 X 29C , -OCH 2 X 29C , -OCX 29C

3, -OCHX29C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX29C

3, -OCHX29C

2, R 30C - substituted or unsubstituted C 1 -C 8 alkyl, R 30C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 30C -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30C -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 30C -substituted or unsubstituted phenyl, or R 30C -substituted or unsubstituted 5 to 6 membered heteroaryl. X 29C is–F, -Cl, -Br, or–I. [0222] R 30C is independently oxo,

halogen, -CX 30C

3, -CHX30C

2, -CH 2 X 30C , -OCH 2 X 30C , -OCX 30C

3, -OCHX30C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31C -substituted or unsubstituted alkyl, R 31C -substituted or unsubstituted heteroalkyl, R 31C -substituted or unsubstituted cycloalkyl, R 31C -substituted or unsubstituted heterocycloalkyl, R 31C -substituted or unsubstituted aryl, or R 31C -substituted or unsubstituted heteroaryl. In embodiments, R 30C is independently oxo, halogen, -CX 30C

3, -CHX30C

2, -CH 2 X 30C , -OCH 2 X 30C , -OCX 30C

3, -OCHX30C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31C -substituted or unsubstituted C 1 -C 8 alkyl, R 31C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 31C -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31C -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 31C -substituted or unsubstituted phenyl, or R 31C -substituted or unsubstituted 5 to 6 membered heteroaryl. X 30C is–F, -Cl, -Br, or–I. [0223] In embodiments, R 4D is independently

hydrogen, -CX 4D

3, -CN, -COOH, -CONH 2 , -CHX4D

2, -CH 2 X 4D , R 29D -substituted or unsubstituted alkyl, R 29D -substituted or unsubstituted heteroalkyl, R 29D -substituted or unsubstituted cycloalkyl, R 29D -substituted or unsubstituted heterocycloalkyl, R 29D -substituted or unsubstituted aryl, or R 29D -substituted or unsubstituted heteroaryl. In embodiments, R 4D is independently

hydrogen, -CX 4D

3, -CN, -COOH, -CONH 2 , -CHX4D

2, -CH 2 X 4D , R 29D -substituted or unsubstituted C 1 -C 8 alkyl, R 29D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29D -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 29D -substituted or unsubstituted phenyl, or R 29D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 4D is–F, -Cl, -Br, or–I. In embodiments, R 4D is independently hydrogen. In embodiments, R 4D is independently unsubstituted methyl. In embodiments, R 4D is independently unsubstituted ethyl. [0224] R 29D is independently oxo,

halogen, -CX 29D

3, -CHX29D

2, -CH 2 X 29D , -OCH 2 X 29D , -OCX 29D

3, -OCHX29D

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30D -substituted or unsubstituted alkyl, R 30D -substituted or unsubstituted heteroalkyl, R 30D -substituted or unsubstituted cycloalkyl, R 30D -substituted or unsubstituted heterocycloalkyl, R 30D -substituted or unsubstituted aryl, or R 30D -substituted or unsubstituted heteroaryl. In embodiments, R 29D is independently oxo, halogen, -CX 29D

3, -CHX29D

2, -CH 2 X 29D , -OCH 2 X 29D , -OCX 29D

3, -OCHX29D

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 30D -substituted or unsubstituted C 1 -C 8 alkyl, R 30D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 30D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30D -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 30D -substituted or unsubstituted phenyl, or R 30D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 29D is–F, -Cl, -Br, or–I. [0225] R 30D is independently oxo,

halogen, -CX 30D

3, -CHX30D

2, -CH 2 X 30D , -OCH 2 X 30D , -OCX 30D

3,

-OCHX 30D

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31D -substituted or unsubstituted alkyl, R 31D -substituted or unsubstituted heteroalkyl, R 31D -substituted or unsubstituted cycloalkyl, R 31D -substituted or unsubstituted heterocycloalkyl, R 31D -substituted or unsubstituted aryl, or R 31D -substituted or unsubstituted heteroaryl. In embodiments, R 30D is independently oxo,

halogen, -CX 30D

3, -CHX30D

2, -CH 2 X 30D , -OCH 2 X 30D , -OCX 30D

3, -OCHX30D

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 31D -substituted or unsubstituted C 1 -C 8 alkyl, R 31D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 31D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31D -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 31D -substituted or unsubstituted phenyl, or R 31D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 30D is–F,-Cl, -Br, or–I. [0226] R 31 , R 31A , R 31B , R 31C , and R 31D are independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0227] In embodiments, R 31 , R 31A , R 31B , R 31C , and R 31D are independently hydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 31 , R 31A , R 31B , R 31C , and R 31D are independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 31 , R 31A , R 31B , R 31C , and R 31D are independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0228] In embodiments, R 4 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4

3, -CHX4

2, -CH 2 X 4 , -O CX 4

3, -OCHX4

2, -OCH 2 X 4 , -SCX 4

3, -SCHX4

2, -SCH 2 X 4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 CH 3 . In embodiments, R 4 is independently–F. In embodiments, R 4 is independently -Cl. In

embodiments, R 4 is independently -Br. In embodiments, R 4 is independently -I. In

embodiments, R 4 is independently -CN. In embodiments, R 4 is independently -NH 2 . In embodiments, R 4 is independently -OH. In embodiments, R 4 is independently -SH. In embodiments, R 4 is independently -COCH 3 . In embodiments, R 4 is independently -COOH. In embodiments, R 4 is independently -COOCH 3 . In embodiments, R 4 is independently -CX 4

3. In embodiments, R 4 is independently -CHX 4

2. In embodiments, R 4 is independently -CH 2 X 4 . In embodiments, R 4 is independently -OCX 4

3. In embodiments, R 4 is independently -OCHX 4

2. In embodiments, R 4 is independently -OCH 2 X 4 . In embodiments, R 4 is independently -SCX 4

3. In embodiments, R 4 is independently -SCHX 4

2. In embodiments, R 4 is independently -SCH 2 X 4 . In embodiments, R 4 is independently -CH 3 . In embodiments, R 4 is independently -CH 2 CH 3 . In embodiments, R 4 is independently -OCH 3 . In embodiments, R 4 is independently -OCH 2 CH 3 . In embodiments, R 4 is independently -NHCH 3 . In embodiments, R 4 is independently -N(CH 3 ) 2 . In embodiments, R 4 is independently -NHCH 2 CH 3 . In embodiments, R 4 is

independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4 is independently -SCH 3 . In embodiments, R 4 is independently -SCH 2 CH 3 . In embodiments, X 4 is independently–F. In embodiments, X 4 is independently -Cl. In

embodiments, X 4 is independently -Br. In embodiments, X 4 is independently -I. [0229] In embodiments, R 4 is independently–OPh. In embodiments, R 4 is independently tert- butyl. In embodiments, R 4 is independently–OCH 2 Ph. In embodiments, R 4 is independently– OCH 2 CH 3 . In embodiments, R 4 is independently–OCH(CH 3 ) 2 . In embodiments, R 4 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4 is independently–OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4 is independently– OCH 2 CHCH 2 . In embodiments, R 4 is independently–OCH 2 CH 2 Ph. In embodiments, R 4 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4 is independently–Ph. In embodiments, R 4 is independently–CH 2 Ph. In embodiments, R 4 is independently–CH 2 CH 2 Ph. In embodiments, R 4 is independently–CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4 is independently–

CH 2 CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4 is independently–CH 2 CH 2 CH(CH 3 ) 2 . [0230] R 4.1 is R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. R 4.1A is R 4A at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4A substituent. R 4.1B is R 4B at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4B substituent. R 4.1C is R 4C at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4C substituent. R 4.1D is R 4D at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4D substituent. The symbol n4.1 is n4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any n4 substituent. The symbol m4.1 is m4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any m4 substituent. The symbol v4.1 is v4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any v4 substituent. In embodiments, R 4.1 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4.1

3, -CHX4.1

2, -CH 2 X 4.1 , -OCX 4.1

3, -OCHX4.1

2, -OCH 2 X 4.1 , -SCX 4.1

3, -SCHX4.1

2, -SCH 2 X 4.1 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OC H 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 C H 3 . In embodiments, R 4.1 is independently–F. In embodiments, R 4.1 is independently -Cl. In embodiments, R 4.1 is independently -Br. In embodiments, R 4.1 is independently -I. In embodiments, R 4.1 is independently -CN. In embodiments, R 4.1 is independently -NH 2 . In embodiments, R 4.1 is independently -OH. In embodiments, R 4.1 is independently -SH. In embodiments, R 4.1 is independently -COCH 3 . In embodiments, R 4.1 is independently -COOH. In embodiments, R 4.1 is independently -COOCH 3 . In embodiments, R 4.1 is independently -CX 4.1

3. In embodiments, R 4.1 is independently -CHX 4.1

2. In embodiments, R 4.1 is

independently -CH 2 X 4.1 . In embodiments, R 4.1 is independently -OCX 4.1

3. In embodiments, R4.1 is independently -OCHX 4.1

2. In embodiments, R 4.1 is independently -OCH 2 X 4.1 . In

embodiments, R 4.1 is independently -SCX 4.1

3. In embodiments, R 4.1 is independently -SCHX 4.1

2. In embodiments, R 4.1 is independently -SCH 2 X 4.1 . In embodiments, R 4.1 is independently -CH 3 . In embodiments, R 4.1 is independently -CH 2 CH 3 . In embodiments, R 4.1 is independently -OCH 3 . In embodiments, R 4.1 is independently -OCH 2 CH 3 . In embodiments, R 4.1 is independently -NHCH 3 . In embodiments, R 4.1 is independently -N(CH 3 ) 2 . In embodiments, R4.1 is independently -NHCH 2 CH 3 . In embodiments, R 4.1 is independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4.1 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4.1 is

independently -SCH 3 . In embodiments, R 4.1 is independently -SCH 2 CH 3 . In embodiments, X4.1 is independently–F. In embodiments, X 4.1 is independently -Cl. In embodiments, X 4.1 is independently -Br. In embodiments, X 4.1 is independently -I. In embodiments, R 4.1 is independently–OPh. In embodiments, R 4.1 is independently tert-butyl. In embodiments, R 4.1 is independently–OCH 2 Ph. In embodiments, R 4.1 is independently–OCH 2 CH 3 . In embodiments, R 4.1 is independently–OCH(CH 3 ) 2 . In embodiments, R 4.1 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.1 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4.1 is independently– OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.1 is independently–OCH 2 CHCH 2 . In embodiments, R 4.1 is independently–OCH 2 CH 2 Ph. In embodiments, R 4.1 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.1 is independently–Ph. In embodiments, R 4.1 is independently–CH 2 Ph. In embodiments, R 4.1 is independently–CH 2 CH 2 Ph. In embodiments, R 4.1 is independently– CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.1 is independently–CH 2 CH 2 CH 2 CH 2 CH 3 . In

embodiments, R 4.1 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4.1 is independently– CH 2 CH 2 CH(CH 3 ) 2 . In embodiments, R 4.1 is independently hydrogen. In embodiments, R 4.1 is independently halogen. In embodiments, R 4.1 is independently -CX 4.1

3. In embodiments, R 4.1 is independently -CHX 4.1

2. In embodiments, R 4.1 is independently -CH 2 X 4.1 . In embodiments, R 4.1 is independently -OCX 4.1

3. In embodiments, R 4.1 is independently -OCH 2 X 4.1 . In embodiments, R 4.1 is independently -OCHX 4.1

2. In embodiments, R 4.1 is independently -CN. In embodiments, R 4.1 is independently -OH. In embodiments, R 4.1 is independently -NH 2 . In embodiments, R 4.1 is independently -COOH. In embodiments, R 4.1 is independently -CONH 2 . In embodiments, R4.1 is independently -NO 2 . In embodiments, R 4.1 is independently–SH. In embodiments, R 4.1 is independently -SO n4.1 R 4.1D . In embodiments, R 4.1 is independently -SO v4.1 NR 4.1A R 4.1B . In embodiments, R 4.1 is independently -NHC(O)NR 4.1A R 4.1B . In embodiments, R 4.1 is

independently -N(O) m4.1 . In embodiments, R 4.1 is independently -NR 4.1A R 4.1B . In embodiments, R 4.1 is independently -C(O)R 4.1C . In embodiments, R 4.1 is independently -C(O)-OR 4.1C . In embodiments, R 4.1 is independently -C(O)NR 4.1A R 4.1B . In embodiments, R 4.1 is

independently -OR 4.1D . In embodiments, R 4.1 is independently -NR 4.1A SO 2 R 4.1D . In

embodiments, R 4.1 is independently -NR 4.1A C(O)R 4.1C . In embodiments, R 4.1 is

independently -NR 4.1A C(O)OR 4.1C . In embodiments, R 4.1 is independently -NR 4.1A OR 4.1C . In embodiments, R 4.1 is independently -SO n4 R 4D . In embodiments, R 4.1 is independently -SO v4 NR 4A R 4B . In embodiments, R 4.1 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4.1 is independently -N(O) m4 . In embodiments, R 4.1 is independently -NR 4A R 4B . In embodiments, R 4.1 is independently -C(O)R 4C . In embodiments, R 4.1 is

independently -C(O)-OR 4C . In embodiments, R 4.1 is independently -C(O)NR 4A R 4B . In embodiments, R 4.1 is independently -OR 4D . In embodiments, R 4.1 is

independently -NR 4A SO 2 R 4D . In embodiments, R 4.1 is independently -NR 4A C(O)R 4C . In embodiments, R 4.1 is independently -NR 4A C(O)OR 4C . In embodiments, R 4.1 is

independently -NR 4A OR 4C . [0231] R 4.2 is R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. R 4.2A is R 4A at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4A substituent. R 4.2B is R 4B at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4B substituent. R 4.2C is R 4C at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4C substituent. R 4.2D is R 4D at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4D substituent. The symbol n4.2 is n4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any n4 substituent. The symbol m4.2 is m4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any m4 substituent. The symbol v4.2 is v4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any v4 substituent. [0232] In embodiments, R 4.2 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4.2

3, -CHX4.2

2, -CH 2 X 4.2 , -OCX 4.2

3, -OCHX4.2

2, -OCH 2 X 4.2 , -SCX 4.2

3, -SCHX4.2

2, -SCH 2 X 4.2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OC H 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 C H 3 . In embodiments, R 4.2 is independently–F. In embodiments, R 4.2 is independently -Cl. In embodiments, R 4.2 is independently -Br. In embodiments, R 4.2 is independently -I. In embodiments, R 4.2 is independently -CN. In embodiments, R 4.2 is independently -NH 2 . In embodiments, R 4.2 is independently -OH. In embodiments, R 4.2 is independently -SH. In embodiments, R 4.2 is independently -COCH 3 . In embodiments, R 4.2 is independently -COOH. In embodiments, R 4.2 is independently -COOCH 3 . In embodiments, R 4.2 is independently -CX 4.2

3. In embodiments, R 4.2 is independently -CHX 4.2

2. In embodiments, R 4.2 is independently -CH 2 X 4.2 . In embodiments, R 4.2 is independently -OCX 4.2

3. In embodiments, R4.2 is independently -OCHX 4.2

2. In embodiments, R 4.2 is independently -OCH 2 X 4.2 . In

embodiments, R 4.2 is independently -SCX 4.2

3. In embodiments, R 4.2 is independently -SCHX 4.2

2. In embodiments, R 4.2 is independently In embodiments, R 4.2 is independently -CH 3 . In embodiments, R 4.2 is independently -CH 2 CH 3 . In embodiments, R 4.2 is independently -OCH 3 . In embodiments, R 4.2 is independently -OCH 2 CH 3 . In embodiments, R 4.2 is

independently -NHCH 3 . In embodiments, R 4.2 is independently -N(CH 3 ) 2 . In embodiments, R4.2 is independently -NHCH 2 CH 3 . In embodiments, R 4.2 is independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4.2 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4.2 is

independently -SCH 3 . In embodiments, R 4.2 is independently -SCH 2 CH 3 . In embodiments, X 4.2 is independently–F. In embodiments, X 4.2 is independently -Cl. In embodiments, X 4.2 is independently -Br. In embodiments, X 4.2 is independently -I. In embodiments, R 4.2 is independently–OPh. In embodiments, R 4.2 is independently tert-butyl. In embodiments, R 4.2 is independently–OCH 2 Ph. In embodiments, R 4.2 is independently–OCH 2 CH 3 . In embodiments, R 4.2 is independently–OCH(CH 3 ) 2 . In embodiments, R 4.2 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.2 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4.2 is independently– OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.2 is independently–OCH 2 CHCH 2 . In embodiments, R 4.2 is independently–OCH 2 CH 2 Ph. In embodiments, R 4.2 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.2 is independently–Ph. In embodiments, R 4.2 is independently–CH 2 Ph. In embodiments, R 4.2 is independently–CH 2 CH 2 Ph. In embodiments, R 4.2 is independently– CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.2 is independently–CH 2 CH 2 CH 2 CH 2 CH 3 . In

embodiments, R 4.2 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4.2 is independently– CH 2 CH 2 CH(CH 3 ) 2 . In embodiments, R 4.2 is independently hydrogen. In embodiments, R 4.2 is independently halogen. In embodiments, R 4.2 is independently -CX 4.2

3. In embodiments, R 4.2 is independently -CHX 4.2

2. In embodiments, R 4.2 is independently -CH 2 X 4.2 . In embodiments, R 4.2 is independently -OCX 4.2

3. In embodiments, R 4.2 is independently -OCH 2 X 4.2 . In embodiments, R 4.2 is independently -OCHX 4.2

2. In embodiments, R 4.2 is independently -CN. In embodiments, R 4.2 is independently -SO n4.2 R 4.2D . In embodiments, R 4.2 is independently -SO v4.2 NR 4.2A R 4.2B . In embodiments, R 4.2 is independently -NHC(O)NR 4.2A R 4.2B . In embodiments, R 4.2 is

independently -N(O) m4.2 . In embodiments, R 4.2 is independently -NR 4.2A R 4.2B . In embodiments, R 4.2 is independently -C(O)R 4.2C . In embodiments, R 4.2 is independently -C(O)-OR 4.2C . In embodiments, R 4.2 is independently -C(O)NR 4.2A R 4.2B . In embodiments, R 4.2 is

independently -OR 4.2D . In embodiments, R 4.2 is independently -NR 4.2A SO D

2R 4.2 . In embodiments, R 4.2 is independently -NR 4.2A C(O)R 4.2C . In embodiments, R 4.2 is

independently -NR 4.2A C(O)OR 4.2C . In embodiments, R 4.2 is independently -NR 4.2A OR 4.2C . In embodiments, R 4.2 is independently -OH. In embodiments, R 4.2 is independently -NH 2 . In embodiments, R 4.2 is independently -COOH. In embodiments, R 4.2 is independently -CONH 2 . In embodiments, R 4.2 is independently -NO 2 . In embodiments, R 4.2 is independently–SH. In embodiments, R 4.2 is independently -SO n4 R 4D . In embodiments, R 4.2 is

independently -SO v4 NR 4A R 4B . In embodiments, R 4.2 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4.2 is independently -N(O) m4 . In embodiments, R 4.2 is independently -NR 4A R 4B . In embodiments, R 4.2 is independently -C(O)R 4C . In embodiments, R 4.2 is

independently -C(O)-OR 4C . In embodiments, R 4.2 is independently -C(O)NR 4A R 4B . In embodiments, R 4.2 is independently -OR 4D . In embodiments, R 4.2 is

independently -NR 4A SO 2 R 4D . In embodiments, R 4.2 is independently -NR 4A C(O)R 4C . In embodiments, R 4.2 is independently -NR 4A C(O)OR 4C . In embodiments, R 4.2 is

independently -NR 4A OR 4C . [0233] R 4.3 is R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. R 4.3A is R 4A at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4A substituent. R 4.3B is R 4B at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4B substituent. R 4.3C is R 4C at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4C substituent. R 4.3D is R 4D at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4D substituent. The symbol n4.3 is n4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any n4 substituent. The symbol m4.3 is m4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any m4 substituent. The symbol v4.3 is v4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any v4 substituent. [0234] In embodiments, R 4.3 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4.3

3, -CHX4.3

2, -CH 2 X 4.3 , -OCX 4.3

3, -OCHX4.3

2, -OCH 2 X 4.3 , -SCX 4.3

3, -SCHX4.3

2, -SCH 2 X 4.3 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OC H 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 C H 3 . In embodiments, R 4.3 is independently–F. In embodiments, R 4.3 is independently -Cl. In embodiments, R 4.3 is independently -Br. In embodiments, R 4.3 is independently -I. In embodiments, R 4.3 is independently -CN. In embodiments, R 4.3 is independently -NH 2 . In embodiments, R 4.3 is independently -OH. In embodiments, R 4.3 is independently -SH. In embodiments, R 4.3 is independently -COCH 3 . In embodiments, R 4.3 is independently -COOH. In embodiments, R 4.3 is independently -COOCH 3 . In embodiments, R 4.3 is independently -CX 4.3

3. In embodiments, R 4.3 is independently -CHX 4.3

2. In embodiments, R 4.3 is

independently -CH 2 X 4.3 . In embodiments, R 4.3 is independently -OCX 4.3

3. In embodiments, R4.3 is independently -OCHX 4.3

2. In embodiments, R 4.3 is independently -OCH 2 X 4.3 . In

embodiments, R 4.3 is independently -SCX 4.3

3. In embodiments, R 4.3 is independently -SCHX 4.3

2. In embodiments, R 4.3 is independently -SCH 2 X 4.3 . In embodiments, R 4.3 is independently -CH 3 . In embodiments, R 4.3 is independently -CH 2 CH 3 . In embodiments, R 4.3 is independently -OCH 3 . In embodiments, R 4.3 is independently -OCH 2 CH 3 . In embodiments, R 4.3 is

independently -NHCH 3 . In embodiments, R 4.3 is independently -N(CH 3 ) 2 . In embodiments, R4.3 is independently -NHCH 2 CH 3 . In embodiments, R 4.3 is independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4.3 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4.3 is

independently -SCH 3 . In embodiments, R 4.3 is independently -SCH 2 CH 3 . In embodiments, X4.3 is independently–F. In embodiments, X 4.3 is independently -Cl. In embodiments, X 4.3 is independently -Br. In embodiments, X 4.3 is independently -I. In embodiments, R 4.3 is independently–OPh. In embodiments, R 4.3 is independently tert-butyl. In embodiments, R 4.3 is independently–OCH 2 Ph. In embodiments, R 4.3 is independently–OCH 2 CH 3 . In embodiments, R 4.3 is independently–OCH(CH 3 ) 2 . In embodiments, R 4.3 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.3 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4.3 is independently– OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.3 is independently–OCH 2 CHCH 2 . In embodiments, R 4.3 is independently–OCH 2 CH 2 Ph. In embodiments, R 4.3 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.3 is independently–Ph. In embodiments, R 4.3 is independently–CH 2 Ph. In embodiments, R 4.3 is independently–CH 2 CH 2 Ph. In embodiments, R 4.3 is independently– CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.3 is independently–CH 2 CH 2 CH 2 CH 2 CH 3 . In

embodiments, R 4.3 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4.3 is independently– CH 2 CH 2 CH(CH 3 ) 2 . In embodiments, R 4.3 is independently hydrogen. In embodiments, R 4.3 is independently halogen. In embodiments, R 4.3 is independently -CX 4.3

3. In embodiments, R 4.3 is independently -CHX 4.3

2. In embodiments, R 4.3 is independently -CH 2 X 4.3 . In embodiments, R 4.3 is independently -OCX 4.3

3. In embodiments, R 4.3 is independently -OCH 2 X 4.3 . In embodiments, R 4.3 is independently -OCHX 4.3

2. In embodiments, R 4.3 is independently -CN. In embodiments, R 4.3 is independently -SO n4.3 R 4.3D . In embodiments, R 4.3 is independently -SO v4.3 NR 4.3A R 4.3B . In embodiments, R 4.3 is independently -NHC(O)NR 4.3A R 4.3B . In embodiments, R 4.3 is

independently -N(O) m4.3 . In embodiments, R 4.3 is independently -NR 4.3A R 4.3B . In embodiments, R 4.3 is independently -C(O)R 4.3C . In embodiments, R 4.3 is independently -C(O)-OR 4.3C . In embodiments, R 4.3 is independently -C(O)NR 4.3A R 4.3B . In embodiments, R 4.3 is

independently -OR 4.3D . In embodiments, R 4.3 is independently -NR 4.3A SO 2 R 4.3D . In

embodiments, R 4.3 is independently -NR 4.3A C(O)R 4.3C . In embodiments, R 4.3 is

independently -NR 4.3A C(O)OR 4.3C . In embodiments, R 4.3 is independently -NR 4.3A OR 4.3C . In embodiments, R 4.3 is independently -OH. In embodiments, R 4.3 is independently -NH 2 . In embodiments, R 4.3 is independently -COOH. In embodiments, R 4.3 is independently -CONH 2 . In embodiments, R 4.3 is independently -NO 2 . In embodiments, R 4.3 is independently–SH. In embodiments, R 4.3 is independently -SO n4 R 4D . In embodiments, R 4.3 is

independently -SO v4 NR 4A R 4B . In embodiments, R 4.3 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4.3 is independently -N(O) m4 . In embodiments, R 4.3 is independently -NR 4A R 4B . In embodiments, R 4.3 is independently -C(O)R 4C . In embodiments, R 4.3 is

independently -C(O)-OR 4C . In embodiments, R 4.3 is independently -C(O)NR 4A R 4B . In embodiments, R 4.3 is independently -OR 4D . In embodiments, R 4.3 is

independently -NR 4A SO 2 R 4D . In embodiments, R 4.3 is independently -NR 4A C(O)R 4C . In embodiments, R 4.3 is independently -NR 4A C(O)OR 4C . In embodiments, R 4.3 is

independently -NR 4A OR 4C . [0235] R 4.4 is R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. R 4.4A is R 4A at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4A substituent. R 4.4B is R 4B at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4B substituent. R 4.4C is R 4C at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4C substituent. R 4.4D is R 4D at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4D substituent. The symbol n4.4 is n4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any n4 substituent. The symbol m4.4 is m4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any m4 substituent. The symbol v4.4 is v4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any v4 substituent. [0236] In embodiments, R 4.4 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4.4

