Compounds and methods for treating HIV infection

1. A compound having the formula:

wherein,

R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted 4,5,6,7-tetrahydrothie no[3,2-b]pyridine, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinolinyl, or substituted or unsubstituted 1,4,6,7-tetrahydro-5λ 2 -pyrazolo[4,3-c]pyridinyl;

R 2 is hydrogen or —NR 2A R 2B ;

R 3 is hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCX 3 3 , —OCH 2 X 3 , —OCHX 3 2 , —CN, —SO n3 R 3D , SO v3 NR 3A R 3B , —NHC(O)NR 3A R 3B , —N(O) m3 ,—NR 3A R 3B , —C(O)R 3C , —C(O)—OR 3C , —C(O)NR 3A R 3B , —OR 3D , —NR 3A SO 2 R 3D , —NR 3A C(O)R 3C , —NR 3A C(O)OR 3C , —NR 3A OR 3C , 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 4 is independently hydrogen, 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 SO 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;

Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , and R 4D is independently hydrogen, —CX 3 , —CN, —NH 2 , —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 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 3A and R 3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl 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;

each X, X 1 , X 2 , X 3 , and X 4 , is independently —F, —Cl, —Br, or —I;

n1, n3, and n4 are independently an integer from 0 to 4; and

m1, m3, m4, v1, v3, and v4 are independently an integer from 1 to 2.

2. The compound of claim 1 having the formula:

wherein

R 3A is hydrogen, —CX 3A 3 , —CHX 3A 2 , —CH 2 X 3A , —C(O)NH 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; and

each X 3A is independently —F, —Cl, —Br, or —I.

3. The compound of claim 2 wherein R 3A is hydrogen.

4. The compound of claim 2 wherein R 2 is hydrogen.

5. The compound of claim 2 , wherein R 1 is R 20 -substituted or unsubstituted piperazinyl, R 20 -substituted or unsubstituted piperidinyl, R 20 -substituted or unsubstituted pyrrolidinyl, R 20 -substituted or unsubstituted 4,5,6,7-tetrahydrothieno[3,2-b]pyridine, or R 20 -substituted or unsubstituted 1,2,3,4-tetrahydroisoquinolinyl, or R 20 -substituted or unsubstituted 1,4,6,7-tetrahydro-5λ 2 -pyrazolo[4,3-c]pyridinyl;

R 20 is independently oxo, 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)OH, —NHC(O)OH, —NHOH, —OCX 20 3 , —OCHX 20 2 , substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; and

X 20 is —F, —Cl, —Br, or —I.

6. The compound of claim 2 , having the formula:

7. The compound of claim 2 , having the formula:

8. The compound of claim 5 , wherein R 20 is independently halogen, —CONH 2 , substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted 5 to 6 membered heteroaryloxy.

9. A method of inhibiting the level of Rev protein activity, inhibiting human immunodeficiency virus (HIV) virion formation in an HIV infected cell, inhibiting HIV viral shedding from an HIV infected cell, inhibiting HIV proliferation, treating an HIV infection, inhibiting the level of HIV Vpu activity in a cell, or modulating an HIV Vpu gene, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

wherein,

R 1 is hydrogen, halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —OCX 1 3 , —OCH 2 X 1 , —OCHX 1 2 , —CN, —SO n1 R 1D , —SO v1 NR 1A R 1B , —NHC(O)NR 1A R 1B , —N(O) m1 , —NR 1A R 1B , —C(O)R 1C , —C(O)—OR 1C , —C(O)NR 1A R 1B , —OR 1D , —NR 1A SO 2 R 1D , —NR 1A C(O)R 1C , —NR 1A C(O)OR 1C , —NR 1A OR 1C , 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 2 is hydrogen, —NR 2A R 2B , —C(O)—R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , 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 3 is hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCX 3 3 , —OCH 2 X 3 , —OCHX 3 2 , —CN, —SO n3 R 3D , —SO v3 NR 3A R 3B , —NHC(O)NR 3A R 3B , —N(O) m3 , —NR 3A R 3B , —C(O)R 3C , —C(O)—OR 3C , —C(O)NR 3A R 3B , —OR 3D , —NR 3A SO 2 R 3D , —NR 3A C(O)R 3C , —NR 3A C(O)OR 3C , —NR 3A OR 3C , 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 4 , R 4A1 , and R 4B1 are independently hydrogen, 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 SO 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; R 4 and R 4A1 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 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B ,R 3C , R 3D , R 4A , R 4B , R 4C , and R 4D is independently hydrogen, —CX 3 , —NH 2 , —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 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2 A and R 2 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 3 A and R 3 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 4 A and R 4 B 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 1 , X 2 , X 3 , and X 4 is independently —F, —Cl, —Br, or —I;

n1, n3, and n4 are independently an integer from 0 to 4; and

m1, m3, m4, v1, v 3 , and v4 are independently an integer from 1 to 2; and

Y 1 is N