3, -CHX4.4

2, -CH 2 X 4.4 , -OCX 4.4

3, -OCHX4.4

2, -OCH 2 X 4.4 , -SCX 4.4

3, -SCHX4.4

2, -SCH 2 X 4.4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OC H 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 C H 3 . In embodiments, R 4.4 is independently–F. In embodiments, R 4.4 is independently -Cl. In embodiments, R 4.4 is independently -Br. In embodiments, R 4.4 is independently -I. In embodiments, R 4.4 is independently -CN. In embodiments, R 4.4 is independently -NH 2 . In embodiments, R 4.4 is independently -OH. In embodiments, R 4.4 is independently -SH. In embodiments, R 4.4 is independently -COCH 3 . In embodiments, R 4.4 is independently -COOH. In embodiments, R 4.4 is independently -COOCH 3 . In embodiments, R 4.4 is independently -CX 4.4

3. In embodiments, R 4.4 is independently -CHX 4.4

2. In embodiments, R 4.4 is

independently -CH 2 X 4.4 . In embodiments, R 4.4 is independently -OCX 4.4

3. In embodiments, R4.4 is independently -OCHX 4.4

2. In embodiments, R 4.4 is independently -OCH 2 X 4.4 . In

embodiments, R 4.4 is independently -SCX 4.4

3. In embodiments, R 4.4 is independently -SCHX 4.4

2. In embodiments, R 4.4 is independently -SCH 2 X 4.4 . In embodiments, R 4.4 is independently -CH 3 . In embodiments, R 4.4 is independently -CH 2 CH 3 . In embodiments, R 4.4 is independently -OCH 3 . In embodiments, R 4.4 is independently -OCH 2 CH 3 . In embodiments, R 4.4 is

independently -NHCH 3 . In embodiments, R 4.4 is independently -N(CH 3 ) 2 . In embodiments, R 4.4 is independently -NHCH 2 CH 3 . In embodiments, R 4.4 is independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4.4 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4.4 is

independently -SCH 3 . In embodiments, R 4.4 is independently -SCH 2 CH 3 . In embodiments, X4.4 is independently–F. In embodiments, X 4.4 is independently -Cl. In embodiments, X 4.4 is independently -Br. In embodiments, X 4.4 is independently -I. In embodiments, R 4.4 is independently–OPh. In embodiments, R 4.4 is independently tert-butyl. In embodiments, R 4.4 is independently–OCH 2 Ph. In embodiments, R 4.4 is independently–OCH 2 CH 3 . In embodiments, R 4.4 is independently–OCH(CH 3 ) 2 . In embodiments, R 4.4 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.4 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4.4 is independently– OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.4 is independently–OCH 2 CHCH 2 . In embodiments, R 4.4 is independently–OCH 2 CH 2 Ph. In embodiments, R 4.4 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.4 is independently–Ph. In embodiments, R 4.4 is independently–CH 2 Ph. In embodiments, R 4.4 is independently–CH 2 CH 2 Ph. In embodiments, R 4.4 is independently– CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.4 is independently–CH 2 CH 2 CH 2 CH 2 CH 3 . In

embodiments, R 4.4 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4.4 is independently– CH 2 CH 2 CH(CH 3 ) 2 . In embodiments, R 4.4 is independently hydrogen. In embodiments, R 4.4 is independently halogen. In embodiments, R 4.4 is independently -CX 4.4

3. In embodiments, R 4.4 is independently -CHX 4.4

2. In embodiments, R 4.4 is independently -CH 2 X 4.4 . In embodiments, R 4.4 is independently -OCX 4.4

3. In embodiments, R 4.4 is independently -OCH 2 X 4.4 . In embodiments, R 4.4 is independently -OCHX 4.4

2. In embodiments, R 4.4 is independently -CN. In embodiments, R 4.4 is independently -SO n4.4 R 4.4D . In embodiments, R 4.4 is independently -SO v4.4 NR 4.4A R 4.4B . In embodiments, R 4.4 is independently -NHC(O)NR 4.4A R 4.4B . In embodiments, R 4.4 is

independently -N(O) m4.4 . In embodiments, R 4.4 is independently -NR 4.4A R 4.4B . In embodiments, R 4.4 is independently -C(O)R 4.4C . In embodiments, R 4.4 is independently -C(O)-OR 4.4C . In embodiments, R 4.4 is independently -C(O)NR 4.4A R 4.4B . In embodiments, R 4.4 is

independently -OR 4.4D . In embodiments, R 4.4 is independently -NR 4.4A SO 2 R 4.4D . In

embodiments, R 4.4 is independently -NR 4.4A C(O)R 4.4C . In embodiments, R 4.4 is

independently -NR 4.4A C(O)OR 4.4C . In embodiments, R 4.4 is independently -NR 4.4A OR 4.4C . In embodiments, R 4.4 is independently -OH. In embodiments, R 4.4 is independently -NH 2 . In embodiments, R 4.4 is independently -COOH. In embodiments, R 4.4 is independently -CONH 2 . In embodiments, R 4.4 is independently -NO 2 . In embodiments, R 4.4 is independently–SH. In embodiments, R 4.4 is independently -SO n4 R 4D . In embodiments, R 4.4 is

independently -SO v4 NR 4A R 4B . In embodiments, R 4.4 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4.4 is independently -N(O) m4 . In embodiments, R 4.4 is independently -NR 4A R 4B . In embodiments, R 4.4 is independently -C(O)R 4C . In embodiments, R 4.4 is

independently -C(O)-OR 4C . In embodiments, R 4.4 is independently -C(O)NR 4A R 4B . In embodiments, R 4.4 is independently -OR 4D . In embodiments, R 4.4 is

independently -NR 4A SO 2 R 4D . In embodiments, R 4.4 is independently -NR 4A C(O)R 4C . In embodiments, R 4.4 is independently -NR 4A C(O)OR 4C . In embodiments, R 4.4 is

independently -NR 4A OR 4C . [0237] R 4.5 is R 4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4 substituent. R 4.5A is R 4A at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4A substituent. R 4.5B is R 4B at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4B substituent. R 4.5C is R 4C at a fixed position (e.g., non- floating as shown in the formula described herein) and may independently be any R 4C substituent. R 4.5D is R 4D at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 4D substituent. The symbol n4.5 is n4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any n4 substituent. The symbol m4.5 is m4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any m4 substituent. The symbol v4.5 is v4 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any v4 substituent. [0238] In embodiments, R 4.5 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4.5

3, -CHX4.5

2, -CH 2 X 4.5 , -OCX 4.5

3, -OCHX4.5

2, -OCH 2 X 4.5 , -SCX 4.5

3, -SCHX4.5

2, -SCH 2 X 4.5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OC H 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 C H 3 . In embodiments, R 4.5 is independently–F. In embodiments, R 4.5 is independently -Cl. In embodiments, R 4.5 is independently -Br. In embodiments, R 4.5 is independently -I. In embodiments, R 4.5 is independently -CN. In embodiments, R 4.5 is independently -NH 2 . In embodiments, R 4.5 is independently -OH. In embodiments, R 4.5 is independently -SH. In embodiments, R 4.5 is independently -COCH 3 . In embodiments, R 4.5 is independently -COOH. In embodiments, R 4.5 is independently -COOCH 3 . In embodiments, R 4.5 is independently -CX 4.5

3. In embodiments, R 4.5 is independently -CHX 4.5

2. In embodiments, R 4.5 is

independently -CH 2 X 4.5 . In embodiments, R 4.5 is independently -OCX 4.5

3. In embodiments, R4.5 is independently -OCHX 4.5

2. In embodiments, R 4.5 is independently -OCH 2 X 4.5 . In

embodiments, R 4.5 is independently -SCX 4.5

3. In embodiments, R 4.5 is independently -SCHX 4.5

2. In embodiments, R 4.5 is independently -SCH 2 X 4.5 . In embodiments, R 4.5 is independently -CH 3 . In embodiments, R 4.5 is independently -CH 2 CH 3 . In embodiments, R 4.5 is independently -OCH 3 . In embodiments, R 4.5 is independently -OCH 2 CH 3 . In embodiments, R 4.5 is

independently -NHCH 3 . In embodiments, R 4.5 is independently -N(CH 3 ) 2 . In embodiments, R4.5 is independently -NHCH 2 CH 3 . In embodiments, R 4.5 is independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 4.5 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 4.5 is

independently -SCH 3 . In embodiments, R 4.5 is independently -SCH 2 CH 3 . In embodiments, X 4.5 is independently–F. In embodiments, X 4.5 is independently -Cl. In embodiments, X 4.5 is independently -Br. In embodiments, X 4.5 is independently -I. In embodiments, R 4.5 is independently–OPh. In embodiments, R 4.5 is independently tert-butyl. In embodiments, R 4.5 is independently–OCH 2 Ph. In embodiments, R 4.5 is independently–OCH 2 CH 3 . In embodiments, R 4.5 is independently–OCH(CH 3 ) 2 . In embodiments, R 4.5 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.5 is independently–OCH 2 CH(CH 3 ) 2 . In embodiments, R 4.5 is independently– OCH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.5 is independently–OCH 2 CHCH 2 . In embodiments, R 4.5 is independently–OCH 2 CH 2 Ph. In embodiments, R 4.5 is independently–OCH 2 CH 2 CH 3 . In embodiments, R 4.5 is independently–Ph. In embodiments, R 4.5 is independently–CH 2 Ph. In embodiments, R 4.5 is independently–CH 2 CH 2 Ph. In embodiments, R 4.5 is independently– CH 2 CH 2 CH 2 CH 3 . In embodiments, R 4.5 is independently–CH 2 CH 2 CH 2 CH 2 CH 3 . In

embodiments, R 4.5 is independently–CH 2 CH(CH 3 ) 2 . In embodiments, R 4.5 is independently– CH 2 CH 2 CH(CH 3 ) 2 . In embodiments, R 4.5 is independently hydrogen. In embodiments, R 4.5 is independently halogen. In embodiments, R 4.5 is independently -CX 4.5

3. In embodiments, R 4.5 is independently -CHX 4.5

2. In embodiments, R 4.5 is independently -CH 2 X 4.5 . In embodiments, R 4.5 is independently -OCX 4.5

3. In embodiments, R 4.5 is independently -OCH 2 X 4.5 . In embodiments, R 4.5 is independently -OCHX 4.5

2. In embodiments, R 4.5 is independently -CN. In embodiments, R 4.5 is independently -SO n4.5 R 4.5D . In embodiments, R 4.5 is independently -SO v4.5 NR 4.5A R 4.5B . In embodiments, R 4.5 is independently -NHC(O)NR 4.5A R 4.5B . In embodiments, R 4.5 is

independently -N(O) m4.5 . In embodiments, R 4.5 is independently -NR 4.5A R 4.5B . In embodiments, R 4.5 is independently -C(O)R 4.5C . In embodiments, R 4.5 is independently -C(O)-OR 4.5C . In embodiments, R 4.5 is independently -C(O)NR 4.5A R 4.5B . In embodiments, R 4.5 is

independently -OR 4.5D . In embodiments, R 4.5 is independently -NR 4.5A SO 2 R 4.5D . In

embodiments, R 4.5 is independently -NR 4.5A C(O)R 4.5C . In embodiments, R 4.5 is

independently -NR 4.5A C(O)OR 4.5C . In embodiments, R 4.5 is independently -NR 4.5A OR 4.5C . In embodiments, R 4.5 is independently -OH. In embodiments, R 4.5 is independently -NH 2 . In embodiments, R 4.5 is independently -COOH. In embodiments, R 4.5 is independently -CONH 2 . In embodiments, R 4.5 is independently -NO 2 . In embodiments, R 4.5 is independently–SH. In embodiments, R 4.5 is independently -SO n4 R 4D . In embodiments, R 4.5 is

independently -SO v4 NR 4A R 4B . In embodiments, R 4.5 is independently -NHC(O)NR 4A R 4B . In embodiments, R 4.5 is independently -N(O) m4 . In embodiments, R 4.5 is independently -NR 4A R 4B . In embodiments, R 4.5 is independently -C(O)R 4C . In embodiments, R 4.5 is

independently -C(O)-OR 4C . In embodiments, R 4.5 is independently -C(O)NR 4A R 4B . In embodiments, R 4.5 is independently -OR 4D . In embodiments, R 4.5 is

independently -NR 4A SO 2 R 4D . In embodiments, R 4.5 is independently -NR 4A C(O)R 4C . In embodiments, R 4.5 is independently -NR 4A C(O)OR 4C . In embodiments, R 4.5 is

independently -NR 4A OR 4C . [0239] In embodiments, z4 is 5. In embodiments, z4 is 4. In embodiments, z4 is 3. In embodiments, z4 is 2. In embodiments, z4 is 1. In embodiments, z4 is 0. [0240] In embodiments, Ring B is 3 to 7 membered heterocycloalkyl. In embodiments, Ring B is 3 to 6 membered heterocycloalkyl. In embodiments, Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, furazanyl, dithiazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In embodiments, Ring B is a 6 membered heterocycloalkyl. In embodiments, Ring B is piperidinyl or piperazinyl. In embodiments, Ring B is 5 to 10 membered heteroaryl. In embodiments, Ring B is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, azaindolyl, benzoisoxazolyl, pyrrolopyridinyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl,

benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. In embodiments, Ring B is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In embodiments, Ring B is a 6 membered heteroaryl. In embodiments, Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. [0241] In embodiments, Ring B is 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl. [0242] In embodiments, Ring B is heterocycloalkyl. In embodiments, Ring B is 3 to 7 membered heterocycloalkyl. In embodiments, Ring B is 3 to 6 membered heterocycloalkyl. In embodiments, Ring B is 3 to 5 membered heterocycloalkyl. In embodiments, Ring B is 5 to 6 membered heterocycloalkyl. In embodiments, Ring B is 3 membered heterocycloalkyl. In embodiments, Ring B is 4 membered heterocycloalkyl. In embodiments, Ring B is 5 membered heterocycloalkyl. In embodiments, Ring B is 6 membered heterocycloalkyl. In embodiments, Ring B is 7 membered heterocycloalkyl. [0243] In embodiments, Ring B is heteroaryl. In embodiments, Ring B is 5 to 10 membered heteroaryl. In embodiments, Ring B is 5 to 9 membered heteroaryl. In embodiments, Ring B is 5 to 6 membered heteroaryl. In embodiments, Ring B is 5 membered heteroaryl. In embodiments, Ring B is 6 membered heteroaryl. In embodiments, Ring B is 9 membered heteroaryl. In embodiments, Ring B is 10 membered heteroaryl. [0244] In embodiments, Ring B is aziridinyl. In embodiments, Ring B is azirinyl. In embodiments, Ring B is diaziridinyl. In embodiments, Ring B is diazirinyl. In embodiments, Ring B is oxaziridinyl. In embodiments, Ring B is azetidinyl. In embodiments, Ring B is azetyl. In embodiments, Ring B is diazetidinyl. In embodiments, Ring B is diazetyl. In embodiments, Ring B is pyrrolidinyl. In embodiments, Ring B is pyrazolidinyl. In embodiments, Ring B is oxazolidinyl. In embodiments, Ring B is isoxazolidinyl. In embodiments, Ring B is

thiazolidinyl. In embodiments, Ring B is isothiazolidinyl. In embodiments, Ring B is furazanyl. In embodiments, Ring B is dithiazolyl. In embodiments, Ring B is piperidinyl. In embodiments, Ring B is piperazinyl. In embodiments, Ring B is morpholinyl. In embodiments, Ring B is thiomorpholinyl. [0245] In embodiments, Ring B is piperidinyl. In embodiments, Ring B is piperazinyl. In embodiments, Ring B is benzofuranyl. In embodiments, Ring B is isobenzofuranyl. In embodiments, Ring B is indolyl. In embodiments, Ring B is isoindolyl. In embodiments, Ring B is benzothienyl. In embodiments, Ring B is benzo[c]thienyl. In embodiments, Ring B is benzimidazolyl. In embodiments, Ring B is azaindolyl. In embodiments, Ring B is

benzoisoxazolyl. In embodiments, Ring B is pyrrolopyridinyl. In embodiments, Ring B is purinyl. In embodiments, Ring B is indazolyl. In embodiments, Ring B is benzoxazolyl. In embodiments, Ring B is benzisoxazolyl. In embodiments, Ring B is benzothiazolyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is quinoxalinyl. In embodiments, Ring B is quinazolinyl. In embodiments, Ring B is cinnolinyl. In embodiments, Ring B is phthalazinyl. In embodiments, Ring B is furanyl. In embodiments, Ring B is pyrrolyl. In embodiments, Ring B is thienyl. In embodiments, Ring B is imidazolyl. In embodiments, Ring B is pyrazolyl. In embodiments, Ring B is oxazolyl. In embodiments, Ring B is isoxazolyl. In embodiments, Ring B is thiazolyl. In embodiments, Ring B is isothiazolyl. In embodiments, Ring B is triazolyl. In embodiments, Ring B is oxadiazolyl. In embodiments, Ring B is thiadiazolyl. In embodiments, Ring B is tetrazolyl. In embodiments, Ring B is pyridinyl. In embodiments, Ring B is pyrazinyl. In embodiments, Ring B is pyrimidinyl. In embodiments, Ring B is pyridazinyl. In embodiments, Ring B is triazinyl. In embodiments, Ring B is 6 membered heteroaryl. In embodiments, Ring B is pyridinyl. In embodiments, Ring B is pyrazinyl. In embodiments, Ring B is pyrimidinyl. In embodiments, Ring B is pyridazinyl. [0246] In embodiments, Ring B is C 3 -C 8 cycloalkyl. In embodiments, Ring B is substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, Ring B is substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 - C 6 cycloalkyl). In embodiments, Ring B is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted

cyclohexanyl, or substituted or unsubstituted cyclopentanyl. In embodiments, Ring B is unsubstituted cyclooctanyl, unsubstituted cycloheptanyl, unsubstituted cyclohexanyl, or unsubstituted cyclopentanyl. In embodiments, Ring B is substituted or unsubstituted

cycloheptanyl. In embodiments, Ring B is substituted or unsubstituted cyclohexanyl. In embodiments, Ring B is substituted or unsubstituted cyclopentanyl. In embodiments, Ring B is unsubstituted cycloheptanyl. In embodiments, Ring B is unsubstituted cyclohexanyl. In embodiments, Ring B is unsubstituted cyclopentanyl. In embodiments, Ring B is unsubstituted cyclopropyl. [0247] In embodiments, R 5 is independently hydrogen. In embodiments, R 5 is independently halogen. In embodiments, R 5 is independently -CX 5

3. In embodiments, R 5 is independently - CHX 5

2. In embodiments, R 5 is independently -CH 2 X 5 . In embodiments, R 5 is

independently -OCX 5

3. In embodiments, R 5 is independently -OCH 2 X 5 . In embodiments, R 5 is independently -OCHX 5

2. In embodiments, R 5 is independently -CN. In embodiments, R 5 is independently -SO n5 R 5D . In embodiments, R 5 is independently -SO v5 NR 5A R 5B . In embodiments, R 5 is independently -NHC(O)NR 5A R 5B . In embodiments, R 5 is independently -N(O) m5 . In embodiments, R 5 is independently -NR 5A R 5B . In embodiments, R 5 is independently -C(O)R 5C . In embodiments, R 5 is independently -C(O)-OR 5C . In embodiments, R 5 is

independently -C(O)NR 5A R 5B . In embodiments, R 5 is independently -OR 5D . In embodiments, R 5 is independently -NR 5A SO 2 R 5D . In embodiments, R 5 is independently -NR 5A C(O)R 5C . In embodiments, R 5 is independently -NR 5A C(O)OR 5C . In embodiments, R 5 is

independently -NR 5A OR 5C . In embodiments, R 5 is independently -OH. In embodiments, R 5 is independently -NH 2 . In embodiments, R 5 is independently -COOH. In embodiments, R 5 is independently -CONH 2 . In embodiments, R 5 is independently -NO 2 . In embodiments, R 5 is independently–SH. In embodiments, R 5 is independently halogen, unsubstituted C 1 -C 3 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independently halogen, unsubstituted methyl, or -OCH 3 . In embodiments, R 5 is Br. In embodiments, R 5 is Cl. In embodiments, R 5 is F. In embodiments, R 5 is -OCH 3 . In embodiments, R 5 is -CH 3 . In embodiments, R 5 is -CF 3 . [0248] In embodiments, R 5 is independently substituted or unsubstituted alkyl. In

embodiments, R 5 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 5 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5 is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 5 is independently substituted or unsubstituted aryl. In embodiments, R 5 is independently substituted or unsubstituted heteroaryl. In embodiments, R 5 is independently substituted alkyl. In embodiments, R 5 is independently substituted heteroalkyl. In embodiments, R 5 is independently substituted cycloalkyl. In embodiments, R 5 is independently, substituted heterocycloalkyl. In embodiments, R 5 is independently substituted aryl. In embodiments, R 5 is independently substituted heteroaryl. In embodiments, R 5 is independently unsubstituted alkyl. In embodiments, R 5 is independently unsubstituted heteroalkyl. In embodiments, R 5 is independently unsubstituted cycloalkyl. In embodiments, R 5 is independently, unsubstituted heterocycloalkyl. In embodiments, R 5 is independently unsubstituted aryl. In embodiments, R 5 is independently unsubstituted heteroaryl. In embodiments, R 5 is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 5 is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5 is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5 is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5 is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 5 is

independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5 is independently substituted C 1 -C 8 alkyl. In embodiments, R 5 is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 5 is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 5 is independently, substituted 3 to 8 membered heterocycloalkyl. In

embodiments, R 5 is independently substituted C 6 -C 10 aryl. In embodiments, R 5 is independently substituted 5 to 10 membered heteroaryl. In embodiments, R 5 is independently unsubstituted C 1 - C 8 alkyl. In embodiments, R 5 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5 is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5 is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 5 is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5 is independently substituted or unsubstituted C 1 - C 4 alkyl. In embodiments, R 5 is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5 is independently, substituted or unsubstituted 3 to 6 membered

heterocycloalkyl. In embodiments, R 5 is independently substituted or unsubstituted phenyl. In embodiments, R 5 is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5 is independently substituted C 1 -C 4 alkyl. In embodiments, R 5 is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 5 is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5 is independently substituted phenyl. In embodiments, R 5 is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 5 is independently unsubstituted C 1 - C 4 alkyl. In embodiments, R 5 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5 is independently unsubstituted phenyl. In embodiments, R 5 is independently unsubstituted 5 to 6 membered heteroaryl. [0249] In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0250] In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted aryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted aryl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted heteroaryl. [0251] In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted C 6 -C 10 aryl. In embodiments, two adjacent R5 substituents may be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted 5 to 10 membered heteroaryl. [0252] In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted phenyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted phenyl. In embodiments, two adjacent R 5 substituents may be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted phenyl. In embodiments, two adjacent R 5 substituents may be joined to form an unsubstituted 5 to 6 membered heteroaryl. [0253] In ng B)-(R 5 ) z5 is ets, ( g

embodiments, -L 2 -(Ring B)-(R 5 ) z5 is . In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is ts, -L 2 - . In

B)-(R 5 ) z5 In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is . In

embodiments, -L 2 -(Ring B)-(R 5 ) z5 is . In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is . , . In embodiments, -L 2 - (Ring B)-(R 5 ) z5 is , ( . In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is embodiments, -L 2 -(Ring B)-(R 5 ) z5 In embodiments, L 2 -(Ring . In embodiments,

.

embodiments, L 2 -(Ring B) is . In

embodiments, L 2 -(Ring B) is . In

embodiments, L 2 -(Ring B) is . In embodiments,

L 2 -(Ring B) is . , .

[0254] In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is , wherein R 5 and z5 are as described herein. R 5.1 is R 5 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 5 substituent. In embodiments, R 5 is–OH, F, COOH, or -C(O)NR 5A R 5B . In embodiments, R 5.1 is hydrogen, -C(O)NR 5A R 5B , -C(N)NR 5A R 5B , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), - C(N)-(substituted or unsubstituted alkyl), or -C(N)-(substituted or unsubstituted cyclopropyl).

[0255] In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is , wherein R 5 and z5 are as described herein. R 5.1 is R 5 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 5 substituent. In embodiments, R 5 is–OH, F, COOH, or -C(O)NR 5A R 5B . In embodiments, R 5.1 is hydrogen, -C(O)NR 5A R 5B , -C(N)NR 5A R 5B , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), - C(N)-(substituted or unsubstituted alkyl), or -C(N)-(substituted or unsubstituted cyclopropyl).

[0256] In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is , wherein R 5 and z5 are as described herein. R 5.1 is R 5 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 5 substituent. In embodiments, R 5 is–OH, F, COOH, or -C(O)NR 5A R 5B . In embodiments, R 5.1 is hydrogen, -C(O)NR 5A R 5B , -C(N)NR 5A R 5B , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), - C(N)-(substituted or unsubstituted alkyl), or -C(N)-(substituted or unsubstituted cyclopropyl).

[0257] In embodiments, -L 2 -(Ring B)-(R 5 ) z5 is , wherein R 5 and z5 are as described herein. R 5.1 is R 5 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 5 substituent. In embodiments, R 5 is–OH, F, COOH, or -C(O)NR 5A R 5B . In embodiments, R 5.1 is hydrogen, -C(O)NR 5A R 5B , -C(N)NR 5A R 5B , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), - C(N)-(substituted or unsubstituted alkyl), or -C(N)-(substituted or unsubstituted cyclopropyl). [0258] In embodiments, R 5 is independently oxo. In embodiments, R 5 is independently halogen. In embodiments, R 5 is independently -F. In embodiments, R 5 is independently -Cl. In embodiments, R 5 is independently–COOH. In embodiments, R 5 is independently - C(O)NR 5A R 5B . [0259] In embodiments, R 5.1 is hydrogen. In embodiments, R 5.1 is substituted or unsubstituted alkyl. In embodiments, R 5.1 is independently substituted or unsubstituted alkyl. In embodiments, R 5.1 is R 32 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5.1 is R 32 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5.1 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5.1 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5.1 is R 32 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is R 32 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is an unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is unsubstituted cyclopropyl. [0260] In embodiments, R 5.1 is R 32 -substituted cyclopropyl. In embodiments, R 5.1 is - 1 is od e ts, s . e bod e ts, . In

s, R 5.1 is . In embodiments, R 5.1 is [0261] In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted C 1 -C 8 alkyl). In embodiments, R 5.1 is -C(N)- (substituted or unsubstituted C 1 -C 6 alkyl). In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted C 1 -C 4 alkyl). In embodiments, R 5.1 is -C(N)-(R 32 -substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-(unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-( R 32 - substituted alkyl). [0262] In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 5.1 is -C(N)-(substituted or unsubstituted C 3 -C 8 cycloalkyl). In embodiments, R5.1 is -C(N)-(substituted or unsubstituted C 3 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(N)- (substituted or unsubstituted C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(N)-( R 32 -substituted or unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(N)-(unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(N)-( R 32 -substituted cycloalkyl). [0263] In embodiments, R 5.1 is -C(O)-(substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 8 alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 6 alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 4 alkyl). In embodiments, R 5.1 is -C(O)-( R 32 -substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-(unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-( R 32 - substituted alkyl). [0264] In embodiments, R 5.1 is -C(O)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 3 -C 8 cycloalkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 3 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(O)- (substituted or unsubstituted C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(O)-( R 32 -substituted or unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(O)-(unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(O)-( R 32 -substituted cycloalkyl). [0265] In embodiments, z4 and z5 are independently an integer from 0 to 2. In embodiments z4 is 0. In embodiments z4 is 1. In embodiments z4 is 2. In embodiments z5 is 0. In

embodiments z5 is 1. In embodiments z5 is 2.

[0266] In embodiments, , wherein R 35 is as described herein.

In embodiments, L 2 -(Ring diments, L 2 -(Ring B) is

R 35.2 , R 35.3 , and R 35.4 is R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, L 2 -(Ring B) is at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In

embodiments, L , wherein R 35.1 and R 35.4 is R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, R 35.1 is halogen. In embodiments, R 35.1 is F.

2 In m im n L 2 - Rin B i h r in R 35 i ri herein.

R 35.2 , R 35.3 , and R 35.4 is R 35 at a fixed position (e.g., non-floating as shown in the formula described herein and ma independently be any R 35 substituent. In embodiments, L 2 -(Ring B) is

, wherein R 35.1 and R 35.4 is R 35 at a fixed position (e.g., non-floating as shown in the formula described herein) and may independently be any R 35 substituent. In embodiments, R 35.1 is halogen. In embodiments, R 35.1 is F. In embodiments, L 2 -(Ring B) is ts, L 2 -(Ring B) is

. [0268] In embodiments, R 5A is independently hydrogen. In embodiments, R 5A is

independently -CX 5A

3. In embodiments, R 5A is independently -CHX 5A

2. In embodiments, R 5A is independently -CH 2 X 5A . In embodiments, R 5A is independently -CN. In embodiments, R 5A is independently -COOH. In embodiments, R 5A is independently -CONH 2 . In embodiments, R 5A is independently substituted or unsubstituted alkyl. In embodiments, R 5A is independently substituted or unsubstituted heteroalkyl. In embodiments, R 5A is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5A is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 5A is independently substituted or unsubstituted aryl. In embodiments, R 5A is independently substituted or unsubstituted heteroaryl. In embodiments, R 5A is independently substituted alkyl. In embodiments, R 5A is independently substituted

heteroalkyl. In embodiments, R 5A is independently substituted cycloalkyl. In embodiments, R 5A is independently, substituted heterocycloalkyl. In embodiments, R 5A is independently substituted aryl. In embodiments, R 5A is independently substituted heteroaryl. In embodiments, R 5A is independently unsubstituted alkyl. In embodiments, R 5A is independently unsubstituted heteroalkyl. In embodiments, R 5A is independently unsubstituted cycloalkyl. In embodiments, R 5A is independently, unsubstituted heterocycloalkyl. In embodiments, R 5A is independently unsubstituted aryl. In embodiments, R 5A is independently unsubstituted heteroaryl. In embodiments, R 5A is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 5A is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5A is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5A is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 5A is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5A is independently substituted C 1 -C 8 alkyl. In embodiments, R 5A is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 5A is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 5A is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A is independently substituted C 6 -C 10 aryl. In embodiments, R 5A is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 5A is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 5A is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5A is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5A is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 5A is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5A is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 5A is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5A is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5A is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A is independently substituted or unsubstituted phenyl. In embodiments, R 5A is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5A is independently substituted C 1 - C 4 alkyl. In embodiments, R 5A is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 5A is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 5A is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A is independently substituted phenyl. In embodiments, R 5A is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 5A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5A is independently unsubstituted 2 to 4 membered heteroalkyl. In

embodiments, R 5A is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5A is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A is independently unsubstituted phenyl. In embodiments, R 5A is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5A is independently unsubstituted methyl. In embodiments, R 5A is independently unsubstituted ethyl. In embodiments, R 5A is independently unsubstituted propyl. In embodiments, R 5A is independently unsubstituted isopropyl. In embodiments, R 5A is independently unsubstituted tert-butyl. [0269] In embodiments, R 5B is independently hydrogen. In embodiments, R 5B is

independently -CX 5B

3. In embodiments, R 5B is independently -CHX 5B

2. In embodiments, R 5B is independently -CH 2 X 5B . In embodiments, R 5B is independently -CN. In embodiments, R 5B is independently -COOH. In embodiments, R 5B is independently -CONH 2 . In embodiments, R 5B is independently substituted or unsubstituted alkyl. In embodiments, R 5B is independently substituted or unsubstituted heteroalkyl. In embodiments, R 5B is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5B is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 5B is independently substituted or unsubstituted aryl. In embodiments, R 5B is independently substituted or unsubstituted heteroaryl. In embodiments, R 5B is independently substituted alkyl. In embodiments, R 5B is independently substituted

heteroalkyl. In embodiments, R 5B is independently substituted cycloalkyl. In embodiments, R 5B is independently, substituted heterocycloalkyl. In embodiments, R 5B is independently substituted aryl. In embodiments, R 5B is independently substituted heteroaryl. In embodiments, R 5B is independently unsubstituted alkyl. In embodiments, R 5B is independently unsubstituted heteroalkyl. In embodiments, R 5B is independently unsubstituted cycloalkyl. In embodiments, R 5B is independently, unsubstituted heterocycloalkyl. In embodiments, R 5B is independently unsubstituted aryl. In embodiments, R 5B is independently unsubstituted heteroaryl. In embodiments, R 5B is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 5B is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5B is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5B is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5B is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 5B is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5B is independently substituted C 1 -C 8 alkyl. In embodiments, R 5B is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 5B is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 5B is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5B is independently substituted C 6 -C 10 aryl. In embodiments, R 5B is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 5B is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 5B is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5B is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5B is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5B is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 5B is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5B is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 5B is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5B is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5B is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5B is independently substituted or unsubstituted phenyl. In embodiments, R 5B is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5B is independently substituted C 1 - C 4 alkyl. In embodiments, R 5B is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 5B is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 5B is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5B is independently substituted phenyl. In embodiments, R 5B is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 5B is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5B is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5B is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5B is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5B is independently unsubstituted phenyl. In embodiments, R 5B is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5B is independently unsubstituted methyl. In embodiments, R 5B is independently unsubstituted ethyl. In embodiments, R 5B is independently unsubstituted propyl. In embodiments, R 5B is independently unsubstituted isopropyl. In embodiments, R 5B is independently unsubstituted tert-butyl. [0270] In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or

unsubstituted heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or

unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a unsubstituted 5 to 6 membered heteroaryl. [0271] In embodiments, R 5C is independently hydrogen. In embodiments, R 5C is

independently -CX 5C

3. In embodiments, R 5C is independently -CHX 5C

2. In embodiments, R 5C is independently -CH 2 X 5C . In embodiments, R 5C is independently -CN. In embodiments, R 5C is independently -COOH. In embodiments, R 5C is independently -CONH 2 . In embodiments, R 5C is independently substituted or unsubstituted alkyl. In embodiments, R 5C is independently substituted or unsubstituted heteroalkyl. In embodiments, R 5C is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5C is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 5C is independently substituted or unsubstituted aryl. In embodiments, R 5C is independently substituted or unsubstituted heteroaryl. In embodiments, R 5C is independently substituted alkyl. In embodiments, R 5C is independently substituted

heteroalkyl. In embodiments, R 5C is independently substituted cycloalkyl. In embodiments, R 5C is independently, substituted heterocycloalkyl. In embodiments, R 5C is independently substituted aryl. In embodiments, R 5C is independently substituted heteroaryl. In embodiments, R 5C is independently unsubstituted alkyl. In embodiments, R 5C is independently unsubstituted heteroalkyl. In embodiments, R 5C is independently unsubstituted cycloalkyl. In embodiments, R 5C is independently, unsubstituted heterocycloalkyl. In embodiments, R 5C is independently unsubstituted aryl. In embodiments, R 5C is independently unsubstituted heteroaryl. In embodiments, R 5C is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 5C is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5C is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5C is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5C is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 5C is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5C is independently substituted C 1 -C 8 alkyl. In embodiments, R 5C is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 5C is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 5C is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5C is independently substituted C 6 -C 10 aryl. In embodiments, R 5C is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 5C is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 5C is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5C is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5C is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5C is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 5C is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5C is

independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 5C is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5C is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5C is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5C is independently substituted or unsubstituted phenyl. In embodiments, R 5C is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5C is independently substituted C 1 - C 4 alkyl. In embodiments, R 5C is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 5C is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 5C is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5C is independently substituted phenyl. In embodiments, R 5C is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 5C is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5C is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5C is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5C is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5C is independently unsubstituted phenyl. In embodiments, R 5C is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5C is independently unsubstituted methyl. In embodiments, R 5C is independently unsubstituted ethyl. In embodiments, R 5C is independently unsubstituted propyl. In embodiments, R 5C is independently unsubstituted isopropyl. In embodiments, R 5C is independently unsubstituted tert-butyl. [0272] In embodiments, R 5D is independently hydrogen. In embodiments, R 5D is independently -CX 5D

3. In embodiments, R 5D is independently -CHX 5D

2. In embodiments, R 5D is independently -CH 2 X 5D . In embodiments, R 5D is independently -CN. In embodiments, R 5D is independently -COOH. In embodiments, R 5D is independently -CONH 2 . In embodiments, R 5D is independently substituted or unsubstituted alkyl. In embodiments, R 5D is independently substituted or unsubstituted heteroalkyl. In embodiments, R 5D is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5D is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R 5D is independently substituted or unsubstituted aryl. In embodiments, R 5D is independently substituted or unsubstituted heteroaryl. In embodiments, R 5D is independently substituted alkyl. In embodiments, R 5D is independently substituted

heteroalkyl. In embodiments, R 5D is independently substituted cycloalkyl. In embodiments, R 5D is independently, substituted heterocycloalkyl. In embodiments, R 5D is independently substituted aryl. In embodiments, R 5D is independently substituted heteroaryl. In embodiments, R 5D is independently unsubstituted alkyl. In embodiments, R 5D is independently unsubstituted heteroalkyl. In embodiments, R 5D is independently unsubstituted cycloalkyl. In embodiments, R 5D is independently, unsubstituted heterocycloalkyl. In embodiments, R 5D is independently unsubstituted aryl. In embodiments, R 5D is independently unsubstituted heteroaryl. In embodiments, R 5D is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 5D is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5D is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5D is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5D is independently substituted or unsubstituted C 6 -C 10 aryl. In embodiments, R 5D is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5D is independently substituted C 1 -C 8 alkyl. In embodiments, R 5D is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R 5D is independently substituted C 3 -C 8 cycloalkyl. In embodiments, R 5D is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5D is independently substituted C 6 -C 10 aryl. In embodiments, R 5D is

independently substituted 5 to 10 membered heteroaryl. In embodiments, R 5D is independently unsubstituted C 1 -C 8 alkyl. In embodiments, R 5D is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R 5D is independently unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5D is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5D is independently unsubstituted C 6 -C 10 aryl. In embodiments, R 5D is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 5D is independently substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 5D is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5D is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5D is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5D is independently substituted or unsubstituted phenyl. In embodiments, R 5D is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5D is independently substituted C 1 - C 4 alkyl. In embodiments, R 5D is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R 5D is independently substituted C 3 -C 6 cycloalkyl. In embodiments, R 5D is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5D is independently substituted phenyl. In embodiments, R 5D is independently substituted 5 to 6 membered heteroaryl. In embodiments, R 5D is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5D is independently unsubstituted 2 to 4 membered heteroalkyl. In

embodiments, R 5D is independently unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 5D is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 5D is independently unsubstituted phenyl. In embodiments, R 5D is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5D is independently unsubstituted methyl. In embodiments, R 5D is independently unsubstituted ethyl. In embodiments, R 5D is independently unsubstituted propyl. In embodiments, R 5D is independently unsubstituted isopropyl. In embodiments, R 5D is independently unsubstituted tert-butyl. [0273] In embodiments, R 5 is independently hydrogen,

halogen, -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCX 5

3, -OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A S O 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -NR 5A OR 5C , R 32 -substituted or unsubstituted alkyl, R 32 -substituted or unsubstituted heteroalkyl, R 32 -substituted or unsubstituted cycloalkyl, R 32 - substituted or unsubstituted heterocycloalkyl, R 32 -substituted or unsubstituted aryl, or R 32 - substituted or unsubstituted heteroaryl. In embodiments, R 5 is independently

halogen, -CX 5

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX5

3, -OCHX5

2, R 32 - substituted or unsubstituted alkyl, R 32 -substituted or unsubstituted heteroalkyl, R 32 -substituted or unsubstituted cycloalkyl, R 32 -substituted or unsubstituted heterocycloalkyl, R 32 -substituted or unsubstituted aryl, or R 32 -substituted or unsubstituted heteroaryl. In embodiments, R 5 is independently

halogen, -CX 5

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 5

3, -OCHX5

2, R 32 -substituted or unsubstituted C 1 -C 8 alkyl, R 32 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 32 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 32 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 32 -substituted or unsubstituted phenyl, or R 32 -substituted or unsubstituted 5 to 6 membered heteroaryl. X 5 is– F,-Cl, -Br, or–I. In embodiments, R 5 is independently hydrogen. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl. [0274] In embodiments, R 5 is -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCH 2 X 5 , -OCX 5

3, or

-OCHX 5

2. In embodiments, R 5 is -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , or

-OCHF 2 . In embodiments, R 5 is unsubstituted cyclopropyl. In embodiments, R 5 is unsubstituted methyl. In embodiments, R 5 is -CF 3 . In embodiments, R 5 is -CHF 2. In embodiments, R5 is -CH 2 F. In embodiments, R 5 is -OCH 2 F. In embodiments, R 5 is -OCF 3 . In embodiments, R5 is -OCHF 2 . [0275] In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted cycloalkyl, R 32 -substituted or unsubstituted heterocycloalkyl, R 32 -substituted or unsubstituted aryl, or R 32 -substituted or unsubstituted heteroaryl. [0276] In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted aryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 - substituted cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted aryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted heteroaryl. [0277] In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent R5 substituents may be joined to form an R 32 -substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted C 6 -C 10 aryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted 5 to 10 membered heteroaryl. [0278] In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted phenyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted C 3 -C 6 cycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted phenyl. In embodiments, two adjacent R 5 substituents may be joined to form an R 32 -substituted 5 to 6 membered heteroaryl. [0279] R 32 is independently oxo, halogen, -CX 32

3, -CHX32

2, -CH 2 X 32 , -OCH 2 X 32 , -OCX 32

3, -OCHX 32

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 33 -substituted or unsubstituted alkyl, R 33 -substituted or unsubstituted heteroalkyl, R 33 - substituted or unsubstituted cycloalkyl, R 33 -substituted or unsubstituted heterocycloalkyl, R 33 - substituted or unsubstituted aryl, or R 33 -substituted or unsubstituted heteroaryl. In embodiments, R 32 is independently oxo, halogen, -CX 32

3, -CHX32

2, -CH 2 X 32 , -OCH 2 X 32 , -OCX 32

3,

-OCHX 32

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 33 -substituted or unsubstituted C 1 -C 8 alkyl, R 33 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 33 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 33 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 33 -substituted or unsubstituted phenyl, or R 33 - substituted or unsubstituted 5 to 6 membered heteroaryl. X 32 is–F,-Cl, -Br, or–I. [0280] R 33 is independently oxo, halogen, -CX 33

3, -CHX33

2, -CH 2 X 33 , -OCH 2 X 33 , -OCX 33

3, -OCHX 33

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 34 -substituted or unsubstituted alkyl, R 34 -substituted or unsubstituted heteroalkyl, R 34 - substituted or unsubstituted cycloalkyl, R 34 -substituted or unsubstituted heterocycloalkyl, R 34 - substituted or unsubstituted aryl, or R 34 -substituted or unsubstituted heteroaryl. In embodiments, R 33 is independently oxo, halogen, -CX 33

3, -CHX33

2, -CH 2 X 33 , -OCH 2 X 33 , -OCX 33

3,

-OCHX 33

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 34 -substituted or unsubstituted C 1 -C 8 alkyl, R 34 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 34 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 34 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 34 -substituted or unsubstituted phenyl, or R 34 - substituted or unsubstituted 5 to 6 membered heteroaryl. X 33 is–F, -Cl, -Br, or–I. [0281] In embodiments, R 5A is independently

hydrogen, -CX 5A

3, -CN, -COOH, -CONH 2 , -CHX5A

2, -CH 2 X 5A , R 32A -substituted or unsubstituted alkyl, R 32A -substituted or unsubstituted heteroalkyl, R 32A -substituted or unsubstituted cycloalkyl, R 32A -substituted or unsubstituted heterocycloalkyl, R 32A -substituted or unsubstituted aryl, or R 32A -substituted or unsubstituted heteroaryl. In embodiments, R 5A is independently

hydrogen, -CX 5A

3, -CN, -COOH, -CONH 2 , -CHX5A

2, -CH 2 X 5A , R 32A -substituted or unsubstituted C 1 -C 8 alkyl, R 32A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 32A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 32A -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 32A -substituted or unsubstituted phenyl, or R 32A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 5A is–F, -Cl, -Br, or–I. In embodiments, R 5A is independently hydrogen. In embodiments, R 5A is independently unsubstituted methyl. In embodiments, R 5A is independently unsubstituted ethyl. [0282] In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32A -substituted or unsubstituted heterocycloalkyl or R 32A - substituted or unsubstituted heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32A -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 32A -substituted or unsubstituted 5 to 6 membered heteroaryl. [0283] R 32A is independently oxo,

halogen, -CX 32A

3, -CHX32A

2, -CH 2 X 32A , -OCH 2 X 32A , -OCX 32A

3,

-OCHX 32A

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33A -substituted or unsubstituted alkyl, R 33A -substituted or unsubstituted heteroalkyl, R 33A -substituted or unsubstituted cycloalkyl, R 33A -substituted or unsubstituted heterocycloalkyl, R 33A -substituted or unsubstituted aryl, or R 33A -substituted or unsubstituted heteroaryl. In embodiments, R 32A is independently oxo,

halogen, -CX 32A

3, -CHX32A

2, -CH 2 X 32A , -OCH 2 X 32A , -OCX 32A

3, -OCHX32A

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33A -substituted or unsubstituted C 1 -C 8 alkyl, R 33A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 33A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 33A -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 33A -substituted or unsubstituted phenyl, or R 33A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 32A is–F, -Cl, -Br, or–I. [0284] R 33A is independently oxo,

halogen, -CX 33A

3, -CHX33A

2, -CH 2 X 33A , -OCH 2 X 33A , -OCX 33A

3, -OCHX33A

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 34A -substituted or unsubstituted alkyl, R 34A -substituted or unsubstituted heteroalkyl, R 34A -substituted or unsubstituted cycloalkyl, R 34A -substituted or unsubstituted heterocycloalkyl, R 34A -substituted or unsubstituted aryl, or R 34A -substituted or unsubstituted heteroaryl. In embodiments, R 33A is independently oxo, halogen, -CX 33A

3, -CHX33A

2, -CH 2 X 33A , -OCH 2 X 33A , -OCX 33A

3,

-OCHX 33A

2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 33A

3, -OCHX33A

2, R 34A -substituted or unsubstituted C 1 -C 8 alkyl, R 34A -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 34A -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 34A -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 34A -substituted or unsubstituted phenyl, or R 34A -substituted or unsubstituted 5 to 6 membered heteroaryl. X 33A is –F,-Cl, -Br, or–I. [0285] In embodiments, R 5B is independently

hydrogen, -CX 5B

3, -CN, -COOH, -CONH 2 , -CHX5B

2, -CH 2 X 5B , R 32B -substituted or unsubstituted alkyl, R 32B -substituted or unsubstituted heteroalkyl, R 32B -substituted or unsubstituted cycloalkyl, R 32B -substituted or unsubstituted heterocycloalkyl, R 32B -substituted or unsubstituted aryl, or R 32B -substituted or unsubstituted heteroaryl. In embodiments, R 5B is independently

hydrogen, -CX 5B

3, -CN, -COOH, -CONH 2 , -CHX5B

2, -CH 2 X 5B , R 32B -substituted or unsubstituted C 1 -C 8 alkyl, R 32B -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 32B -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 32B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 32B -substituted or unsubstituted phenyl, or R 32B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 5B is–F, -Cl, -Br, or–I. In embodiments, R 5B is independently hydrogen. In embodiments, R 5B is independently unsubstituted methyl. In embodiments, R 5B is independently unsubstituted ethyl. [0286] In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32B -substituted or unsubstituted heterocycloalkyl or R 32B - substituted or unsubstituted heteroaryl. In embodiments, R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32B -substituted or unsubstituted 3 to 6 membered heterocycloalkyl or R 32B -substituted or unsubstituted 5 to 6 membered heteroaryl. [0287] R 32B is independently oxo,

halogen, -CX 32B

3, -CHX32B

2, -CH 2 X 32B , -OCH 2 X 32B , -OCX 32B

3, -OCHX32B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH,

-NHOH, R 33B -substituted or unsubstituted alkyl, R 33B -substituted or unsubstituted heteroalkyl, R 33B -substituted or unsubstituted cycloalkyl, R 33B -substituted or unsubstituted heterocycloalkyl, R 33B -substituted or unsubstituted aryl, or R 33B -substituted or unsubstituted heteroaryl. In embodiments, R 32B is independently oxo,

halogen, -CX 32B

3, -CHX32B

2, -CH 2 X 32B , -OCH 2 X 32B , -OCX 32B

3, -OCHX32B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33B -substituted or unsubstituted C 1 -C 8 alkyl, R 33B -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 33B -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 33B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 33B -substituted or unsubstituted phenyl, or R 33B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 32B is–F, -Cl, -Br, or–I. [0288] R 33B is independently oxo,

halogen, -CX 33B

3, -CHX33B

2, -CH 2 X 33B , -OCH 2 X 33B , -OCX 33B

3, -OCHX33B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 34B -substituted or unsubstituted alkyl, R 34B -substituted or unsubstituted heteroalkyl, R 34B -substituted or unsubstituted cycloalkyl, R 34B -substituted or unsubstituted heterocycloalkyl, R 34B -substituted or unsubstituted aryl, or R 34B -substituted or unsubstituted heteroaryl. In embodiments, R 33B is independently oxo, halogen, -CX 33B

3, -CHX33B

2, -CH 2 X 33B , -OCH 2 X 33B , -OCX 33B

3, -OCHX33B

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 34B -substituted or unsubstituted C 1 -C 8 alkyl, R 34B -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 34B -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 34B -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 34B -substituted or unsubstituted phenyl, or R 34B -substituted or unsubstituted 5 to 6 membered heteroaryl. X 33B is–F,-Cl, -Br, or–I. [0289] In embodiments, R 5C is independently

hydrogen, -CX 5C

3, -CN, -COOH, -CONH 2 , -CHX5C

2, -CH 2 X 5C , R 32C -substituted or unsubstituted alkyl, R 32C -substituted or unsubstituted heteroalkyl, R 32C -substituted or unsubstituted cycloalkyl, R 32C -substituted or unsubstituted heterocycloalkyl, R 32C -substituted or unsubstituted aryl, or R 32C -substituted or unsubstituted heteroaryl. In embodiments, R 5C is independently

hydrogen, -CX 5C

3, -CN, -COOH, -CONH 2 , -CHX5C

2, -CH 2 X 5C , R 32C -substituted or unsubstituted C 1 -C 8 alkyl, R 32C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 32C -substituted or unsubstituted C

3-C 8 cycloalkyl, R -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 32C -substituted or unsubstituted phenyl, or R 32C -substituted or unsubstituted 5 to 6 membered heteroaryl. X 5C is–F, -Cl, -Br, or–I. In embodiments, R 5C is independently hydrogen. In embodiments, R 5C is independently unsubstituted methyl. In embodiments, R 5C is independently unsubstituted ethyl. [0290] R 32C is independently oxo,

halogen, -CX 32C

3, -CHX32C

2, -CH 2 X 32C , -OCH 2 X 32C , -OCX 32C

3, -OCHX32C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33C -substituted or unsubstituted alkyl, R 33C -substituted or unsubstituted heteroalkyl, R 33C -substituted or unsubstituted cycloalkyl, R 33C -substituted or unsubstituted heterocycloalkyl, R 33C -substituted or unsubstituted aryl, or R 33C -substituted or unsubstituted heteroaryl. In embodiments, R 32C is independently oxo, halogen, -CX 32C

3, -CHX32C

2, -CH 2 X 32C , -OCH 2 X 32C , -OCX 32C

3, -OCHX32C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33C -substituted or unsubstituted C 1 -C 8 alkyl, R 33C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 33C -substituted or unsubstituted C

3-C 8 cycloalkyl, R -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 33C -substituted or unsubstituted phenyl, or R 33C -substituted or unsubstituted 5 to 6 membered heteroaryl. is–F, -Cl, -Br, or–I. [0291] R 33C is independently oxo,

halogen, -CX 33C

3, -CHX33C

2, -CH 2 X 33C , -OCH 2 X 33C , -OCX 33C

3, -OCHX33C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 34C -substituted or unsubstituted alkyl, R 34C -substituted or unsubstituted heteroalkyl, R 34C -substituted or unsubstituted cycloalkyl, R 34C -substituted or unsubstituted heterocycloalkyl, R 34C -substituted or unsubstituted aryl, or R 34C -substituted or unsubstituted heteroaryl. In embodiments, R 33C is independently oxo, halogen, -CX 33C

3, -CHX33C

2, -CH 2 X 33C , -OCH 2 X 33C , -OCX 33C

3, -OCHX33C

2, -CN, -OH, -NH 2 , -C OOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , - ONH 2 , -NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 34C -substituted or unsubstituted C 1 -C 8 alkyl, R 34C -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 34C -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 34C -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 34C -substituted or unsubstituted phenyl, or R 34C -substituted or unsubstituted 5 to 6 membered heteroaryl. is–F, -Cl, -Br, or–I. [0292] In embodiments, R 5D is independently

hydrogen, -CX 5D

3, -CN, -COOH, -CONH 2 , -CHX5D

2, -CH 2 X 5D , R 32D -substituted or unsubstituted alkyl, R 32D -substituted or unsubstituted heteroalkyl, R 32D -substituted or unsubstituted cycloalkyl, R 32D -substituted or unsubstituted heterocycloalkyl, R 32D -substituted or unsubstituted aryl, or R 32D -substituted or unsubstituted heteroaryl. In embodiments, R 5D is independently

hydrogen, -CX 5D

3, -CN, -COOH, -CONH 2 , -CHX5D

2, -CH 2 X 5D , R 32D -substituted or unsubstituted C 1 -C 8 alkyl, R 32D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 32D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 32D -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 32D -substituted or unsubstituted phenyl, or R 32D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 5D is–F, -Cl, -Br, or–I. In embodiments, R 5D is independently hydrogen. In embodiments, R 5D is independently unsubstituted methyl. In embodiments, R 5D is independently unsubstituted ethyl. [0293] R 32D is independently oxo,

halogen, -CX 32D

3, -CHX32D

2, -CH 2 X 32D , -OCH 2 X 32D , -OCX 32D

3, -OCHX32D

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33D -substituted or unsubstituted alkyl, R 33D -substituted or unsubstituted heteroalkyl, R 33D -substituted or unsubstituted cycloalkyl, R 33D -substituted or unsubstituted heterocycloalkyl, R 33D -substituted or unsubstituted aryl, or R 33D -substituted or unsubstituted heteroaryl. In embodiments, R 32D is independently oxo, halogen, -CX 32D

3, -CHX32D

2, -CH 2 X 32D , -OCH 2 X 32D , -OCX 32D

3, -OCHX32D

2, -CN, -OH, -NH 2 , - COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , - ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, R 33D -substituted or unsubstituted C 1 -C 8 alkyl, R 33D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 33D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 33D -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, R 33D -substituted or unsubstituted phenyl, or R 33D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 32D is–F, -Cl, -Br, or–I. [0294] R 33D is independently oxo,

halogen, -CX 33D

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 33D

3, -OCHX33D

2, R 34D -substituted or unsubstituted alkyl, R 34D -substituted or unsubstituted heteroalkyl, R 34D -substituted or unsubstituted cycloalkyl, R 34D -substituted or unsubstituted heterocycloalkyl, R 34D -substituted or unsubstituted aryl, or R 34D -substituted or unsubstituted heteroaryl. In embodiments, R 33D is independently oxo,

halogen, -CX 33D

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 33D

3, -OCHX33D

2, R 34D -substituted or unsubstituted C 1 -C 8 alkyl, R 34D -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 34D -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 34D -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 34D -substituted or unsubstituted phenyl, or R 34D -substituted or unsubstituted 5 to 6 membered heteroaryl. X 33D is –F,-Cl, -Br, or–I. [0295] R 34 , R 34A , R 34B , R 34C , and R 34D are independently hydrogen, oxo,

halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H , -SO 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0296] In embodiments, R 34 , R 34A , R 34B , R 34C , and R 34D are independently hydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 34 , R 34A , R 34B , R 34C , and R 34D are independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 ,

- NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 34 , R 34A , R 34B , R 34C , and R 34D are independently oxo,

halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , - NHC(O)NHNH 2 , - NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0297] In embodiments, R 5 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX5

3, -CHX5

2, -CH 2 X 5 , -O CX 5

3, -OCHX5

2, -OCH 2 X 5 , -SCX 5

3, -SCHX5

2, -SCH 2 X 5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 CH 3 . In embodiments, R 5 is independently–F. In embodiments, R 5 is independently -Cl. In embodiments, R 5 is independently -Br. In embodiments, R 5 is independently -I. In

embodiments, R 5 is independently -CN. In embodiments, R 5 is independently -NH 2 . In embodiments, R 5 is independently -OH. In embodiments, R 5 is independently -SH. In embodiments, R 5 is independently -COCH 3 . In embodiments, R 5 is independently -COOH. In embodiments, R 5 is independently -COOCH 3 . In embodiments, R 5 is independently -CX 5

3. In embodiments, R 5 is independently -CHX 5

2. In embodiments, R 5 is independently -CH 2 X 5 . In embodiments, R 5 is independently -OCX 5

3. In embodiments, R 5 is independently -OCHX 5

2. In embodiments, R 5 is independently -OCH 2 X 5 . In embodiments, R 5 is independently -SCX 5

3. In embodiments, R 5 is independently -SCHX 5

2. In embodiments, R 5 is independently -SCH 2 X 5 . In embodiments, R 5 is independently -CH 3 . In embodiments, R 5 is independently -CH 2 CH 3 . In embodiments, R 5 is independently -OCH 3 . In embodiments, R 5 is independently -OCH 2 CH 3 . In embodiments, R 5 is independently -NHCH 3 . In embodiments, R 5 is independently -N(CH 3 ) 2 . In embodiments, R 5 is independently -NHCH 2 CH 3 . In embodiments, R 5 is

independently -N(CH 3 )(CH 2 CH 3 ). In embodiments, R 5 is independently -N(CH 2 CH 3 ) 2 . In embodiments, R 5 is independently -SCH 3 . In embodiments, R 5 is independently -SCH 2 CH 3 . [0298] In embodiments, z5 is 5. In embodiments, z5 is 4. In embodiments, z5 is 3. In embodiments, z5 is 2. In embodiments, z5 is 1. In embodiments, z5 is 0. [0299] In embodiments, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4. [0300] In embodiments, m4 is 1. In embodiments, m4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2. [0301] In embodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments, v5 is 2. [0302] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, Ring B, z4, and z5 are as described herein.

[0303] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, Ring B, z4, and z5 are as described herein. [0304] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, and z5 are as described herein.

[0305] In embodiments, the compound has the formula: L 2 , R 4 , R 5 , Ring B, z4, and z5 are as described herein.

[0306] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 2 , and z4 are as described herein.

[0307] In embodiments, the compound has the formula: L 1 , L 2 , R 4 , R 2 , and z4 are as described herein. [0308] In embodiments, the compound has the formula: . L 1 , R 2 , and z4 are as described herein.

[0309] In embodiments, the compound has the formula: . L 1 , R 2 , and z4 are as described herein.

[0310] In embodiments, the compound has the formula: . L 1 , Ring B, z5, and z4 are as described herein. In embodiments, Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl.

[0311] In embodiments, the compound has the formula: . L 1 , Ring B, z5, and z4 are as described herein. In embodiments, Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl.

[0312] In embodiments, the compound has the formula: . L 1 , Ring B, z5, and z4 are as described herein. In embodiments, Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl.

[0313] In embodiments, the compound has the formula: . L 1 , Ring B, z5, and z4 are as described herein. In embodiments, Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl.

[0314] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 2 , and z4 are as described herein.

[0315] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, Ring B, z4, and z5 are as described herein.

[0316] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, Ring B, z4, and z5 are as described herein.

[0317] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, and z5 are as described herein. [0318] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 2 , and z4 are as described herein.

[0319] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 2 , and z4 are as described herein.

[0320] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 2 , and z4 are as described herein. [0321] In embodiments, the compound has the formula: . L 1 , R 2 , R 4 , Ring A, and z4 are as described herein.

[0322] In embodiments, the compound has the formula . [0323] In embodiments, the compound has the formula: L 1 , R 4 , Ring A, and z4 are as described herein. [0324] In embodiments, the compound has the formula: . L 1 , R 4 , Ring A, and z4 are as described herein.

[0325] In embodiments, the compound has the formula: . L 1 , R 4 , Ring A, and z4 are as described herein. [0326] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0327] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0328] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0329] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0330] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0331] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0332] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0333] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0334] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0335] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0336] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0337] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0338] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0339] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0340] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0341] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0342] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0343] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0344] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0345] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0346] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0347] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0348] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0349] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0350] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0351] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0352] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0353] In embodiments, the compound has the formula: . L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0354] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0355] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0356] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0357] In embodiments, the compound has the formula: . L 1 , L 2 , R 4.1 , R 4.2 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0358] In embodiments, the compound has the formula: . L 1 , L 2 , R 4.1 , R 4.3 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0359] In embodiments, the compound has the formula: . L 1 , L 2 , R 4.2 , R 4.4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0360] In embodiments, the compound has . L 1 , L 2 , R 4.1 , R 4.4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0361] In embodiments, the compound has the formula:

R 4.1 , R 4.5 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0362] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0363] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0364] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0365] In embodiments, the compound has the formula: L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0366] In embodiments, the compound has the formula: L 2 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0367] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0368] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0369] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0370] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0371] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0372] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0373] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0374] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0375] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0376] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0377] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0378] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0379] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0380] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0381] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0382] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0383] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0384] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0385] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0386] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0387] In embodiments, the compound has . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0388] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0389] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0390] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0391] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0392] In embodiments, the compound has the formula: . L 1 , L 2 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0393] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0394] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0395] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0396] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0397] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0398] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0399] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0400] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0401] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0402] In embodiments, the compound has the formula: L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0403] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0404] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0405] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0406] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0407] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0408] In embodiments, the compound has the formula: , Ring B, z4, z5, and Y 1 are as described herein. [0409] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0410] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0411] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0412] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0413] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0414] In embodiments, the compound has the formula: , Ring B, z4, z5, and Y 1 are as described herein.

[0415] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0416] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0417] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0418] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0419] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0420] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0421] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0422] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0423] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0424] In embodiments, the compound has the formula: . L 1 , R 4.1 , R 4.2 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0425] In embodiments, the compound has the formula: . L 1 , R 4.1 , R 4.3 , R 5 , Ring B, z5, and Y 1 are as described herein. [0426] In embodiments, the compound has the formula: R 4.2 , R 4.4 , R 5 , Ring B, z5, and Y 1 are as described herein. [0427] In embodiments, the compound has the formula: . L 1 , R 4.1 , R 4.5 , R 5 , Ring B, z5, and Y 1 are as described herein.

[0428] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0429] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0430] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0431] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein. [0432] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring B, z4, z5, and Y 1 are as described herein.

[0433] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, Ring B, z4, z5, and Y 1 are as described herein. [0434] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, Ring B, z4, z5, and Y 1 are as described herein.

[0435] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0436] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0437] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0438] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0439] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0440] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0441] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0442] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0443] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0444] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0445] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0446] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0447] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0448] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0449] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein. [0450] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0451] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0452] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0453] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

[0454] In embodiments, the compound has the formula: . L 1 , R 4 , R 5 , Ring A, z4, z5, and Y 1 are as described herein.

compoun as e ormua: .

[0456] In embodiments, the compound has the formula: . R 4 , R 5 , Ring B, z4, and z5 are as described herein. In embodiments, the compound has the formula:

. R 4 , R 5 , Ring B, z4, and z5 are as described herein. In embodiments,

the compound has the formula: . R 4 , R 5 , Ring B, z4, and z5 are as described herein.

[0457] In embodiments, the compound has the formula: . R 4 , R 5 , z4, and z5 are as described herein. In embodiments, the compound has the formula:

. R 4 , R 5 , z4, and z5 are as described herein. In embodiments, the

compound has the formula: . R 4 , R 5 , z4, and z5 are as described herein.

[0458] In embodiments the comound has the formula: . In

embodiments, the . In embodiments, the

compound has the ormua: .

[0459] In an aspect is provided a compound having the formula: (III); Y 1 , R 2 , R 3 , R 4 , L 2 , z4 are as described herein. L 1 is–O-, -S-,–N(R 3 )-, or substituted or unsubstituted C 1 -C 3 alkylene. In embodiments, L 1 is substituted or unsubstituted C 1 -C 3 alkylene (e.g., C 1 -C 2 alkylene, C 2 -C 3 alkylene, n-propylene, isopropylene, ethylene, or methylene). In embodiments, L 1 is unsubstituted C 1 -C 3 alkylene (e.g., C 1 -C 2 alkylene, C 2 -C 3 alkylene, n- propylene, isopropylene, ethylene, or methylene). In embodiments, R 2 is substituted or unsubstituted alkyl. In embodiments, R 2 is substituted alkyl. In embodiments, R 2 is

unsubstituted alkyl. In embodiments, R 2 is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted C 1 -C 8 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is substituted C 1 -C 4 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is R 23 - substituted or unsubstituted alkyl. In embodiments, R 2 is R 23 -substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl. In m im n R 2 i n ubstituted pentyl. In embodiments, the compound of formula (III) is

; Y 1 , R 2 , L 1 , and L 2 are as described herein. In embodiments, the compound of formula (III) is Y 1 , R 2 , and L 2 are as described herein. In

embodiments, the compound of formula (III) is ; Y 1 , R 2 , R 4 , z4, L 1 , and L 2 are as described herein. In embodiments, the compound of formula (III) is

; Y 1 , R 2 , R 4 , z4, and L 2 are as described herein. In embodiments, the

compound of formula (III) is ; Y 1 , R 2 , and L 2 are as described herein. In embodiments, the compound of formula (III) is ; R 2 and L 2 are as

described herein. In embodiments, the compound .

In embodiments, the compound of formula (III) is

[0460] In embodiments, the compound has the f

wherein, A is–C(R 4 )= or–N=; R 4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halogen, -CF 3 , -OCH 3 , -CN, -SO 2 CH 3 , -SO 2 NHR 4B , -OCF 3 ; R 5 is independently oxo, halogen, -COOH, or -C(O)NR 5A R 5B ; R 5.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, -C(O)NR 5A R 5B , , - C(N)-(substituted or unsubstituted alkyl), -C(N)-(substituted or unsubstituted cycloalkyl), -C(O)- (substituted or unsubstituted alkyl), or -C(O)-(substituted or unsubstituted cycloalkyl); z4 and z5 are independently an integer from 0 to 2; and R 5A and R 5B are independently hydrogen or substituted or unsubstituted alkyl. [0461] In embodiments, the compound has the formula:

A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently –C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein. [0462] In embodiments, the compound has the formula:

A 2 , A 3 , A 4 , and A 5 , are each independently– C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein. [046 has the formula:

wherein, A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently –C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein.

[0464] In embodiments, the compound has the formula:

wherein, A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently –C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein.

[0465] In embodiments, the compound has the formula:

wherein, A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently –C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein. has the formula:

herein, A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently –C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein.

[0467] In embodiments, the compound has the formula:

A 2 , A 3 , A 4 , and A 5 , are each independently– C(R 4 )= or–N=; and wherein L 1 , R 4 , z4, R 5 , z5, and R 5.1 are as described herein. [0468] In embodiments, A is–C(R 4 )=. In embodiments, A is–N=. In embodiments, A is– CH=. [0469] In embodiments, R 4 is independently substituted or unsubstituted alkyl. In

embodiments, R 4 is R 29 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 - C 4 alkyl). In embodiments, R 4 is R 29 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4 is R 29 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 4 is R 29 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 4 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 4 is unsubstituted cyclopropyl. In embodiments, R 4 is R 29 -substituted cyclopropyl. In embodiments, R 4 is independently halogen. In embodiments, R 4 is independently -CF 3 . In embodiments, R 4 is independently -OCH 3 . In embodiments, R 4 is independently–CN. In embodiments, R 4 is independently -SO 2 CH 3 . In embodiments, R 4 is independently -SO 2 NHR 4B . In embodiments, R 4 is independently -OCF 3 . In embodiments, R 4 is -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCH 2 X 4 , -OCX 4

3, or -OCHX 4

2. In embodiments, R 4 is -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , or -OCHF 2 . In embodiments, R 4 is unsubstituted cyclopropyl. In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is -CF 3 . In embodiments, R 4 is -CHF 2. In embodiments, R 4 is -CH 2 F. In embodiments, R 4 is -OCH 2 F. In embodiments, R 4 is -OCF 3 . In embodiments, R 4 is -OCHF 2 . [0470] In embodiments, R 5 is independently oxo. In embodiments, R 5 is independently halogen. In embodiments, R 5 is independently -F. In embodiments, R 5 is independently -Cl. In embodiments, R 5 is independently–COOH. In embodiments, R 5 is independently - C(O)NR 5A R 5B . [0471] In embodiments, R 5.1 is hydrogen. In embodiments, R 5.1 is substituted or unsubstituted alkyl. In embodiments, R 5.1 is independently substituted or unsubstituted alkyl. In embodiments, R 5.1 is R 32 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5.1 is R 32 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5.1 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). [0472] In embodiments, R 5.1 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 5.1 is R 32 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is R 32 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R5.1 is unsubstituted cyclopropyl. In embodiments, R 5.1 is R 32 -substituted cyclopropyl. In

emb im n R 5.1 i - R 5A R 5B In m im n R 5.1 i In m im nts,

R 5.1 . In

m im n R 5.1 i In m im nts, R 5.1 is . In embodiments, R 5.1 is

. [0473] In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-(C 5.1

1-C 8 alkyl). In embodiments, R 5.1 is -C(N)-(C 1 -C 6 alkyl). In embodiments, R is -C(N)-(C 1 -C 4 alkyl). In embodiments, R 5.1 is -C(N)-(R 32 -substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-(unsubstituted alkyl). In embodiments, R 5.1 is -C(N)-(R 32 -substituted alkyl). [0474] In embodiments, R 5.1 is -C(N)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 5.1 is -C(N)-(C 3 -C 8 cycloalkyl). In embodiments, R 5.1 is -C(N)-(C 3 -C 6

cycloalkyl). In embodiments, R 5.1 is -C(N)-(C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(N)- (R 32 -substituted or unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(N)-(unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(N)-(R 32 -substituted cycloalkyl). [0475] In embodiments, R 5.1 is -C(O)-(substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 8 alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 6 alkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 1 -C 4 alkyl). In embodiments, R 5.1 is -C(O)-(R 32 -substituted or unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-(unsubstituted alkyl). In embodiments, R 5.1 is -C(O)-(R 32 - substituted alkyl). [0476] In embodiments, R 5.1 is -C(O)-(substituted or unsubstituted cycloalkyl). In

embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 3 -C 8 cycloalkyl). In embodiments, R 5.1 is -C(O)-( substituted or unsubstituted C 3 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(O)- (substituted or unsubstituted C 5 -C 6 cycloalkyl). In embodiments, R 5.1 is -C(O)-(R 32 -substituted or unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(O)-(unsubstituted cycloalkyl). In embodiments, R 5.1 is -C(O)-(R 32 -substituted cycloalkyl). [0477] In embodiments, z4 and z5 are independently an integer from 0 to 2. In embodiments z4 is 0. In embodiments z4 is 1. In embodiments z4 is 2. In embodiments z5 is 0. In

embodiments z5 is 1. In embodiments z5 is 2. [0478] In embodiments, R 5A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 5A is independently substituted or unsubstituted alkyl. In embodiments, R 5A is R 32A -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5A is R 32A -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5A is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5A is hydrogen. [0479] In embodiments, R 5B is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 5B is independently substituted or unsubstituted alkyl. In embodiments, R 5B is R 32B -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5B is R 32B -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5B is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 5B is hydrogen.

[0480] In embodiments, the compound has the formula: , wherein L 1 , R 2 , and R 1 are as described herein.

[0481] In embodiments, the compound has the formula: and R 1 are as described herein.

[0482] In embodiments, the compound has the formula: , wherein L 1 , R 2 , and R 1 are as described herein.

[0483] In embodiments, the compound has the formula: , wherein L 1 and R 1 are

as described herein. In embodiments, the compound has the formula: , wherein L 1 and R 1 are as described herein. In embodiments, the compound has the formula: , wherein L 1 and R 1 are as described herein.

1

[0484] In embodiments, the compound has the formula: , wherein L 1 and R 1 are as described herein. [0485] In embodiments, the compound (e.g., described herein) inhibits TgCDPK1 more potently than other CDPK proteins (e.g., kinases containing intermediate sized gatekeeper residues (e.g., Ser, Thr, or Ala)). In embodiments, the potency of inhibition is measured by IC50 (e.g., in an in vivo assay, in a cell assay, in an in vitro assay). In embodiments, the potency of inhibition is measured by binding affinity (e.g., in an in vivo assay, in a cell assay, in an in vitro assay). In embodiments, the compound inhibits TgCDPK1 at least 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, or 100000 times more potently than the compound inhibits other CDPK proteins (e.g., kinases containing intermediate sized gatekeeper residues (e.g., Ser, Thr, or Ala)). [0486] In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) more potently than a homologous human protein (e.g., human kinases such as Src kinase). In embodiments, the potency of inhibition is measured by IC50 (e.g., in an in vivo assay, in a cell assay, in an in vitro assay). In embodiments, the potency of inhibition is measured by binding affinity (e.g., in an in vivo assay, in a cell assay, in an in vitro assay). In embodiments, the compound inhibits a parasite CDPK1 (e.g., TgCDPK1) at least 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, or 100000 times more potently than the compound inhibits a homologous human protein (e.g., human kinases such as Src kinase). [0487] In embodiments, the compound (e.g., described herein) has a half-life of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1,000 hours. In embodiments, the compound (e.g., described herein) has a half-life of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 100000 hours. In embodiments, the compound (e.g., described herein) has a half-life of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1,000 hours. In embodiments, the half-life is a plasma half-life. In embodiments, the half-life is a tissue half-life. In embodiments, the half-life is the half-life in a cell. In embodiments, the half-life is a blood half-life. [0488] In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 1µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.5 µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.2 µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.15 µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.01µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.02µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.03µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.04µM, relative to the absence of the compound. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of at least 0.05µM, relative to the absence of the compound. [0489] In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 1µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.5 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.2 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.15 µM. In

embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.01µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.02µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.03µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.04µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) of about 0.05µM. [0490] In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.001 µM to about 1 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.001 µM to about 0.75 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.002 µM to about 0.6 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.5 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.3 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.25 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.2 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.007 µM to about 0.25 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.01 µM to about 0.25 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.15 µM. In embodiments, the compound (e.g., described herein) inhibits a parasite CDPK1 (e.g., TgCDPK1) with an IC50 (e.g., measured using a standard assay in the art or an assay described herein) is about 0.003 µM to about 0.10 µM. [0491] In embodiments, the compound is any one of the compounds described herein (e.g., in an aspect, embodiment, claim, figure, table, or example). [0492] In embodiments, the compound described herein may include multiple instances of R 4 and/or R 5 , and/or other variables. In such embodiments, each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each R 4 and/or R 5 , is different, they may be referred to, for example, as R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , respectively, wherein the definition of R 4 is assumed by R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 and R 5 is assumed by R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 . The variables used within a definition of R 4 and R 5 and/or other variables that appear at multiple instances and are different may similarly be appropriately labeled to distinguish each group for greater clarity.

[0493] In embodiments, the compound has the formula: ,

,

and R20 are independently–OH, -OCH 3 , -NH 2 , -NHCH 3 , unsubstituted heterocycle, or unsubstituted aryl. [0494] In embodiments, the compound has the formula: , wherein L 1 and R 4 are as described herein.

[0495] In embodiments, the compound has the formula: , wherein L 1 and R 4 are as described herein. In embodiments, R 4 is halogen.

[0496] In embodiments, the compound has the formula: , wherein L 1 , A, and R 20 are as described herein. In embodiments, A is–CH=. In embodiments A is -N=. In embodiments, R 20 is unsubstituted C 1 -C 3 alkyl. In embodiments, R 20 is unsubstituted methyl.

[0497] In embodiments, the compound has the formula: , wherein C is S, N, or O.

[0498] In embodiments, the compound has the formula: , wherein L 1 and R 20 are as described herein. [0499] In embodiments, the compound is: ,

,

,

,

,

[0501] In embodiments, the compound is . [0502] In embodiments, the compound is . [0503] In embodiments, the compound is .

[0504] In embodiments, the compound is [0505] In embodiments, the compound is

[0506] In embodiments, the compound is [0507] In embodiments, the compound is [0508] In embodiments, the compound is

[0509] In embodiments, the compound is [0510] In embodiments, the compound is .

[0511] In embodiments, the compound is [0512] In embodiments, the compound is

[0513] In embodiments, the compound is

[0514] In embodiments, the compound is [0515] In embodiments, the compound is [0516] In embodiments, the compound is . [0517] In embodiments, the compound is . [0518] In embodiments, the compound is . [0519] In embodiments, the compound is .

[0520] In embodiments, the compound is . [0521] In embodiments, the compound is . [0522] In embodiments, the compound is . [0523] In embodiments, the compound is .

[0524] In embodiments, the compound is . [0525] In embodiments, the compound is . [0526] In embodiments, the compound is . [0527] In embodiments, the compound is .

[0528] In embodiments, the compound is . [0529] In embodiments, the compound is

[0530] In embodiments, the compound is

[0531] In embodiments, the compound is . [0532] In embodiments, the compound is . [0533] In embodiments, the compound is . [0534] In embodiments, the compound is [0535] In embodiments, the compound is [0536] In embodiments, the compound is . [0537] In embodiments, the compound is

[0538] In embodiments, the compound is . [0539] In embodiments, the compound is

[0540] In embodiments, the compound is .

[0541] In embodiments, the compound is [0542] In embodiments, the compound is [0543] In embodiments, the compound is [0544] In embodiments, the compound is [0545] In embodiments, the compound is

[0546] In embodiments, the compound is . [0547] In embodiments, the compound is

[0548] In embodiments, the compound is [0549] In embodiments, the compound is . [0550] In embodiments, the compound is .

[0551] In embodiments, the compound is .

[0552] In embodiments, the compound is . [0553] In embodiments, the compound is . [0554] In embodiments, the compound is [0555] In embodiments, the compound is [0556] In embodiments, the compound is

[0557] In embodiments, the compound is .

[0558] In embodiments, the compound is [0559] In embodiments, the compound is

[0560] In embodiments, the compound is .

[0561] In embodiments, the compound is .

[0562] In embodiments, the compound is .

[0563] In embodiments, the compound is [0564] In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure). [0565] In embodiments, L 2 is not a substituted C 1 -C 2 alkylene. In embodiments, L 2 is not an oxo substituted methylene. In embodiments, L 2 is not a substituted methylene. In embodiments, L 2 is not a substituted ethylene. In embodiments, L 2 is not an unsubstituted C 1 -C 2 alkylene. In embodiments, L 2 is not an unsubstituted methylene. In embodiments, L 2 is not an unsubstituted ethylene. In embodiments, L 2 is not an oxo substituted heteroalkylene. In embodiments, L 2 is not an oxo substituted 2 to 3 membered heteroalkylene. In embodiments, L 2 is not an oxo substituted 2 to 4 membered heteroalkylene. In embodiments, L 2 is not an oxo substituted 2 to 5 membered heteroalkylene. In embodiments, L 2 is not an oxo substituted 2 to 6 membered heteroalkylene. In embodiments, R 2 is not unsubstituted tert-butyl. In embodiments, L 1 is not methylene. In embodiments, when L 1 is an unsubstituted methylene, L 2 is not a bond. In embodiments, when L 1 is an unsubstituted methylene, R 2 is not a substituted or unsubstituted alkyl. In embodiments, when L 1 is an unsubstituted methylene, R 2 is not an unsubstituted alkyl. In embodiments, when L 1 is an unsubstituted methylene, R 2 is not an unsubstituted C 1 -C 4 alkyl. In embodiments, when L 1 is an unsubstituted methylene, R 2 is not an unsubstituted tert-butyl. [0566] In embodiments, the compound is not CZ43, LJQ-145, LJQ-138, 3ClB-PP1, or CZ75. In embodiments, the compound is not CZ43. In embodiments, the compound is not LJQ-145. In embodiments, the compound is not LJQ-138. In embodiments, the compound is not 3ClB-PP1. In embodiments, the compound is not CZ75.

[0567] In embodiments, the compound is not: h r in L 1 is–O-, -NH-, -C(O)-, or unsubstituted methylene. In embodiments, L 2 -R 2 is not . [0568] In embodiments, R 1 is not substituted or unsubstituted naphthyl. In embodiments, R 1 is not substituted na hth l. In embodiments R 1 is not unsubstituted na hth l. In embodiments, L 1 -

R 1 is not . In embodiments,

R 20 is as described herein. [0569] In embodiments, the compound is 3CIB-PP1, FUR6-157, CZ75, MLC468, LZH118, GXJ276, GXJ186, FUR7-68, FUR 6-139, GXJ184, GXJ178, GXJ176, GXJ177, GXJ230, GXJ229, GXJ237, GXJ261, FUR6-6, FUR6-11, FUR6-13, FUR6-12, FUR7-27, FUR7-30, FUR7-36, FUR7-89, FUR7-77, FUR 5-56, FUR 7-76, or FUR7-2. In embodiments, the compound is 3CIB-PP1. In embodiments, the compound is FUR6-157. In embodiments, the compound is CZ75. In embodiments, the compound is MLC468. In embodiments, the compound is LZH118. In embodiments, the compound is GXJ276. In embodiments, the compound is GXJ186. In embodiments, the compound is FUR7-68. In embodiments, the compound is FUR 6- 139. In embodiments, the compound is GXJ184. In embodiments, the compound is GXJ178. In embodiments, the compound is GXJ176. In embodiments, the compound is GXJ177. In embodiments, the compound is GXJ230. In embodiments, the compound is GXJ229. In embodiments, the compound is GXJ237. In embodiments, the compound is GXJ261. In embodiments, the compound is FUR6-6. In embodiments, the compound is FUR6-11. In embodiments, the compound is FUR6-13. In embodiments, the compound is FUR6-12. In embodiments, the compound is FUR7-27. In embodiments, the compound is FUR7-30. In embodiments, the compound is FUR7-36. In embodiments, the compound is FUR7-89. In embodiments, the compound is FUR7-77. In embodiments, the compound is FUR 5-56. In embodiments, the compound is FUR 7-76. In embodiments, the compound is FUR7-2. [0570] In embodiments, the compound is CZ43, LJQ-145, LJQ-138, WXT-2, FUR6-95, FUR 5-57, or FUR6-159. In embodiments, the compound is the compound is CZ43. In embodiments, the compound is LJQ-145. In embodiments, the compound is LJQ-138. In embodiments, the compound is WXT-2. In embodiments, the compound is FUR6-95. In embodiments, the compound is FUR 5-57. In embodiments, the compound is FUR6-159. [0571] In embodiments, the compound is FUR 6-161, FUR 6-142, FUR 6-160, FUR 6-140, FUR 6-162, FUR 6-140B, FUR 6-145, FUR 6-141, FUR 6-142B, FUR 6-124, FUR 6-123, FUR 6-99, FUR 6-15, FUR 6-100, FUR 6-106, FUR 6-102, FUR 6-107, FUR 6-104, FUR 6-111, FUR 6-105, FUR 6-103, FUR 6-133, FUR 6-132, FUR 6-144, FUR 6-146, FUR 6-147, FUR 6-162B, or HYC29. In embodiments, the compound is FUR 6-161. In embodiments, the compound is FUR 6-142. In embodiments, the compound is FUR 6-160. In embodiments, the compound is FUR 6-140. In embodiments, the compound is FUR 6-162. In embodiments, the compound is FUR 6-140B. In embodiments, the compound is FUR 6-145. In embodiments, the compound is FUR 6-141. In embodiments, the compound is FUR 6-142B. In embodiments, the compound is FUR 6-124. In embodiments, the compound is FUR 6-123. In embodiments, the compound is FUR 6-99. In embodiments, the compound is FUR 6-15. In embodiments, the compound is FUR 6-100. In embodiments, the compound is FUR 6-106. In embodiments, the compound is FUR 6- 102. In embodiments, the compound is FUR 6-107. In embodiments, the compound is FUR 6- 104. In embodiments, the compound is FUR 6-111. In embodiments, the compound is FUR 6- 105. In embodiments, the compound is FUR 6-103. In embodiments, the compound is FUR 6- 133. In embodiments, the compound is FUR 6-132. In embodiments, the compound is FUR 6- 144. In embodiments, the compound is FUR 6-146. In embodiments, the compound is FUR 6- 147. In embodiments, the compound is FUR 6-162B. In embodiments, the compound is HYC29. III. Pharmaceutical compositions

[0572] In another aspect is provided a pharmaceutical composition including a

pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. in an embodiment, example, figure, table, or claim). [0573] In embodiments of the pharmaceutical compositions, the compound, or

pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount. [0574] In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. [0575] In embodiments, the second agent is an antibiotic. In embodiments, the second agent is pyrimethanime. In embodiments, the second agent is a sulfonamide drug. In embodiments, the second agent is clindamycin. In embodiments, the sulfonamide drug is sulfadiazine. In embodiments, the secondary agent is artemisinin or atovaquone, or a derivative thereof. In embodiments, the sulfonamide drug is sulfamethoaxazole. IV. Methods of treatment

[0576] In an aspect is provided a method of treating an Apicomplexa infection (e.g., Babesia spp., Plasmodium spp., Cryptosporidium parvum, Cyclospora cayetanensis, Cryptosporidium hominis, Isospora belli, Neospora caninum, Sarcicystis neurona, or Toxoplasma gondii) infection, the method including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the method further includes preventing reactivation of Apicomplexa tachyzoite, bradyzoite, oocysts, sporocyst, sporozoite, or enteroepithelial stage within tissue cysts. In embodiments, the method further includes preventing reactivation of Apicomplexa tachyzoite stage within tissue cysts. In embodiments, the method further includes preventing reactivation of Apicomplexa bradyzoite stage within tissue cysts. In embodiments, the method further includes preventing reactivation of

Apicomplexa oocyst stage within tissue cysts. In embodiments, the method further includes preventing reactivation of Apicomplexa sporocyst stage within tissue cysts. In embodiments, the method further includes preventing reactivation of Apicomplexa sporozoite stage within tissue cysts. In embodiments, the method further includes preventing reactivation of Apicomplexa enteroepithelial stage within tissue cysts. [0577] In an aspect is provided a compound as described herein for use as a medicament. In embodiments, the medicament is useful for treating a disease caused by an infectious agent (e.g., Apicomplexa, Babesia spp., Plasmodium spp., Cryptosporidium hominis, Cryptosporidium parvum, Cyclospora cayetanensis, Isospora belli, Neospora caninum, or Toxoplasma gondii).

[0578] In embodiments, the compound has the formula: , wherein Y 1 is–N= or–CH=; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl; L 1 is–O-, -S-, or–N(R 3 )-; L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and X 3 is independently halogen.

[0579] In an aspect is provided a compound as described herein for use in the treatment of a disease caused by an infectious agent (e.g., Apicomplexa, Babesia spp., Plasmodium spp., Cryptosporidium parvum, Cryptosporidium hominis, Cyclospora cayetanensis, Isospora belli, Neospora caninum, or Toxoplasma gondii). [0580] In embodiments, the Apicomplexa infection is a systemic infection including the central nervous system, placenta, retina, and the brain. In embodiments, the Apicomplexa infection is in the central nervous system. In embodiments, the Apicomplexa infection is in the placenta. In embodiments, the Apicomplexa infection is in the retina. In embodiments, the Apicomplexa infection is in the brain. In embodiments, the method includes preventing chronic Apicomplexa infection. In embodiments, the method includes preventing reactivation of the Apicomplexa in tissue cysts. In embodiments, the method includes reducing Apicomplexa survival, relative to a control (e.g., the absence of the compound described herein). In embodiments, the method includes reducing Apicomplexa proliferation, relative to a control (e.g., the absence of the compound described herein). In embodiments, the method includes reducing Apicomplexa egress from a cell, relative to a control (e.g., Apicomplexa egress in the absence of the compound described herein). In embodiments, the method includes reducing Apicomplexa invasion of a cell, relative to a control (e.g., Apicomplexa invasion in the absence of the compound described herein). In embodiments, the method includes reducing Apicomplexa motility, relative to a control (e.g., Apicomplexa motility in the absence of the compound described herein). In embodiments, the method includes reducing microneme (e.g., organelles involved in motility and invasion) protein release, relative to a control (e.g., microneme protein releases in the absence of the compound described herein). [0581] In embodiments, the Apicomplexa is Babesia spp., Plasmodium spp., Cryptosporidium parvum, Cryptosporidium hominis, Cyclospora cayetanensis, Isospora belli, Neospora caninum, or Toxoplasma gondii. In embodiments, the Apicomplexa is Toxoplasma gondii. [0582] In embodiments, the Apicomplexa infection is a chronic infection (e.g., toxoplasmosis). In embodiments, the method includes reducing or eliminating Apicomplexa tissue cysts present during chronic infection. In embodiments, the Apicomplexa infection is an acute infection (e.g., toxoplasmosis). In embodiments, the Apicomplexa infection is a congenital infection (e.g., toxoplasmosis). In embodiments, the Apicomplexa infection is in a newborn (e.g.,

toxoplasmosis). In embodiments, the Apicomplexa infection is in an infant (e.g.,

toxoplasmosis). In embodiments, the method includes preventing chronic (e.g., recurring) Apicomplexa infection. Chronic toxoplasmosis has also been associated with bipolar disorder, obsessive compulsive disorder, and addiction, See Acta Psychiatr Scand.2015 Sep;132(3):161- 79. doi: 10.1111/acps.12423. Epub 2015 Apr 15. In embodiments, the Apicomplexa infection is in an HIV-positive subject. In embodiments, the Apicomplexa infection is in an

immunocompromised subject. [0583] In an aspect is provided a method of treating an Apicomplexa associated disease, the method including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the disease is encephalitis. In embodiments, the disease is schizophrenia. In embodiments, the disease is toxoplasmosis (e.g., chronic toxoplasmosis, acute toxoplasmosis, congenital toxoplasmosis, or toxoplasmosis in a newborn infant). In

embodiments, the disease is toxoplasmic encephalitis. In embodiments, the disease is ocular toxoplasmosis. In embodiments, the disease is babesiosis, malaria, cryptosporidiosis, cyclosporiasis, isosporiasis, neosporosis, sarcocystosis, or toxoplasmosis. In embodiments, the disease is schizophrenia. In embodiments, the disease is bipolar disorder, obsessive compulsive disorder, or addiction. [0584] In embodiments, the method further includes co-administering pyrimethanime, a sulfonamide drug, or clindamycin. In embodiments, the sulfonamide drug is sulfadiazine. In embodiments, the secondary agent is artemisinin or atovaquone. In embodiments, the sulfonamide drug is sulfamethoaxazole. [0585] In embodiments, the treatment is prevention. In embodiments, the treatment does not include prevention. In embodiments, the compounds set forth herein are provided as

pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient. In embodiments, the disease is described herein, including in an aspect, embodiment, example, figure, table, definition, or claim. V. Methods of modulating calcium dependent protein kinase 1

[0586] In an aspect is provided a method of modulating calcium dependent protein kinase 1 (e.g., a parasite CDPK1, an Apicomplexa CDPK1, TgCDPK1, CpCDPK1) activity, the method including: contacting the calcium dependent protein kinase 1 with an effective amount of a compound described herein. In embodiments, the CDPK1 is a CDPK1 from Toxoplasma gondii, Cryptosporidium parvum, Cryptosporidium hominis, Neospora canimum, or Sarcocystis neurona. In embodiments, the CDPK1 is a CDPK1 from Toxoplasma gondii. [0587] In embodiments, the compound has the formula: , wherein Y 1 is–N= or–CH=; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl; L 1 is–O-, -S-, or–N(R 3 )-; L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and X 3 is independently halogen.

[0588] In an aspect is provided a method of inhibiting calcium dependent protein kinase (CDPK) activity, the method including contacting the calcium dependent protein kinase with an effective amount of a compound described herein. In embodiments the CDPK is Toxoplasma gondii CDPK1 (TgCDPK1). In embodiments the CDPK is Cryptosporidium parvum CDPK1 (CpCDPK1). In embodiments, the CDPK is a CDPK from Toxoplasma gondii, Cryptosporidium parvum, Cryptosporidium hominis, Neospora canimum, or Sarcocystis neurona. In

embodiments, the CDPK is a CDPK from Toxoplasma gondii. In embodiments, the CDPK is Toxoplasma gondii CDPK1 (TgCDPK1), N. caninum Liverpool CDPK1 (NcCDPK1), C.

parvum Iowa II CDPK1 (CpCDPK1), P. falciparum CDPK4 (PfCDPK4) Toxoplasma gondi mutant G128S CDPK1 (TgG128SCDPK1), P. falciparum 3d7 CDPK1 (PfCDPK1), B. bovis T2Bo CDPK4 (BbCDPK4), E. tanella CDPK1 (EtCDPK1), or Toxoplasma gondi mutant G128S CDPK1 (TgG128TCDPK1). [0589] In an aspect is provided a method of inhibiting calcium dependent protein kinase 1 (e.g., a parasite CDPK1, an Apicomplexa CDPK1, or TgCDPK1) activity, the method including: contacting the calcium dependent protein kinase 1 with an effective amount of a compound described herein. In embodiments, inhibiting includes the reduction of calcium dependent protein kinase 1 (e.g., a parasite CDPK1, an Apicomplexa CDPK1, or TgCDPK1) activity relative to the absence of an effective amount of a compound described herein. In embodiments, the method includes inhibiting TgCDPK1 activity. [0590] In embodiments, the calcium dependent protein kinase 1 is in a cell. In embodiments, the cell is an Apicomplexa cell (e.g., Toxoplasma gondii cell). In some embodiments, the cell is a mammalian cell, such as a human cell. The cell may be isolated in vitro, form part of a tissue in vitro, or may form part of an organism. [0591] Modulating CDPK1 (e.g., TgCDPK1) activity includes directly or indirectly affecting one or more functions of calcium dependent protein kinase 1 and/or one or more downstream effects of calcium dependent protein kinase 1 activity. VI. EMBODIMENTS

[0592] Embodiment P1. A compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen. [0593] Embodiment P2. The compound of embodiment P1, wherein R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0594] Embodiment P3. The compound of one of embodiments P1 to P2, wherein R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0595] Embodiment P4. The compound of one of embodiments P1 to P3, wherein L 2 is a substituted or unsubstituted C 1 -C 5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. [0596] Embodiment P5. The compound of one of embodiments P1 to P3, wherein L 2 is a– CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, or–CH 2 NH-. [0597] Embodiment P6. The compound of one of embodiments P1 to P5, wherein R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. [0598] Embodiment P7. The compound of one of embodiments P1 to P6, having the formula:

(I) wherein,

Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; R 4 is halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCX 4

3, - OCH D

2X 4 , -OCHX 4

2, -CN, -SO n4 R 4 , -SO v4 NR 4A R 4B , -NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(

R 4A OR 4C , 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 5 is halogen, -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCX 5

3, - OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C( O)R 5C , -C(O)-OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A SO 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -N R 5A OR 5C , 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; Each R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D is independently

hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 4 , and X 5 is independently–F, -Cl, -Br, or–I;

n4 and n5 are independently an integer from 0 to 4; and

m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6. [0599] Embodiment P8. The compound of one of embodiments P1 to P7, wherein L 1 is– O-. [0600] Embodiment P9. The compound of one of embodiments P1 to P7, wherein L 1 is -S-. [0601] Embodiment P10. The compound of one of embodiments P1 to P7, wherein L 1 is– N(R 3 )-. [0602] Embodiment P11. The compound of embodiment P10, wherein R 3 is hydrogen. [0603] Embodiment P12. The compound of one of embodiments P7 to P11, wherein Ring A is phenyl. [0604] Embodiment P13. The compound of one of embodiments P7 to P11, wherein Ring A is napththyl. [0605] Embodiment P14. The compound of one of embodiments P7 to P11, wherein Ring A is 5 to 10 membered heteroaryl. [0606] Embodiment P15. The compound of one of embodiments P7 to P11, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl,

benzimidazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0607] Embodiment P16. The compound of one of embodiments P7 to P11, wherein Ring A is 5 to 9 membered heteroaryl. [0608] Embodiment P17. The compound of one of embodiments P7 to P11, wherein Ring A is 5 to 6 membered heteroaryl. [0609] Embodiment P18. The compound of one of embodiments P7 to P11, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. [0610] Embodiment P19. The compound of one of embodiments P7 to P18, wherein R 4 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4

3, -CHX4

2, -CH 2 X 4 , -O CX 4

3, -OCHX4

2, -OCH 2 X 4 , -SCX 4

3, -SCHX4

2, -SCH 2 X 4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 CH 3 . [0611] Embodiment P20. The compound of one of embodiments P1 to P19, wherein z4 is 2. [0612] Embodiment P21. The compound of one of embodiments P1 to P19, wherein z4 is 1. [0613] Embodiment P22. The compound of one of embodiments P1 to P19, wherein z4 is 0. [0614] Embodiment P23. The compound of one of embodiments P1 to P22, wherein L 2 is– CH 2 -. [0615] Embodiment P24. The compound of one of embodiments P1 to P22, wherein L 2 is -CH 2 CH 2 -. [0616] Embodiment P25. The compound of one of embodiments P1 to 22, wherein L 2 is -CH 2 O-. [0617] Embodiment P26. The compound of one of embodiments P1 to P22, wherein L 2 is -CH 2 S-. [0618] Embodiment P27. The compound of one of embodiments P1 to P22, wherein L 2 is– CH 2 NH-. [0619] Embodiment P28. The compound of one of embodiments P7 to P27, wherein Ring B is 3 to 7 membered heterocycloalkyl. [0620] Embodiment P29. The compound of one of embodiments P7 to 27, wherein Ring B is 3 to 6 membered heterocycloalkyl. [0621] Embodiment P30. The compound of one of embodiments P7 to P27, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. [0622] Embodiment P31. The compound of one of embodiments P7 to P27, wherein Ring B is a 6 membered heterocycloalkyl. [0623] Embodiment P32. The compound of one of embodiments P7 to P27, wherein Ring B is piperidinyl or piperazinyl. [0624] Embodiment P33. The compound of one of embodiments P7 to P27, wherein Ring B is 5 to 10 membered heteroaryl. [0625] Embodiment P34. The compound of one of embodiments P7 to P27, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl,

quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0626] Embodiment P35. The compound of one of embodiments P7 to P27, wherein Ring B is a 6 membered heteroaryl. [0627] Embodiment P36. The compound of one of embodiments P7 to P27, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. [0628] Embodiment P37. The compound of one of embodiments P7 to P36, wherein R 5 is– F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX5

3, -CHX5

2, -CH 2 X 5 , -O CX 5

3, -OCHX5

2, -OCH 2 X 5 , -SCX 5

3, -SCHX5

2, -SCH 2 X 5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 , or -SCH 2 CH 3 . [0629] Embodiment P38. The compound of one of embodiments P7 to P37, wherein z5 is 2. [0630] Embodiment P39. The compound of one of embodiments P7 to P37, wherein z5 is 1. [0631] Embodiment P40. The compound of one of embodiments P7 to P37, wherein z5 is 0. [0632] Embodiment P41. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of embodiments P1 to P40, or a pharmaceutically acceptable salt thereof. [0633] Embodiment P42. A method of inhibiting calcium dependent protein kinase 1 activity, said method comprising: contacting the calcium dependent protein kinase 1 with an effective amount of a compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen. [0634] Embodiment P43. A method of treating an Apicomplexa infection, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen. [0635] Embodiment P44. The method of embodiment P43, wherein the Apicomplexa infection is in the brain. [0636] Embodiment P45. The method of one of embodiments P43 to P44, comprising preventing chronic Apicomplexa infection. [0637] Embodiment P46. The method of one of embodiments P43 to P44, comprising preventing reactivation of the Apicomplexa in cysts. [0638] Embodiment P47. The method of one of embodiments P43 to P46, comprising reducing Apicomplexa survival. [0639] Embodiment P48. The method of one of embodiments P43 to P46, comprising reducing Apicomplexa proliferation. [0640] Embodiment P49. The method of one of embodiments P43 to P46, comprising reducing Apicomplexa egress from a cell. [0641] Embodiment P50. The method of one of embodiments P43 to P46, comprising reducing Apicomplexa invasion of a cell. [0642] Embodiment P51. The method of one of embodiments P43 to P46, comprising reducing Apicomplexa motility. [0643] Embodiment P52. The method of one of embodiments P43 to P51, comprising reducing microneme protein release. [0644] Embodiment P53. The method of one of embodiments P43 to P52, wherein the Apicomplexa is Toxoplasma gondii. [0645] Embodiment P54. A method of treating an Apicomplexa associated disease, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen. [0646] Embodiment P55. The method of embodiment P54, wherein the disease is encephalitis. [0647] Embodiment P56. The method of embodiment P54, wherein the disease is schizophrenia. [0648] Embodiment P57. The method of embodiment 54, wherein the disease is

toxoplasmosis. [0649] Embodiment P58. The method of embodiment P54, wherein the disease is toxoplasmic encephalitis. [0650] Embodiment P59. The method of embodiment P54, wherein the disease is ocular toxoplasmosis. [0651] Embodiment P60. The method of one of embodiments P57 to P59, further comprising co-administering pyrimethamine, a sulfonamide drug, or clindamycin. [0652] Embodiment P61. The method of embodiment P60, wherein the sulfonamide drug is sulfadiazine. [0653] Embodiment P62. The method of one of embodiments P42 to P61, wherein R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0654] Embodiment P63. The method of one of embodiments P42 to P61, wherein R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0655] Embodiment P64. The method of one of embodiments P42 to P63, wherein L 2 is a bond, substituted or unsubstituted C 1 -C 5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. [0656] Embodiment P65. The method of one of embodiments P42 to P63, wherein L 2 is a bond,–CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, or–CH 2 NH-. [0657] Embodiment P66. The method of one of embodiments P42 to P65, wherein R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. [0658] Embodiment P67. The method of one of embodiments P42 to P66, wherein the compound has the formula:

(I) wherein,

Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; R 4 is halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCX 4

3, - OCH 2 X 4 , -OCHX 4

2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C( O)R 4C , -C(O)-OR 4C , -C(O)NR 4A R 4B , -OR 4D , -NR 4A SO 2 R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -N R 4A OR 4C , 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 5 is halogen, -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCX 5

3, - OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C( O)R 5C , -C(O)-OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A SO 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -N R 5A OR 5C , 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;

Each R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D is independently

hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 4 , and X 5 is independently–F, -Cl, -Br, or–I;

n4 and n5 are independently an integer from 0 to 4; and

m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6. [0659] Embodiment P68. The method of one of embodiments P42 to P67, wherein L 1 is–O-. [0660] Embodiment P69. The method of one of embodiments P42 to P67, wherein L 1 is -S-. [0661] Embodiment P70. The method of one of embodiments P42 to P67, wherein L 1 is– N(R 3 )-. [0662] Embodiment P71. The method of embodiment P70, wherein R 3 is hydrogen. [0663] Embodiment P72. The method of one of embodiments P67 to P71, wherein Ring A is phenyl. [0664] Embodiment P73. The method of one of embodiments P67 to P71, wherein Ring A is napththyl. [0665] Embodiment P74. The method of one of embodiments P67 to P71, wherein Ring A is 5 to 10 membered heteroaryl. [0666] Embodiment P75. The method of one of embodiments P67 to P71, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl,

benzimidazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0667] Embodiment P76. The method of one of embodiments P67 to P71, wherein Ring A is 5 to 9 membered heteroaryl. [0668] Embodiment P77. The method of one of embodiments P67 to P71, wherein Ring A is 5 to 6 membered heteroaryl. [0669] Embodiment P78. The method of one of embodiments P67 to P71, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. [0670] Embodiment P79. The method of one of embodiments P67 to P78, wherein R 4 is independently - F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4

3, -CHX4

2, -CH 2 X 4 , -O CX 4

3, -OCHX4

2, -OCH 2 X 4 , -SCX 4

3, -SCHX4

2, -SCH 2 X 4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 CH 3 . [0671] Embodiment P80. The method of one of embodiments P42 to P79, wherein z4 is 2. [0672] Embodiment P81. The method of one of embodiments P42 to P79, wherein z4 is 1. [0673] Embodiment P82. The method of one of embodiments P42 to P79, wherein z4 is 0. [0674] Embodiment P83. The method of one of embodiments P42 to P82, wherein L 2 is a bond. [0675] Embodiment P84. The method of one of embodiments P42 to P82, wherein L 2 is– CH 2 -. [0676] Embodiment P85. The method of one of embodiments P42 to P82, wherein L 2 [0677] Embodiment P86. The method of one of embodiments P42 to P82, wherein L 2 is -CH 2 O-. [0678] Embodiment P87. The method of one of embodiments P42 to P82, wherein L 2

[0679] Embodiment P88. The method of one of embodiments P42 to P82, wherein L 2 is– CH 2 NH-. [0680] Embodiment P89. The method of one of embodiments P67 to P88, wherein Ring B is 3 to 7 membered heterocycloalkyl. [0681] Embodiment P90. The method of one of embodiments P67 to P88, wherein Ring B is 3 to 6 membered heterocycloalkyl. [0682] Embodiment P91. The method of one of embodiments P67 to P88, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. [0683] Embodiment P92. The method of one of embodiments P67 to P88, wherein Ring B is a 6 membered heterocycloalkyl. [0684] Embodiment P93. The method of one of embodiments P67 to P88, wherein Ring B is piperidinyl or piperazinyl. [0685] Embodiment P94. The method of one of embodiments P67 to P88, wherein Ring B is 5 to 10 membered heteroaryl. [0686] Embodiment P95. The method of one of embodiments P67 to P88, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0687] Embodiment P96. The method of one of embodiments P67 to P88, wherein Ring B is a 6 membered heteroaryl. [0688] Embodiment P97. The method of one of embodiments P67 to P88, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. [0689] Embodiment P98. The method of one of embodiments P67 to P97, wherein R 5 is– F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX5

3, -CHX5

2, -CH 2 X 5 , -O CX 5

3, -OCHX5

2, -OCH 2 X 5 , -SCX 5

3, -SCHX5

2, -SCH 2 X 5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 , or -SCH 2 CH 3 . [0690] Embodiment P99. The method of one of embodiments P67 to P98, wherein z5 is 2. [0691] Embodiment P100. The method of one of embodiments P67 to P98, wherein z5 is 1. [0692] Embodiment P101. The method of one of embodiments P67 to P98, wherein z5 is 0. VII. Additional Embodiments

[0693] Embodiment 1. A compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen.

[0694] Embodiment 2. The compound of embodiment 1, wherein R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0695] Embodiment 3. The compound of one of embodiments 1 to 2, wherein R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5 to 10 membered heteroaryl, or substituted or unsubstituted C 3 -C 8 cycloalkyl. [0696] Embodiment 4. The compound of one of embodiments 1 to 3, wherein L 2 is a substituted or unsubstituted C 1 -C 5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. [0697] Embodiment 5. The compound of one of embodiments 1 to 3, wherein L 2 is a– CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, or–CH 2 NH-. [0698] Embodiment 6. The compound of one of embodiments 1 to 5, wherein R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. [0699] Embodiment 7. The compound of one of embodiments 1 to 6, having the formula:

(I) wherein,

Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C 3 - C 8 cycloalkyl;

R 4 is halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCX 4

3, - OCH 2 X 4 , -OCHX 4

2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C( O)R 4C , -C(O)-OR 4C , -C(O)NR 4A R 4B , -OR 4D , -NR 4A SO 2 R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -N R 4A OR 4C , 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 5 is halogen, -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCX 5

3, - OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C( O)R 5C , -C(O)-OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A SO 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -N R 5A OR 5C , 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;

Each R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 4 , and X 5 is independently–F, -Cl, -Br, or–I;

n4 and n5 are independently an integer from 0 to 4; and

m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6.

[0700] Embodiment 8. The compound of one of embodiments 1 to 7, wherein L 1 is–O-. [0701] Embodiment 9. The compound of one of embodiments 1 to 7, wherein L 1 is -S-. [0702] Embodiment 10. The compound of one of embodiments 1 to 7, wherein L 1 is– N(R 3 )-. [0703] Embodiment 11. The compound of embodiment 10, wherein R 3 is hydrogen. [0704] Embodiment 12. The compound of one of embodiments 7 to 11, wherein Ring A is phenyl. [0705] Embodiment 13. The compound of one of embodiments 7 to 11, wherein Ring A is napththyl. [0706] Embodiment 14. The compound of one of embodiments 7 to 11, wherein Ring A is 5 to 10 membered heteroaryl. [0707] Embodiment 15. The compound of one of embodiments 7 to 11, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, azaindolyl, benzoisoxazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0708] Embodiment 16. The compound of one of embodiments 7 to 11, wherein Ring A is 5 to 9 membered heteroaryl. [0709] Embodiment 17. The compound of one of embodiments 7 to 11, wherein Ring A is 5 to 6 membered heteroaryl. [0710] Embodiment 18. The compound of one of embodiments 7 to 11, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. [0711] Embodiment 19. The compound of one of embodiments 7 to 18, wherein R 4 is independently -F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4

3, -CHX 4

2, -CH 2 X 4 , -OCX 4

3, -OCHX4

2, -OCH 2 X 4 , -SCX 4

3, -SCHX4

2, -SCH 2 X 4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SC H 2 CH 3 . [0712] Embodiment 20. The compound of one of embodiments 1 to 19, wherein z4 is 2. [0713] Embodiment 21. The compound of one of embodiments 1 to 19, wherein z4 is 1. [0714] Embodiment 22. The compound of one of embodiments 1 to 19, wherein z4 is 0. [0715] Embodiment 23. The compound of one of embodiments 1 to 22, wherein L 2 is– CH 2 -. [0716] Embodiment 24. The compound of one of embodiments 1 to 22, wherein L 2 is -CH 2 CH 2 -. [0717] Embodiment 25. The compound of one of embodiments 1 to 22, wherein L 2 is -CH 2 O-. [0718] Embodiment 26. The compound of one of embodiments 1 to 22, wherein L 2 is -CH 2 S-. [0719] Embodiment 27. The compound of one of embodiments 1 to 22, wherein L 2 is– CH 2 NH-. [0720] Embodiment 28. The compound of one of embodiments 7 to 27, wherein Ring B is 3 to 7 membered heterocycloalkyl. [0721] Embodiment 29. The compound of one of embodiments 7 to 27, wherein Ring B is 3 to 6 membered heterocycloalkyl. [0722] Embodiment 30. The compound of one of embodiments 7 to 27, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. [0723] Embodiment 31. The compound of one of embodiments 7 to 27, wherein Ring B is a 6 membered heterocycloalkyl. [0724] Embodiment 32. The compound of one of embodiments 7 to 27, wherein Ring B is piperidinyl or piperazinyl. [0725] Embodiment 33. The compound of one of embodiments 7 to 27, wherein Ring B is a C 3 -C 8 substituted or unsubstituted cycloalkyl. [0726] Embodiment 34. The compound of one of embodiments 7 to 27, wherein Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl. [0727] Embodiment 35. The compound of one of embodiments 7 to 27, wherein Ring B is substituted or unsubstituted cyclopentanyl. [0728] Embodiment 36. The compound of one of embodiments 7 to 27, wherein Ring B is 5 to 10 membered heteroaryl. [0729] Embodiment 37. The compound of one of embodiments 7 to 27, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0730] Embodiment 38. The compound of one of embodiments 7 to 27, wherein Ring B is a 6 membered heteroaryl. [0731] Embodiment 39. The compound of one of embodiments 7 to 27, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. [0732] Embodiment 40. The compound of one of embodiments 7 to 39, wherein R 5 is– F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX5

3, -CHX5

2, -CH 2 X 5 , -O CX 5

3, -OCHX5

2, -OCH 2 X 5 , -SCX 5

3, -SCHX5

2, -SCH 2 X 5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 , or -SCH 2 CH 3 . [0733] Embodiment 41. The compound of one of embodiments 7 to 40, wherein z5 is 2. [0734] Embodiment 42. The compound of one of embodiments 7 to 40, wherein z5 is 1. [0735] Embodiment 43. The compound of one of embodiments 7 to 40, wherein z5 is 0. [0736] Embodiment 44. The compound of embodiment 1, having the formula:

wherein, A 1 , A 2 , A 3 , A 4 , and A 5 , are each independently–C(R 4 )= or–N=;

R 4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halogen, -CF 3 , -OCH 3 , -CN, -SO 2 CH 3 , -SO 2 NHR 4B , -OCF 3 ;

R 5 is independently oxo, halogen, -COOH, or -C(O)NR 5A R 5B ;

R 5.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted

cycloalkyl, -C(O)NR 5A R 5B , , -C(N)-(substituted or unsubstituted alkyl), -C(N)- (substituted or unsubstituted cycloalkyl), -C(O)-(substituted or unsubstituted alkyl), or -C(O)- (substituted or unsubstituted cycloalkyl);

z4 and z5 are independently an integer from 0 to 2; and

R 5A and R 5B are independently hydrogen or substituted or unsubstituted alkyl.

[0737] Embodiment 45. The compound of embodiment 44, wherein z5 is 2. [0738] Embodiment 46. The compound of embodiment 44 or 45, wherein R 5.1 is substituted or unsubstituted cyclopropyl. [0739] Embodiment 47. The compound of embodiment 1, wherein L 2 -R 2 has the formula:

R 23 is independently oxo,

halogen, -CX 23

3, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , - NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCX 23

3, -OCHX23

2, 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 23.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclopropyl, -C(O)-(substituted or unsubstituted alkyl), -C(O)-(substituted or unsubstituted cyclopropyl), -C(N)-alkyl, -C(N)-cyclopropyl; and

z2 is an integer from 0 to 9.

[0740] Embodiment 48. The compound of embodiment 1, having the formula:

.

[0741] Embodiment 49. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of embodiments 1 to 48, or a pharmaceutically acceptable salt thereof. [0742] Embodiment 50. A method of inhibiting calcium dependent protein kinase 1 activity, said method comprising: contacting the calcium dependent protein kinase 1 with an effective amount of a compound having the formula: (I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen.

[0743] Embodiment 51. The method of embodiment 50, wherein R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. [0744] Embodiment 52. A method of treating an Apicomplexa infection, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L 1 is–O-, -S-, or–N(R 3 )-; L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen.

[0745] Embodiment 53. The method of embodiment 52, wherein R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. [0746] Embodiment 54. The method of one of embodiments 50 or 52, further comprising preventing reactivation of Apicomplexa bradyzoite stages that exist within tissue cysts. [0747] Embodiment 55. The method of one of embodiments 50 or 52, wherein the Apicomplexa infection is in central nervous system. [0748] Embodiment 56. The method of one of embodiments 50 or 52, wherein the Apicomplexa infection is in the brain and the eye. [0749] Embodiment 57. The method of one of embodiments 50 or 52, wherein the Apicomplexa infection is in the brain. [0750] Embodiment 58. The method of one of embodiments 52 to 57, comprising preventing chronic Apicomplexa infection. [0751] Embodiment 59. The method of one of embodiments 52 to 57, comprising reducing or eliminating Apicomplexa tissue cysts present during chronic infection. [0752] Embodiment 60. The method of one of embodiments 52 to 57, comprising preventing reactivation of the Apicomplexa in cysts. [0753] Embodiment 61. The method of one of embodiments 52 to 60, comprising reducing Apicomplexa survival. [0754] Embodiment 62. The method of one of embodiments 52 to 60, comprising reducing Apicomplexa proliferation. [0755] Embodiment 63. The method of one of embodiments 52 to 60, comprising reducing Apicomplexa egress from a cell. [0756] Embodiment 64. The method of one of embodiments 52 to 60, comprising reducing Apicomplexa invasion of a cell. [0757] Embodiment 65. The method of one of embodiments 52 to 60, comprising reducing Apicomplexa motility. [0758] Embodiment 66. The method of one of embodiments 52 to 65, comprising reducing microneme protein release. [0759] Embodiment 67. The method of one of embodiments 52 to 66, wherein the

Apicomplexa is Toxoplasma gondii. [0760] Embodiment 68. A method of treating an Apicomplexa associated disease, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

(I) wherein,

Y 1 is–N= or–CH=;

R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl;

L 1 is–O-, -S-, or–N(R 3 )-;

L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and

X 3 is independently halogen.

[0761] Embodiment 69. The method of embodiment 68, wherein R 2 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. [0762] Embodiment 70. The method of one of embodiments 68 to 69, wherein the disease is encephalitis. [0763] Embodiment 71. The method of one of embodiments 68 to 69, wherein the disease is schizophrenia. [0764] Embodiment 72. The method of one of embodiments 68 to 69, wherein the disease is toxoplasmosis. [0765] Embodiment 73. The method of one of embodiments 68 to 69, wherein the disease is toxoplasmic encephalitis. [0766] Embodiment 74. The method of one of embodiments 68 to 69, wherein the disease is ocular toxoplasmosis. [0767] Embodiment 75. The method of one of embodiments 72 to 74, further comprising co-administering pyrimethamine, a sulfonamide drug, or clindamycin. [0768] Embodiment 76. The method of embodiment 75, wherein the sulfonamide drug is sulfadiazine or sulfamethoxazole. [0769] Embodiment 77. The method of one of embodiments 50 to 76, wherein R 1 is substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0770] Embodiment 78. The method of one of embodiments 50 to 76, wherein R 2 is substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 10 membered heteroaryl. [0771] Embodiment 79. The method of one of embodiments 50 to 78, wherein L 2 is a bond, substituted or unsubstituted C 1 -C 5 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene. [0772] Embodiment 80. The method of one of embodiments 50 to 78, wherein L 2 is a bond, –CH 2 -, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, or–CH 2 NH-. [0773] Embodiment 81. The method of one of embodiments 50 to 80, wherein R 3 is hydrogen, -CN, -COOH, -CX 3

3, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. [0774] Embodiment 82. The method of one of embodiments 50 to 81, wherein the compound has the formula:

wherein,

Ring A is C 6 -C 10 aryl or 5 to 10 membered heteroaryl;

Ring B is 3 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C 3 - C 8 cycloalkyl;

R 4 is halogen, -CX 4

3, -CHX4

2, -CH 2 X 4 , -OCX 4

3, - OCH 2 X 4 , -OCHX 4

2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NHC(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C( O)R 4C , -C(O)-OR 4C , -C(O)NR 4A R 4B , -OR 4D , -NR 4A SO 2 R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -N R 4A OR 4C , 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 5 is halogen, -CX 5

3, -CHX5

2, -CH 2 X 5 , -OCX 5

3, - OCH 2 X 5 , -OCHX 5

2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C( O)R 5C , -C(O)-OR 5C , -C(O)NR 5A R 5B , -OR 5D , -NR 5A SO 2 R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -N R 5A OR 5C , 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;

Each R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 4 , and X 5 is independently–F, -Cl, -Br, or–I; n4 and n5 are independently an integer from 0 to 4; and

m4, m5, v4, and v5 are independently an integer from 1 to 2.

z4 is an integer from 0 to 9; and

z5 is an integer from 0 to 6.

[0775] Embodiment 83. The method of one of embodiments 50 to 82, wherein L 1 is–O-. [0776] Embodiment 84. The method of one of embodiments 50 to 82, wherein L 1 is -S-. [0777] Embodiment 85. The method of one of embodiments 50 to 82, wherein L 1 is– N(R 3 )-. [0778] Embodiment 86. The method of embodiment 85, wherein R 3 is hydrogen. [0779] Embodiment 87. The method of one of embodiments 82 to 86, wherein Ring A is phenyl. [0780] Embodiment 88. The method of one of embodiments 82 to 86, wherein Ring A is napththyl. [0781] Embodiment 89. The method of one of embodiments 82 to 86, wherein Ring A is 5 to 10 membered heteroaryl. [0782] Embodiment 90. The method of one of embodiments 82 to 86, wherein Ring A is benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl,

benzimidazolyl, azaindolyl, benzoisoxazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0783] Embodiment 91. The method of one of embodiments 82 to 86, wherein Ring A is 5 to 9 membered heteroaryl. [0784] Embodiment 92. The method of one of embodiments 82 to 86, wherein Ring A is 5 to 6 membered heteroaryl. [0785] Embodiment 93. The method of one of embodiments 82 to 86, wherein Ring A is furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. [0786] Embodiment 94. The method of one of embodiments 82 to 93, wherein R 4 is independently–

F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX4

3, -CHX4

2, -CH 2 X 4 , -O CX 4

3, -OCHX4

2, -OCH 2 X 4 , -SCX 4

3, -SCHX4

2, -SCH 2 X 4 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 ,or -SCH 2 CH 3 . [0787] Embodiment 95. The method of one of embodiments 50 to 94, wherein z4 is 2. [0788] Embodiment 96. The method of one of embodiments 50 to 94, wherein z4 is 1. [0789] Embodiment 97. The method of one of embodiments 50 to 94, wherein z4 is 0. [0790] Embodiment 98. The method of one of embodiments 50 to 97, wherein L 2 is a bond. [0791] Embodiment 99. The method of one of embodiments 50 to 97, wherein L 2 is–CH 2 -. [0792] Embodiment 100. The method of one of embodiments 50 to 97, wherein L 2 [0793] Embodiment 101. The method of one of embodiments 50 to 97, wherein L 2 is -CH 2 O-. [0794] Embodiment 102. The method of one of embodiments 50 to 97, wherein L 2 is -CH 2 S-. [0795] Embodiment 103. The method of one of embodiments 50 to 97, wherein L 2 is– CH 2 NH-. [0796] Embodiment 104. The method of one of embodiments 82 to 103, wherein Ring B is 3 to 7 membered heterocycloalkyl. [0797] Embodiment 105. The method of one of embodiments 82 to 103, wherein Ring B is 3 to 6 membered heterocycloalkyl. [0798] Embodiment 106. The method of one of embodiments 82 to 103, wherein Ring B is aziridinyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetyl, diazetidinyl, diazetyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. [0799] Embodiment 107. The method of one of embodiments 82 to 103, wherein Ring B is a 6 membered heterocycloalkyl. [0800] Embodiment 108. The method of one of embodiments 82 to 103, wherein Ring B is piperidinyl or piperazinyl. [0801] Embodiment 109. The method of one of embodiments 82 to 103, wherein Ring B is 5 to 10 membered heteroaryl. [0802] Embodiment 110. The method of one of embodiments 82 to 103, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or phthalazinyl. [0803] Embodiment 111. The method of one of embodiments 82 to 103, wherein Ring B is a C 3 -C 8 substituted or unsubstituted cycloalkyl. [0804] Embodiment 112. The method of one of embodiments 82 to 103, wherein Ring B is substituted or unsubstituted cyclooctanyl, substituted or unsubstituted cycloheptanyl, substituted or unsubstituted cyclohexanyl, or substituted or unsubstituted cyclopentanyl. [0805] Embodiment 113. The method of one of embodiments 82 to 103, wherein Ring B is substituted or unsubstituted cyclopentanyl. [0806] Embodiment 114. The method of one of embodiments 82 to 103, wherein Ring B is a 6 membered heteroaryl. [0807] Embodiment 115. The method of one of embodiments 82 to 103, wherein Ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. [0808] Embodiment 116. The method of one of embodiments 82 to 115, wherein R 5 is– F, -Cl, -Br, -I, -CN, -NH 2 , -OH, -SH, -COCH 3 , -COOH, -COOCH 3 , -CX5

3, -CHX5

2, -CH 2 X 5 , -O CX 5

3, -OCHX5

2, -OCH 2 X 5 , -SCX 5

3, -SCHX5

2, -SCH 2 X 5 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , -SCH 3 , or -SCH 2 CH 3 . [0809] Embodiment 117. The method of one of embodiments 82 to 116, wherein z5 is 2. [0810] Embodiment 118. The method of one of embodiments 82 to 116, wherein z5 is 1. [0811] Embodiment 119. The method of one of embodiments 82 to 116, wherein z5 is 0. [0812] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application 67893547v.1 and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES

Example A: Synthesis and characterization

[0813] Materials obtained commercially were reagent grade and were used without further purification. Preparation of compounds begins from commercially available or prepared t-butyl protected pyrazolopyrimidine (See, for example Lourido Shokat and Sibley J Med Chem.2013 Apr 11;56(7):3068-77; Hanefeld, U., Rees, C. W., White, A. J. P. & Williams, D. J. J. Am.

Chem. Soc. Perkin Trans.11545–1552 (1996); Schenone, S., Radi, M., Musumeci, F., Brullo, C. & Botta, M. Chem. Rev.114, 7189–7238 (2014); and Bulawa, C. E., Devit, M. & Elbaum, D. EP20080848219 (2010)) which are incorporated herein by reference in their entirerty) or commercially available pyrrolopyrimidine which are briefly described here: Scheme 1: Scaffold synthesis

I9 [0814] Example 1: 5-amino-1-(tert-butyl)-1H-pyrazole-4-carbonitrile (I1): . In a 250mL flame-dried argon purged round bottom flask, triethylamine (1.78g, 17.7mmol), and t- butyl hydrazine hydrochloride (1.56g, 12.5mmol) are dissolved in anhydrous ethanol (85mL). Ethoxymethylenemalononitrile (1.98g, 17.7mmol) is added slowly and reaction mixture is brought to reflux at 82°C for 3 hours. The solvent is removed in vacuo and 10% ethyl acetate / hexane is added (5mL) and the mixture is sonicated (or simply utilize recrystallization from 10% ethyl acetate / hexane). The resulting crystalline solid is filtered, and washed with ether to yield I1. LC-MS (ES+) calcd for C 8 H 12 N 4 (M+H) + 165.11, found 165.05.

[0815] Example 2: 1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I2): . Formamide (35mL) is added to intermediate I1 (~2.75g) and the mixture is headed to 180°C for 3 hours. Upon cooling, the mixture is added to water and extracted with ethyl acetate using sodium bicarbonate to wash the organic followed by a careful water wash as to avoid emulsion and lastly a wash with saturated brine. The organic layer is dried in vacuo and is recrystallized from a small amount of ether to yield intermediate I2. LC-MS (ES+) calcd for C 9 H 13 N 5 (M+H)+ 192.12, found 192.21. [0816] Example 3: 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I3):

. Intermediate I2 (~300mgs) is suspended in water (7mL) and bromine (188uL, 2 equivalents) is added and the reaction mixture is stirred at room temperature for 1 hour followed by stirring at 100°C for 1 hour. Upon cooling, the precipitated product is separated by filtration and the filtrate is stirred in 5% aqueous sodium hydrogen sulfite (12mL) for 30 minutes and the solution is treated with 5mL of saturated aqueous sodium bicarbonate. The precipitate is separated by filtration, washed with water and dried to yield brominated intermediate I3. LC-MS (ES+) calcd for C 9 H 12 BrN 5 (M+H) + 270.03, found 270.55, 272.40. [0817] Synthesis of pyrazolopyrimidines without t-butyl modification at N1 proceeds similarly although hydrazine is utilized instead of a derivatized hydrazine reagent to yield intermediate I4 followed by similar procedures in generating intermediates I2 and I3 to yield intermediates I5 and I6.

[0818] Example 4: 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I6):

250mL argon purged, flame-dried flask, 50mL DMF was added to dissolve 5g (37mmol) of starting material I5. NBS (6.5g, 36.5mmol) was added and the reaction heated to 60°C overnight. Upon cooling, and completion of reaction monitored by TLC, precipitate was filtered to yield intermediate I6. LC-MS (ES+) calcd for C 5 H 4 BrN 5 (M+H) + 213.97, found 213.76, 215.71.

[0819] Example 5: 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I7): . In a 100mL argon purged, flame-dried flask, 30mL DMF was added to dissolve 5g (37mmol) of starting material I5. NIS (12.3g, 54.7mmol) was added and the reaction was heated to 80°C overnight. Upon cooling, and completion of reaction monitored by TLC, precipitate was filtered to yield intermediate I7. Water was added to filtrate and resulting precipitant was also filtered to yield a second batch of intermediate I7. LC-MS (ES+) calcd for C 5 H 4 IN 5 (M+H) + 261.95, found 261.87.

[0820] Example 6: 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (I8): . In a 20mL scintillation vial, purchased pyrrolopyrimidine (1g, 7.45mmol) was dissolved in 7mL of chloroform. NIS (2.18g, 9.69mmol) was added and reaction was refluxed for 2 hours. Upon cooling, precipitate was filtered to yield intermediate I8. LC-MS (ES+) calcd for C 6 H 5 IN 4 (M+H) + 260.96, found 260.61. [0821] Example 7: 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (I9): . In a 20mL scintillation vial, purchased pyrrolopyrimidine (2g, 14.9mmol) was dissolved in 7mL of chloroform. NBS (3.5g, 19.38mmol) was added and reaction was refluxed for 2 hours. As dibromination was observed in addition to desired intermediate I9, silica gel chromatography (DCM/MeOH) was required to obtain desired intermediate I9. LC-MS (ES+) calcd for

C 6 H 5 BrN 4 (M+H) + 212.97, found 212.68, 214.68. Subsequent reactions also utilized commercial sources of I9. [0822] Scheme 2: Intermediate Coupling, Deprotection and Alkylation.

(X = Br, I) Process A Process B Process C (Y = N, H)

(Z = O, N, S, C) Process D Process E

(Y = N, H) [0823] Addition of alcohol, amine or thiol in the presence of catalyst generates ether (Process A), amine (Process B) and thioether (Process C) linked compounds respectively. Deprotection of t-butyl (Process D) followed by alkylation (Process E) generates advanced compounds with diversity at R 5 . Preparation can also proceed with R 5 already installed followed by catalyst assisted coupling. Representative procedures for each example follow. [0824] Example 8: 1-(tert-butyl)-3-(3-chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimid in-4-amine (GXJ-184). [0825] Process A : . Synthesis proceeds by Ullman coupling (Ma and Cai, Org Lett 2003). To an argon purged vial with magnetic stir bar is added intermediate I2 (85mg, 0.315mmol), 3-chlorophenol (60.7mg, 0.473mmol, 1.5eq), N,N-dimethylglycine (19.5mg, 0.189mmol, 0.6eq), and cesium carbonate (205.3mg, 0.63mmol, 2eq) in 1mL dioxane. After stirring for 5 minutes at room temperature is added copper iodide (12mg, 0.063mmol, 20mol%) and reaction is heated to 120C and stirred overnight. Reaction completion is monitored by LC/MS. After reaction is complete, water is added and compound is extracted with

dichloromethane. Purification is conducted using silica column with ethyl acetate– hexane to yield GXJ184 (60mgs, 60%). LC-MS (ES+) calcd for C 15 H 16 ClN 5 O (M+H) + 318.10, found 317.84. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.55 (t, J = 2.1 Hz, 1H), 7.47– 7.36 (m, 2H), 7.23 (ddd, J = 7.7, 2.0, 1.3 Hz, 1H), 1.66 (s, 9H). [0520] Example 9: 1-(tert-butyl)-N 3 -(naphthalen-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,4- diamine.

[0826] Process B: . Synthesis proceeds via Pd-assisted Buchwald coupling (Fors et al. JACS 2009) due to electron-rich indole presenting difficulty with Ullman coupling. To an 1 dram argon purged vial with magnetic stir bar is added intermediate I2 (50mg,

0.185mmol), 1-napthylamine (32mg, 0.223mmol), potassium tert-butoxide (56mg, 0.50mmol), and BrettPhosPd G3 (6mg, 3.6mol%) in 1mL dioxane and stirred at 90°C overnight. Reaction completion is monitored by LC/MS. After reaction is complete, reaction is purified by HPLC using acetonitrile– water in the presence of 0.1% formic acid yield product FUR 6-124 (<10%). LC-MS (ES+) calcd for C 19 H 20 N 6 (M+H) + 333.17, found 333.00. [0827] Example 10: 5-((3-chlorophenyl)thio)-7H-pyrrolo[2,3-d]pyrimidin-4-aminem ine. [0828] Process C: . Synthesis proceeds via Ullman coupling. To a 20mL argon purged scintillation vial with magnetic stir bar is added intermediate I8 (150mg,

0.577mmol), 3-chlorobenzenethiol (67uL, 0.557mmol), copper iodide (5.6mg, 0.029mmol), potassium carbonate (206mg, 1.49mmol), 2-propanol (1322uL, 17.3mmol), and ethylene glycol (166uL, 3mmol). Reaction is heated to 130°C for 1 hour and then cooled to room temperature for one hour. Purification by HPLC using acetonitrile– water in the presence of 0.1% formic acid yields intermediate 5-((3-chlorophenyl)thio)-7H-pyrrolo[2,3-d]pyrimidin-4-aminem ine (25.1mg, 15.7%). LC-MS (ES+) calcd for C 12 H 9 ClN 4 S (M+H) + 277.02, found 277.40.

[0829] Example 11: 3-((1H-indol-3-yl)thio)-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyr imidin-4- amine (FUR6-159).

[0830] Synthesis proceeds via Pd-assisted Buchwald coupling. In a 20mL argon-purged scintillation vial with magnetic stir bar was added

intermediate I3 (100mg, 0.370mmol), N,N-diisopropylethylamine (129uL, 0.740mmol), Pd(dba) 2 (10.6mg, 5mol%), XantPhos (10.7mg, 5mol%), and 3-mercaptoindole (55.2mg, 0.370mmol) in 1.5mL dioxane. Reaction was run overnight at 110°C and then cooled to room temperature. Purification by HPLC using acetonitrile– water in the presence of 0.1% formic acid yields FUR6-159. LC-MS (ES+) calcd for C 17 H 18 N 6 S (M+H) + 339.13, found 339.53. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.37– 7.29 (m, 1H), 7.04 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 6.96 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 1.60 (s, 9H). [0831] Example 12: 3-(3-chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [0832] Process D: . Synthesis proceeds easily through acid deprotection of GXJ184. In a vial with magnetic stir bar is added 1-(tert-butyl)-3-(3-chlorophenoxy)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (20mgs, 0.63mmol) formic acid (1mL) and hydrochloric acid (0.1mL). The solution is refluxed for 2 hours, cooled and intermediate 3-(3-chlorophenoxy)-1H- pyrazolo[3,4-d]pyrimidin-4-amine is purified by HPLC using acetonitrile– water with 0.1% formic acid. Yield 85% (14.2mg) LC/MS ES+ calcd for C 11 H 8 ClN 5 O (M+H) + 262.04, found 261.97. [0833] Example 13: 3-(3-chlorophenoxy)-1-((3,3-difluoropiperidin-4-yl)methyl)-1 H- pyrazolo[3,4-d]pyrimidin-4-amine (FUR7-27).

[0834] Process E: . Synthesis proceeds by alkylation of

pyrazolopyrimidine intermediate (Lourido Shokat and Sibley 2013 Journal of Medicinal Chemistry). In an argon purged 20mL scintillation vial vial with magnetic stir bar is added 3-(3- chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (225mgs, 0.860mmol), tert-butyl 4- (bromomethyl)-3,3-difluoropiperidine-1-carboxylate (311.6mg, 0.946mmol), and cesium carbonate (841mg, 2.58mmol) in 4.5mL dry DMF. Reaction is heated to 80°C overnight followed by cooling and the resulting tert-butyl 4-((4-amino-3-(3-chlorophenoxy)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3,3-difluoropiperidine -1-carboxylate intermediate is purified by silica chromatography with hexanes and 3:1 ethylacetate:ethanol. Boc deprotection with trifluoroacetic acid followed by HPLC yields FUR 7-27 (116mgs, 34.2%) LC/MS ES+ calcd for C 17 H 17 ClF 2 N 6 O (M+H) + 395.1, found 395.74. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.48– 7.26 (m, 3H), 7.19 (dd, J = 7.7, 1.9 Hz, 1H), 4.38 (dd, J = 14.1, 5.0 Hz, 1H), 4.12 (dd, J = 14.1, 9.2 Hz, 1H), 3.14– 2.96 (m, 1H), 2.88– 2.63 (m, 2H), 1.31 (ddd, J = 28.8, 10.4, 4.0 Hz, 2H), 1.10 (t, J = 7.3 Hz, 1H). [0835] Example 14: 3-(3-chlorophenoxy)-1-((1-methylpiperidin-4-yl)methyl)-1H-

pyrazolo[3,4-d]pyrimidin-4-amine (FUR7-30), . Synthesis proceeds by reductive alkylation of 3-(3-chlorophenoxy)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4 - d]pyrimidin-4-amine (GXJ237). In a 1 dram vial with magnetic stir bar, GJX237 (25mg, 0.070mmol) was dissolved in methanol (200uL). A solution of formaldehyde (52uL of 37%, 0.70mmol) in 2% acetic acid was added to the reaction and was stirred for 10 minutes at room temperature. Sodium cyanoborohydride (21.9mg, 0.349mmol) was added and the reaction was stirred for 3 hours at room temperature. Purification by HPLC using acetonitrile– water in the presence of 0.1% formic acid yields (FUR7-30). LC/MS ES+ calcd for C 18 H 21 ClN 6 O (M+H)+ 373.15, found 372.82. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d, J = 3.9 Hz, 2H), 7.41 (t, J = 2.2 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.30– 7.25 (m, 1H), 7.21– 7.14 (m, 1H), 3.97 (d, J = 7.1 Hz, 2H), 2.74 (dt, J = 12.2, 3.6 Hz, 2H), 2.14 (s, 3H), 2.01– 1.84 (m, 2H), 1.84– 1.62 (m, 1H), 1.45 – 1.33 (m, 2H), 1.24– 1.09 (m, 2H). [0836] Example 15: 1-(tert-butyl)-3-(3-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidi n-4-amine

(3ClB-PP1), . Compound was previously published and characterized (Lourido Shokat and Sibley 2013). [0837] Example 16: 3-(3-chlorobenzyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-

d]pyrimidin-4-amine (FUR6-157), . Compound was synthesized using processes D and E from 3ClB-PP1. LC/MS ES+ calcd for Chemical Formula: C 18 H 21 ClN 6 (M+H) + 357.15, found 357.57. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d, J = 2.3 Hz, 1H), 7.28– 7.21 (m, 2H), 7.19 (dd, J = 8.2, 1.8 Hz, 1H), 7.16– 7.09 (m, 1H), 4.30 (s, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.15 (dt, J = 13.0, 3.3 Hz, 2H), 2.74 (td, J = 12.7, 2.9 Hz, 2H), 2.12 (dtd, J = 15.4, 7.7, 4.5 Hz, 1H), 1.54 (dd, J = 14.2, 3.6 Hz, 2H), 1.39– 1.20 (m, 2H). [0838] Example 17: 1-(tert-butyl)-3-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-d]pyri midin-4-

amine (CZ75), . Compound was previously published and characterized (Lourido Shokat and Sibley 2013). [0839] Example 18: 3-(3,5-difluorobenzyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[ 3,4-

d]pyrimidin-4-amine (MLC468), .Compound was synthesized using process D and E from CZ75. LC/MS ES+ calcd for Chemical Formula: C 18 H 20 F 2 N 6 (M+H) + 359.17, found 359.27. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.06 (tt, J = 9.4, 2.4 Hz, 1H), 7.00 – 6.91 (m, 1H), 4.39 (s, 2H), 4.14 (d, J = 7.1 Hz, 2H), 3.10– 2.95 (m, 2H), 2.16– 1.96 (m, 1H), 1.46 (d, J = 13.0 Hz, 2H), 1.38 (d, J = 1.9 Hz, 1H), 1.28– 1.09 (m, 2H). [0840] Example 19: 1-(tert-butyl)-N 3 -(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,4-

diamine (LZH118), . LC/MS ES+ calcd for Chemical Formula: C 15 H 17 ClN 6 (M+H) + 317.12, found 317.35. 1 H NMR (CDCl 3 ) δ 8.33 (1H), 7.20– 7.17 (2H), 7.02– 6.90 (2H), 6.78-6.76 (1H), 6.10 (1H), 5.28 (2H), 1.80 (9H). [0841] Example 20: N 3 -(3-chlorophenyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo [3,4-

d]pyrimidine-3,4-diamine (GXJ276), . LC/MS ES+ calcd for Chemical Formula: C 17 H 20 ClN 7 (M+H) + 358.15, found 358.06. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.11 (s, 1H), 7.83 (t, J = 2.1 Hz, 1H), 7.62 (s, 2H), 7.58 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 6.89 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.14– 3.02 (m, 2H), 2.64 (td, J = 12.4, 2.7 Hz, 2H), 2.08 (ddt, J = 11.4, 7.8, 3.8 Hz, 1H), 1.89 (s, 1H), 1.57 (d, J = 12.8 Hz, 2H), 1.27 (dd, J = 13.1, 3.8 Hz, 2H). [0842] Example 21: 1-(tert-butyl)-3-((3-chlorophenyl)thio)-1H-pyrazolo[3,4-d]py rimidin-4-

amine (GXJ186), . LC/MS ES+ calcd for Chemical Formula: C 15 H 16 ClN 5 S (M+H) + 334.08, found 333.98. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.38– 7.26 (m, 3H), 7.09 (dt, J = 7.7, 1.4 Hz, 1H), 1.75 (s, 9H). [0843] Exam le 22: 1- tert-but l -3-(m-tolylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

(FUR7-68), pound was synthesized using process C from intermediate I3 similar to example 11. LC/MS ES+ calcd for Chemical Formula: C 16 H 19 N 5 S (M+H) + 314.14, found 314.52. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.04 (ddt, J = 7.6, 1.8, 0.9 Hz, 1H), 6.95 (ddt, J = 7.8, 1.8, 0.8 Hz, 1H), 2.24 (s, 3H), 1.74 (s, 9H).

[0844] Example 23: 5-((3-chlorophenyl)thio)-7-(piperidin-4-ylmethyl)-7H-pyrrolo [2,3-

d]pyrimidin-4-amine (FUR6-139) , . Compound was synthesized using Process E from intermediate in example 10. LC/MS ES+ calcd for Chemical Formula:

C 18 H 20 ClN 5 S (M+H) + 374.11, found 374.43. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 2H), 8.09 (s, 1H), 7.67 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.7, 2.0 Hz, 1H), 7.01 (t, J = 1.9 Hz, 1H), 6.99– 6.94 (m, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.06 (d, J = 12.1 Hz, 2H), 2.58 (t, J = 11.9 Hz, 2H), 2.03 (s, 1H), 1.46 (d, J = 13.0 Hz, 2H), 1.30– 1.14 (m, 2H). [0845] Example 24: 1-(tert-butyl)-3-(3-(trifluoromethyl)phenoxy)-1H-pyrazolo[3, 4-

d]pyrimidin-4-amine (GXJ178): . LC/MS ES+ calcd for Chemical

Formula: C 16 H 16 F 3 N 5 O (M+H) + 352.13, found 351.94. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.90 (t, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.3, 2.4 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.57– 7.51 (m, 1H), 1.66 (s, 9H). [0846] Exam le 25: 1- tert-butyl)-3-(m-tolyloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ami ne

(GXJ176 LC/MS ES+ calcd for Chemical Formula: C 16 H 19 N 5 O (M+H)+ 298.16, found 298.27. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.20– 7.07 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 2.32 (s, 3H), 1.65 (s, 9H). [0847] Exam le 26: 3- 3-bromophenoxy)-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4 -amine

(GXJ177): . LC/MS ES+ calcd for Chemical Formula: C 15 H 16 BrN 5 O (M+H)+ 362.05, found 362.30, 364.11. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.72– 7.67 (m, 1H), 7.48– 7.33 (m, 3H), 1.66 (s, 9H). [0848] Example 27: 1-(tert-butyl)-3-(3-methoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimi din-4-

amine (GXJ230):

(M+H) + 314.15, found 314.13. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.29 (t, J = 8.2 Hz, 1H), 7.03 (t, J = 2.4 Hz, 1H), 6.93 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H), 6.74 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H), 3.76 (s, 3H), 1.66 (s, 9H). [0849] Example 28: 1-(tert-butyl)-3-(3,5-difluorophenoxy)-1H-pyrazolo[3,4-d]pyr imidin-4-

amine (GXJ229): . LC/MS ES+ calcd for Chemical Formula: C 15 H 15 F 2 N 5 O (M+H) + 320.12, found 320.20 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.29– 7.22 (m, 2H), 7.07 (d, J = 2.3 Hz, 1H), 1.67 (s, 9H). [0850] Example 29: 3-(3-chlorophenoxy)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4 -

d]pyrimidin-4-amine (GXJ237): . Compound was synthesized using Process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 17 H 19 ClN 6 O (M+H) + 359.13, found 359.08. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.46 (t, J = 2.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.31 (ddd, J = 8.3, 2.4, 1.1 Hz, 1H), 7.20 (dt, J = 8.0, 1.5 Hz, 1H), 4.04 (s, 2H), 3.15 (dt, J = 13.0, 3.5 Hz, 2H), 2.73 (td, J = 12.7, 3.0 Hz, 2H), 2.04 (dtt, J = 14.9, 7.1, 2.9 Hz, 1H), 1.64– 1.49 (m, 2H), 1.28 (qd, J = 12.6, 4.0 Hz, 2H). [0851] Example 30: 3-(3-chloro-4-fluorophenoxy)-1-(piperidin-4-ylmethyl)-1H-pyr azolo[3,4-

d]pyrimidin-4-amine (GXJ261): . LC/MS ES+ calcd for Chemical Formula: C 17 H 18 ClFN 6 O (M+H) + 377.12, found 376.88. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.03 (s, 2H), 8.19 (s, 1H), 7.79– 7.71 (m, 1H), 7.53– 7.44 (m, 2H), 4.08 (d, J = 6.9 Hz, 2H), 3.18 (dt, J = 11.5, 2.9 Hz, 2H), 2.77 (td, J = 12.6, 3.0 Hz, 2H), 2.10 (dt, J = 7.5, 3.7 Hz, 1H), 1.61 (dd, J = 14.2, 3.5 Hz, 2H), 1.44 (tt, J = 12.2, 6.3 Hz, 2H). [0852] Example 31: 3-(3-chlorophenoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-

d]pyrimidin-4-amine (FUR6-6), . Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 17 H 13 ClN 6 O (M+H) + 353.08, found 353.14. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (d, J = 5.0 Hz, 2H), 8.15 (s, 1H), 7.45 (t, J = 2.1 Hz, 1H), 7.40– 7.29 (m, 2H), 7.19 (dt, J = 7.8, 1.8 Hz, 1H), 7.08– 7.01 (m, 2H), 5.38 (s, 2H). [0853] Example 32: 3-(3-chlorophenoxy)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[3,4 -

d]pyrimidin-4-amine (FUR6-11), . Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 17 H 19 ClN 6 O (M+H) + 359.13, found 359.52. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.46 (t, J = 2.1 Hz, 1H), 7.43– 7.30 (m, 2H), 7.20 (dt, J = 7.8, 1.6 Hz, 1H), 4.15– 3.97 (m, 2H), 3.13– 2.90 (m, 2H), 2.71– 2.49 (m, 2H), 2.15 (td, J = 7.9, 4.2 Hz, 1H), 1.74– 1.37 (m, 3H), 1.21– 1.05 (m, 1H). [0854] Example 33: 3-(3-chlorophenoxy)-1-(pyrrolidin-3-ylmethyl)-1H-pyrazolo[3, 4-

d]pyrimidin-4-amine (FUR6-13), . Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 16 H 17 ClN 6 O (M+H) + 345.11, found 345.43. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.55 (t, J = 2.2 Hz, 1H), 7.51– 7.35 (m, 2H), 7.28 (dt, J = 7.8, 1.5 Hz, 1H), 4.27 (qd, J = 14.1, 7.0 Hz, 2H), 3.22 (td, J = 11.2, 10.7, 6.2 Hz, 2H), 3.08 (dt, J = 11.4, 7.9 Hz, 1H), 2.95 (dd, J = 11.6, 7.9 Hz, 1H), 2.84– 2.58 (m, 1H), 2.03– 1.82 (m, 1H), 1.73– 1.53 (m, 1H). [0855] Example 34: 1-(azetidin-3-ylmethyl)-3-(3-chlorophenoxy)-1H-pyrazolo[3,4-

d]pyrimidin-4-amine (FUR6-12), .Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 15 H 15 ClN 6 O (M+H) + 331.10, found 331.44. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.49 (t, J = 2.1 Hz, 1H), 7.40– 7.31 (m, 2H), 7.20 (dt, J = 7.7, 1.6 Hz, 1H), 4.33 (d, J = 6.6 Hz, 2H), 3.94– 3.59 (m, 4H), 3.11 (s, 1H).

[0856] Example 35: 4-((4-amino-3-(3-chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin- 1-

yl)methyl)piperidin-2-one (FUR7-36), .Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula:

C 15 H 15 ClN 6 O (M+H) + 373.11, found 373.23. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.45 (t, J = 2.2 Hz, 1H), 7.41– 7.34 (m, 2H), 7.31 (dd, J = 8.2, 2.3 Hz, 1H), 7.22– 7.17 (m, 1H), 4.05 (d, J = 7.0 Hz, 2H), 3.09 (ddt, J = 12.3, 6.2, 3.6 Hz, 1H), 2.98 (td, J = 11.4, 4.5 Hz, 1H), 2.32– 2.18 (m, 1H), 2.01 (ddd, J = 17.3, 5.4, 1.5 Hz, 1H), 1.86 (dd, J = 17.3, 10.5 Hz, 1H), 1.58 (dd, J = 13.4, 3.8 Hz, 1H), 1.29 (d, J = 9.6 Hz, 1H). [0857] Example 36: 3-(3-chlorophenoxy)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-

pyrazolo[3,4-d]pyrimidin-4-amine (FUR7-89), .Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 17 H 18 ClN 5 O 2 (M+H) + 360.11, found 360.92. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.50– 7.26 (m, 3H), 7.19 (dt, J = 8.0, 1.4 Hz, 1H), 4.00 (d, J = 7.1 Hz, 2H), 3.73 (ddd, J = 11.5, 4.5, 1.9 Hz, 2H), 3.15 (td, J = 11.7, 2.1 Hz, 2H), 2.00 (ddq, J = 11.3, 7.8, 3.9 Hz, 1H), 1.32 (dd, J = 13.8, 3.3 Hz, 2H), 1.16 (qd, J = 12.0, 4.4 Hz, 2H). [0858] Example 37: 1-(piperidin-4-ylmethyl)-3-(m-tolylthio)-1H-pyrazolo[3,4-d]p yrimidin-4-

amine (FUR7-77), .Compound was synthesized starting from intermediate I7 followed by Process C similar to Example 10 and followed by Process E similar to example 13. LC/MS ES+ calcd for Chemical Formula: C 18 H 22 N 6 S (M+H) + 355.16, found 355.91. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.09– 6.89 (m, 2H), 4.21 (d, J = 6.6 Hz, 1H), 3.14 (s, 2H), 2.72 (d, J = 12.8 Hz, 2H), 2.16 (s, 3H), 1.54 (d, J = 12.7 Hz, 2H), 1.37 – 1.21 (m, 3H). [0859] Example 38: 3-((3-chlorophenyl)thio)-1-(piperidin-4-ylmethyl)-1H-pyrazol o[3,4-

d]pyrimidin-4-amine (FUR5-56), . Compound was synthesized starting from intermediate I7 followed by Process C similar to Example 10 and followed by Process E similar to example 13. LC/MS ES+ calcd for Chemical Formula: C 17 H 19 ClN 6 S (M+H) + 375.11, found 375.56. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J = 11.3 Hz, 1H), 8.26 (s, 1H), 7.32– 7.22 (m, 3H), 7.13 (dt, J = 7.6, 1.7 Hz, 1H), 4.26 (d, J = 7.0 Hz, 2H), 3.19 (d, J = 12.4 Hz, 2H), 2.87– 2.71 (m, 2H), 2.18 (ddp, J = 11.0, 7.2, 3.6 Hz, 1H), 1.64– 1.54 (m, 2H), 1.33 (qd, J = 12.5, 4.0 Hz, 2H) [0860] Example 39: 3-((3-chlorophenyl)thio)-1-((3,3-difluoropiperidin-4-yl)meth yl)-1H-

pyrazolo[3,4-d]pyrimidin-4-amine (FUR7-76), . Compound was synthesized starting from intermediate I7 followed by Process C similar to Example 10 and followed by Process E similar to example 13. LC/MS ES+ calcd for Chemical Formula: C 17 H 17 ClF 2 N 6 S (M+H) + 411.09, found 411.88. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.33 – 7.18 (m, 3H), 7.10 (dt, J = 7.6, 1.6 Hz, 1H), 4.61 (dd, J = 14.0, 5.3 Hz, 1H), 4.28 (dd, J = 14.0, 8.9 Hz, 1H), 2.96 (td, J = 12.6, 4.6 Hz, 1H), 2.83– 2.51 (m, 3H), 1.30 (td, J = 10.7, 9.8, 3.8 Hz, 2H). [0861] Example 40: 3-(3-chlorophenoxy)-1-((1-(trifluoromethyl)cyclopropyl)methy l)-1H-

pyrazolo[3,4-d]pyrimidin-4-amine (FUR7-2), . Compound was synthesized using process E from intermediate in example 12. LC/MS ES+ calcd for Chemical Formula: C 16 H 13 ClF 3 N 5 O (M+H) + 384.08, found 383.76. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.46 (t, J = 2.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.2, 2.3 Hz, 1H), 7.23– 7.16 (m, 1H), 4.38 (s, 2H), 1.05 (d, J = 5.3 Hz, 2H), 0.96 (t, J = 3.5 Hz, 2H). [0862] Example 41: 3-(benzo b thio hen-3- lmethyl)-1-(tert-butyl)-1H-pyrazolo[3,4-

d]pyrimidin-4-amine (CZ43), Compound was synthesized using synthetic methods previously described (Sebastian Sibley and Shokat 2013). LC/MS ES+ calcd for Chemical Formula: C 18 H 19 N 5 S (M+H) + 338.14, found 338.29. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 8.05– 8.00 (m, 1H), 7.98– 7.92 (m, 1H), 7.42 (d, J = 1.1 Hz, 1H), 7.37 (tt, J = 7.2, 5.5 Hz, 2H), 4.55 (d, J = 1.2 Hz, 2H), 1.70 (s, 9H). [0863] Example 42: 3-(benzofuran-3-ylmethyl)-1-(tert-butyl)-1H-pyrazolo[3,4-d]p yrimidin-4-

amine (LJQ145), . Compound was synthesized using synthetic methods previously described (Sebastian Sibley and Shokat 2013). LC/MS ES+ calcd for Chemical Formula: C 18 H 19 N 5 O (M+H) + 321.16, found 321.36. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.91 (d, J = 1.1 Hz, 1H), 7.61 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H), 7.52 (dt, J = 8.2, 0.9 Hz, 1H), 7.27 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.19 (td, J = 7.5, 1.0 Hz, 1H), 4.39 (d, J = 1.2 Hz, 2H), 1.70 (s, 9H). [0864] Example 43: 3-((1H-indol-3-yl)methyl)-1-(tert-butyl)-1H-pyrazolo[3,4-d]p yrimidin-4-

amine (LJQ138), . Compound was synthesized using synthetic methods previously described (Sebastian Sibley and Shokat 2013). LC/MS ES+ calcd for Chemical Formula: C 18 H 20 N 6 (M+H) + 321.17, found 322.38. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 8.07 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35– 7.27 (m, 2H), 7.03 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.95– 6.86 (m, 1H), 4.36 (s, 2H), 1.72 (s, 6H). [0865] Example 44: 3-((1H-indol-3-yl)methyl)-1-((1-(trifluoromethyl)cyclopropyl )methyl)-

1H-pyrazolo[3,4-d]pyrimidin-4-amine (WXT-2), . Compound was synthesized using processes D and E from LJQ138. LC/MS ES+ calcd for Chemical Formula: C 19 H 17 F 3 N 6 (M+H) + 387.15. 1 H NMR (CDCl 3 ) δ 8.29 (1H), 7.55– 7.53 (1H), 7.42– 7.40 (1H), 7.25– 7.23 (1H), 7.14– 7.11 (1H), 6.97– 6.96 (1H), 4.68 (2H), 4.42 (2H), 1.11– 1.08 (4H) [0866] Example 45: 3-((1H-indol-3-yl)methyl)-1-(piperidin-4-ylmethyl)-1H-pyrazo lo[3,4-

d]pyrimidin-4-amine (FUR6-95), . Compound was synthesized using processes D and E from LJQ138. LC/MS ES+ calcd for Chemical Formula: C 20 H 23 N 7 (M+H)+ 362.20, found 362.64. [0867] Example 46: 3-((1H-indol-3-yl)thio)-1-(piperidin-4-ylmethyl)-1H-pyrazolo [3,4-

d]pyrimidin-4-amine (FUR5-57) , . Compound was synthesized starting from intermediate I7 followed by Process C similar to Example 10 and followed by Process E similar to example 13. LC/MS ES+ calcd for Chemical Formula: C 19 H 21 N 7 S (M+H) + 380.16, found 380.48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.05 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.94 (td, J = 7.5, 7.0, 0.9 Hz, 1H), 4.07 (d, 2H), 3.01 (d, J = 12.3 Hz, 2H), 2.65– 2.49 (m, 2H), 2.00 (dtd, J = 11.1, 7.4, 3.7 Hz, 1H), 1.39 (d, J = 13.3 Hz, 2H), 1.20 (tt, J = 13.2, 7.0 Hz, 2H).

[0868] NMR data for FUR 6-160: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.37– 7.29 (m, 1H), 7.04 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 6.96 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 1.60 (s, 9H).

[0869] NMR data for FUR 6NMR data for FUR 6-161: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.18 (s, 1H), 7.47– 7.34 (m, 2H), 7.17– 7.04 (m, 2H), 4.19 (d, J = 6.8 Hz, 2H), 3.16– 2.97 (m, 2H), 2.62 (td, J = 12.5, 2.8 Hz, 2H), 2.07 (qd, J = 7.6, 4.1 Hz, 1H), 1.54 (dd, J = 14.0, 3.5 Hz, 2H), 1.28 (qd, J = 12.5, 3.9 Hz, 2H).

[0870] NMR data for FUR 6-162: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 7.78 (s, 1H), 7.35 (dt, J = 6.0, 3.6 Hz, 2H), 7.09– 6.98 (m, 2H), 4.87 (hept, J = 6.6 Hz, 1H), 1.41 (d, J = 6.8 Hz, 6H).

[0871] NMR data for FUR 6-162B: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (s, 1H), 7.91 (s, 1H), 7.71– 7.61 (m, 1H), 7.55– 7.46 (m, 1H), 7.13 (pd, J = 7.2, 1.4 Hz, 2H), 6.97 (s, 2H), 5.24 (hept, J = 6.8 Hz, 1H), 4.85 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H), 1.36 (d, J = 6.8 Hz, 6H).

[0872] NMR data for FUR 6-141: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.22 (s, 1H), 7.95 (d, J = 13.2 Hz, 1H), 7.70– 7.53 (m, 2H), 7.45 (d, J = 9.6 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 3.96 (dd, J = 29.9, 6.6 Hz, 2H), 3.06 (s, 2H), 2.66– 2.54 (m, 2H), 1.93 (s, 1H), 1.46 (dd, J = 25.1, 13.1 Hz, 2H), 1.21 (s, 2H).

[0873] NMR data for HYC29: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.51 (t, J = 2.2 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.37 (ddd, J = 8.4, 2.4, 1.0 Hz, 1H), 7.25 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 4.93 (hept, J = 6.6 Hz, 1H), 1.39 (d, J = 6.7 Hz, 6H). [0874] Compound FUR 6-157 was synthesized according to process E. NMR data for FUR 6-

157: . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d, J = 2.3 Hz, 1H), 7.28– 7.21 (m, 2H), 7.19 (dd, J = 8.2, 1.8 Hz, 1H), 7.16– 7.09 (m, 1H), 4.30 (s, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.15 (dt, J = 13.0, 3.3 Hz, 2H), 2.74 (td, J = 12.7, 2.9 Hz, 2H), 2.12 (dtd, J = 15.4, 7.7, 4.5 Hz, 1H), 1.54 (dd, J = 14.2, 3.6 Hz, 2H), 1.39– 1.20 (m, 2H). [0875] NMR data for compound FUR 6-139, . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 2H), 8.09 (s, 1H), 7.67 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.7, 2.0 Hz, 1H), 7.01 (t, J = 1.9 Hz, 1H), 6.99– 6.94 (m, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.06 (d, J = 12.1 Hz, 2H), 2.58 (t, J = 11.9 Hz, 2H), 2.03 (s, 1H), 1.46 (d, J = 13.0 Hz, 2H), 1.30– 1.14 (m, 2H).

[0876] Compound GXJ-184, , was synthesized according to process A. The LC-MS ES + for GXJ-184 was 318.10 (317.84) (observed).

[0877] The NMR data for compound GXJ-176, , is 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.20– 7.07 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 2.32 (s, 3H), 1.65 (s, 9H).

[0878] The compound GXJ-237, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.46 (t, J = 2.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.31 (ddd, J = 8.3, 2.4, 1.1 Hz, 1H), 7.20 (dt, J = 8.0, 1.5 Hz, 1H), 4.04 (s, 2H), 3.15 (dt, J = 13.0, 3.5 Hz, 2H), 2.73 (td, J = 12.7, 3.0 Hz, 2H), 2.04 (dtt, J = 14.9, 7.1, 2.9 Hz, 1H), 1.64– 1.49 (m, 2H), 1.28 (qd, J = 12.6, 4.0 Hz, 2H).

[0879] The compound FUR 6-6, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (d, J = 5.0 Hz, 2H), 8.15 (s, 1H), 7.45 (t, J = 2.1 Hz, 1H), 7.40– 7.29 (m, 2H), 7.19 (dt, J = 7.8, 1.8 Hz, 1H), 7.08– 7.01 (m, 2H), 5.38 (s, 2H).

[0880] The compound FUR 6-11, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.55 (t, J = 2.2 Hz, 1H), 7.51– 7.35 (m, 2H), 7.28 (dt, J = 7.8, 1.5 Hz, 1H), 4.27 (qd, J = 14.1, 7.0 Hz, 2H), 3.22 (td, J = 11.2, 10.7, 6.2 Hz, 2H), 3.08 (dt, J = 11.4, 7.9 Hz, 1H), 2.95 (dd, J = 11.6, 7.9 Hz, 1H), 2.84– 2.58 (m, 1H), 2.03– 1.82 (m, 1H), 1.73– 1.53 (m, 1H).

[0881] The compound FUR 6-13, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.55 (t, J = 2.2 Hz, 1H), 7.51– 7.35 (m, 2H), 7.28 (dt, J = 7.8, 1.5 Hz, 1H), 4.27 (qd, J = 14.1, 7.0 Hz, 2H), 3.22 (td, J = 11.2, 10.7, 6.2 Hz, 2H), 3.08 (dt, J = 11.4, 7.9 Hz, 1H), 2.95 (dd, J = 11.6, 7.9 Hz, 1H), 2.84– 2.58 (m, 1H), 2.03– 1.82 (m, 1H), 1.73– 1.53 (m, 1H).

[0882] The compound FUR 6-12, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.49 (t, J = 2.1 Hz, 1H), 7.40– 7.31 (m, 2H), 7.20 (dt, J = 7.7, 1.6 Hz, 1H), 4.33 (d, J = 6.6 Hz, 2H), 3.94– 3.59 (m, 4H), 3.11 (s, 1H).

[0883] The compound FUR 7-27, , was synthesized according to process A (D, E). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.48– 7.26 (m, 3H), 7.19 (dd, J = 7.7, 1.9 Hz, 1H), 4.38 (dd, J = 14.1, 5.0 Hz, 1H), 4.12 (dd, J = 14.1, 9.2 Hz, 1H), 3.14– 2.96 (m, 1H), 2.88– 2.63 (m, 2H), 1.31 (ddd, J = 28.8, 10.4, 4.0 Hz, 2H), 1.10 (t, J = 7.3 Hz, 1H).

[0884] The compound 7-30, , was synthesized according to process E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d, J = 3.9 Hz, 2H), 7.41 (t, J = 2.2 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.30– 7.25 (m, 1H), 7.21– 7.14 (m, 1H), 3.97 (d, J = 7.1 Hz, 2H), 2.74 (dt, J = 12.2, 3.6 Hz, 2H), 2.14 (s, 3H), 2.01– 1.84 (m, 2H), 1.84– 1.62 (m, 1H), 1.45– 1.33 (m, 2H), 1.24– 1.09 (m, 2H). [0885] The compound FUR 7-36, , was synthesized according to process E.

[0886] The compound FUR 7-89, , was synthesized according to process E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.50– 7.26 (m, 3H), 7.19 (dt, J = 8.0, 1.4 Hz, 1H), 4.00 (d, J = 7.1 Hz, 2H), 3.73 (ddd, J = 11.5, 4.5, 1.9 Hz, 2H), 3.15 (td, J = 11.7, 2.1 Hz, 2H), 2.00 (ddq, J = 11.3, 7.8, 3.9 Hz, 1H), 1.32 (dd, J = 13.8, 3.3 Hz, 2H), 1.16 (qd, J = 12.0, 4.4 Hz, 2H).

[0887] The compound FUR 7-77, , was synthesized according to process C, E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.09– 6.89 (m, 2H), 4.21 (d, J = 6.6 Hz, 1H), 3.14 (s, 2H), 2.72 (d, J = 12.8 Hz, 2H), 2.16 (s, 3H), 1.54 (d, J = 12.7 Hz, 2H), 1.37– 1.21 (m, 3H). [0888] The compound FUR 5-56, , was synthesized according to process C, E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J = 11.3 Hz, 1H), 8.26 (s, 1H), 7.32– 7.22 (m, 3H), 7.13 (dt, J = 7.6, 1.7 Hz, 1H), 4.26 (d, J = 7.0 Hz, 2H), 3.19 (d, J = 12.4 Hz, 2H), 2.87– 2.71 (m, 2H), 2.18 (ddp, J = 11.0, 7.2, 3.6 Hz, 1H), 1.64– 1.54 (m, 2H), 1.33 (qd, J = 12.5, 4.0 Hz, 2H).

[0889] The compound FUR 7-76, , was synthesized according to process C, E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.33– 7.18 (m, 3H), 7.10 (dt, J = 7.6, 1.6 Hz, 1H), 4.61 (dd, J = 14.0, 5.3 Hz, 1H), 4.28 (dd, J = 14.0, 8.9 Hz, 1H), 2.96 (td, J = 12.6, 4.6 Hz, 1H), 2.83– 2.51 (m, 3H), 1.30 (td, J = 10.7, 9.8, 3.8 Hz, 2H).

[0890] The compound FUR 7-2, , was synthesized according to process A. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.46 (t, J = 2.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.2, 2.3 Hz, 1H), 7.23– 7.16 (m, 1H), 4.38 (s, 2H), 1.05 (d, J = 5.3 Hz, 2H), 0.96 (t, J = 3.5 Hz, 2H). [0891] The NMR data for compound LJQ-138, , is: 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 8.07 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35– 7.27 (m, 2H), 7.03 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.95– 6.86 (m, 1H), 4.36 (s, 2H), 1.72 (s, 6H).

[0892] The compound FUR 5-57, , was synthesized according to process C, E. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.05 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.94 (td, J = 7.5, 7.0, 0.9 Hz, 1H), 4.07 (d, 2H), 3.01 (d, J = 12.3 Hz, 2H), 2.65– 2.49 (m, 2H), 2.00 (dtd, J = 11.1, 7.4, 3.7 Hz, 1H), 1.39 (d, J = 13.3 Hz, 2H), 1.20 (tt, J = 13.2, 7.0 Hz, 2H).

[0893] The compound FUR 6-159, , was synthesized according to process C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.37– 7.29 (m, 1H), 7.04 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 6.96 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 1.60 (s, 9H). [0894] Compound and characterization table.

Example B: Expression and purification of active kinases

[0895] Full length CDPK1 was PCR amplified from a T. gondii RH cDNA library generated using the SMART cDNA synthesis kit (Clontech). The primers contained restriction sites that were used to directionally clone the PCR product, NdeI to XhoI, into the pET-22b(+) vector, in frame with a C-terminal hexahistidine tag. Single mutation of the codon corresponding to glycine 128 was achieved using the QuikChange II Site-Directed Mutagenesis Kit (Agilent

Technologies), with specific primers designed according to manufacturer instructions. Plasmids were transformed into BL21(DE3)V2RpAcYc-LIC+LamP E. coli, which express the LamP phosphatase, as described previously. Following overnight growth in Terrific Broth at 37°C, cells were diluted 1:50 in fresh medium and cultured for 3 h at 37°C, then cooled to 15°C, induced by addition of 1 mM IPTG, and cultured overnight. Cells were lysed in CelLyticB solution (Sigma Aldrich), and proteins purified using HIS-select Nickel Affinity Gel following manufacturers instructions (Sigma-Aldrich). Purified proteins were dialyzed (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.125% Chelex 100) and stored in 20% glycerol at -80°C. Protein purity and concentration were determined by SDS-PAGE followed by staining with SYPRO Ruby (Invitrogen). [0896] Kinase assays were conducted using a peptide-based ELISA based on the syntide-2 peptide (Calbiochem). Syntide-2 peptide (10 mg/ml) was used to coat 96-well plates by overnight incubation in carbonate coating buffer (pH 9.6) at 4°C. Following washing in Tris tween (50 mM Tris-HCl, pH 7.5, 0.2% Tween20), plates were blocked with 3% BSA in Tris- tween for 2 h at room temperature, and further washing steps were conducted with Tris-tween. Kinase reactions were conducted at 30°C for 20 min in kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 2.5 mM CaCl2, 0.1 mM EGTA, 0.005% Tween20) containing appropriate amounts of ATP (Km for each enzyme) and enzyme dilutions (see below).

Phosphorylated syntide peptides were detected with mAb MS-6E6 (MBL Intl. Corp.,), followed by peroxidase-conjugated goat-anti-mouse IgG, developed with the substrate 3,3′,5,5′- Tetramethylbenzidine (TMB) and detected by absorbance at 450 nm. The activity of human calmodulin dependent kinase II alpha (αCaMKII) was tested using the CaM Kinase II Assay CycLex kit (MBL Intl. Corp.,). [0897] For testing CDPK1, purified enzymes were tested with increasing amounts of purified enzyme added to establish their half-maximal activity from a dose-response curve. The Km for ATP was determined for each enzyme tested at its half-maximum and by serial dilution of ATP. The sensitivity of CDPK1 forms were tested at their individual half-maximal activities and Km values for ATP. Samples were conducted in triplicate for all assays. For screening different compounds, serial dilutions of compounds were under the optimized conditions for CDPK1. Data were analyzed using Prism (GraphPad) to determine IC 50 values by plotting normalized, log-transformed data (X axis), using non-linear regression analysis as a sigmoidal dose response curve with variable slope. [0898] CDPKs are a plant-like family of kinases that is not found in humans, but found in a variety of apicomplexan parasites. CDPK1 is one member of the kinase family and it is an essential gene in T. gondii. CDPK1 is a target of inhibitors of the compounds as described herein because it has a glycine gatekeeper. Other CDPKs may also show sensitivity to some of these inhibitors and thus may be targets for treatment of parasitic infection. For example, T. gondii (TgCDPK1), N. caninum Liverpool (NcCDPK1), C. parvum Iowa II (CpCDPK1), all have glycine gatekeepers. Additional CDPK targets include P. falciparum (PfCDPK4) and Toxo. gondi mutant G128S (TgG128SCDPK1), both of which have serine gatekeeper residues. Targets with Threonine gatekeepers include P. falciparum 3d7 (PfCDPK1), B. bovis T2Bo (BbCDPK4), E. tanella (EtCDPK1), and Toxo. gondi mutant G128S (TgG128TCDPK1). [0899] For example, CDPK1 in Cryptosporidium parvum, Cryptosporidium hominis, Neospora caninum, and Sarcocystis neurona, share features of the ATP binding pocket with CDPK1 in Toxoplasma gondii and thus are likely to be inhibited by the compounds described here. Other CDPKs that are important in parasite biology and which may also be susceptible include: CPKD1 in Plasmodium falciparum, this enzyme is important in red cell invasion by merozpotes as well as development of ookinetes on the mosquito. CDPK6 in Toxoplasma gondii, this enzyme is important in cell division. CPKD2 in Toxoplasma gondii, this enzyme is important in carbohydrate metabolism in bradyzoites. Example C: Inhibition of parasite growth in vitro

[0900] Inhibition of parasite growth was determined using the 2F clone of the type I RH strain that expresses the E. coli β-galactoside enzyme (β-Gal), as described previously. Compounds were dissolved in DMSO at 10 mM stock and diluted in medium containing 1% DMSO, which also served as a no compound control. Freshly harvested parasites were mixed with compounds and preincubated for 20 min at room temperature before being used to challenge confluent monolayers of human foreskin fibroblasts (HFF) grown in 96-well plates containing DMEM supplemented with 10% FBS. All samples were tested in triplicate. Following addition of 5×10 2 parasites / well containing dilutions of compounds and/or 1% DMSO, plates were centrifuged at ~ 300 g for 5 min and returned to culture at 37°C, 5% CO 2. HFF cultures were challenged with parasites and compound dilutions, washed in warm PBS after 2, 4, 24 and 48 hours, and returned to culture in DMEM supplemented with 10% FBS at 37°C, 5% CO 2 . To compare the effects of different compounds, HFF cultures were challenged with parasites and compound dilutions, washed in warm PBS after 4 h, and returned to culture in DMEM supplemented with 10% FBS at 37°C, 5% CO 2 . Replication was stopped at 72 h by addition of 1% Triton X-100 and β-gal activity was determined following addition of 1 mM chlorophenol red-β-D-galactopyranoside and monitoring of absorbtion at 570 nm, as described previously. Data were analyzed using Prism (GraphPad) to determine EC 50 values by plotting normalized, log-transformed data (X axis), using non-linear regression analysis as a sigmoidal dose response curve with variable slope. [0901] A conditional knockout strain of CDPK1 (CDPK1-cKO), which expresses CDP1 under control of a tet-off promoter, complemented with either wild type or G 128 M CDPK1 expressed under its endogenous promoter, is used to assess the specificity of compounds. Parasite strains are grown for 72 h in the presence of 1 μg/ml anhydrotetracycline (ATc; Clontech), and kept in the presence of ATc for the course of the assay. Parasites are harvested and incubated 20 min at 37°C in DMEM containing 10% FBS and different compound concentrations or vehicle control (1 % DMSO). Confluent monolayers of HFF cells in 96-well plates are infected with the pre- treated parasites at a concentration of 10 5 per well, and sedimented onto the host cells by centrifugation at 300g for 2 minutes. Infection is allowed to proceed at 37°C, 5% CO 2 , for 1 hour, prior to rinsing the monolayers 5 times with 37°C PBS to remove extracellular parasites. DMEM containing 10% FBS and 1 μg/ml ATc is added to all wells, and parasites are allowed to replicate for 72 hours. Host cell lysis is quantified by staining monolayers with crystal violet and measuring the absorbance at 570 nm. [0902] The stability of compounds in vitro was tested in using rat liver microsomes as performed by Absorption Systems Inc (Exton, PA). In brief, compounds were mixed with rat liver microsomes activated with 1 mM NADPH and loss of compound was followed at 10, 20, 30 and 60 min. The percentages of remaining compounds were calculated from the peak area ratio vs. standard for each starting compound by LC-MS. The half-life was estimated as t 1/2 = 0.693 / K, where K is the slope of a plot of the natural log of percent of remaining compound vs. time. The intrinsic clearance (Cl int ) was calculated as k/D, where K is defined above and D is the protein concentration in the microsome preparation. LogP was estimated using ChemDraw Ultra. [0903] Table 1. Physical parameters and in vitro activities of select compounds. 1 Apparent permeability (Papp), apical to basolateral (A-B). 2 Apparent permeability (Papp) basolateral to apical (B-A). 3 Papp (B to A) / Papp (A to B). 4 CI Iint = k/P, where k is the elimination rate constant and P is the protein concentration in the assay. 5 Inhibition of replication of human HFF cells.

[0904] Table 2. In vivo pharmacokinetic properties of select compounds. 1 Cmax for po route, Co (initial conc.); 2 CL, clearance; 3 Vss steady-state volume of distribution; 4 Oral availability determined from AUC last .

GXJ18 iv 3 - 5471.09 1146.49 1149.9 1.5 43.48 1.10 - 4 9 6 po 10 0.25 1136.36 1172.75 1279.2 - - - 31

0 GXJ17 iv 3 - 2741.80 619.33 625.04 1.7 80 2.32 - 6 4 po 10 0.25 76.69 85.47 91.42 - - - 4 GXJ23 iv 3 - 535.79 449.57 523.99 3.6 95.42 19.5 - 7 8 9 po 10 2.00 182.56 757.85 891.24 - - - 51 FUR7- iv 3 - 1205.19 975.90 988.58 1.5 50.58 3.68 - 27 6 po 10 0.25 1048.80 3058.44 3547.9 - - - 94

5

[0905] Table 3. Compound analogs and activity.

FUR6-95 0.023875 >10 >60 92.70 >10 1.58 FUR 5-57 0.32485 >10 12 96.99 >10 2.27 FUR6-159 0.202200 >10 2.6 97.66 >10 3.27

[0906] Table 4. Compound analogs and cLogP characterization.

Example D: Murine infection model of toxoplasmosis

[0907] To assess the ability of compounds to protect against lethal infection in vivo, a murine model is used and challenged with lethal doses of a type II strain of T. gondii, similar to previously described protocols. Balb/C female mice at 8 to 10 weeks of age are injected i.p. with 10 4 PRU-Luc-GFP parasites per animal. Compounds are reconstituted in dimethyl sulfoxide (DMSO) and diluted in PBS prior to injection into mice. Mice are treated beginning on the day of infection and continuing for ten days with daily i.p. injections of the specified compound at 1- 5 mg/kg containing 5% DMSO, or DMSO control. Survival is monitored for 30 days following infection. After 30 days, animals are sacrificed, brains removed and homogenized, and tissue cysts are enumerated by microscopic examination after staining with fluorescently labeled lectin (Dolichos biflorus) as described previously. Animals are maintained in an AAALAC-approved facility overseen by the Institutional Animal Care Committee at Washington University. [0908] Additionally, apicomplexans contain from 6-11 related CDPKs, depending on the species (Cell Host Microbe 2009 Jun 18;5(6):612-22), which is incorporated herein by reference in its entirety. Toxoplasma gondii contains 14 CDPKs (Infect Immun.2016 Apr 22;84(5):1262- 73. doi: 10.1128/IAI.01173-15). In addition to TgCDPK1, which controls invasion and egress, TgCDPK2 and TgCPDK6 have also been shown to play essential roles in bradyzoite

development and cell division, respectively. Although these enzymes differ slightly from TgCDPK1 in the ATP binding pocket, which is targeted by the inhibitors described herein, some of these compounds may also serve as potent inhibitors of these other CDPKs. Plasmodium also contains a number of CDPKs, including an enzyme called CDPK1 (although it is not a direct ortholog of TgCDPK1, it is a member of this kinase family), which is important in infection of red blood cells, as well as development of ookinetes in the mosquito during development.

Additional roles for CDPKs in parasites may be defined by future studies and some of these enzymes may also be inhibited by the compounds described herein.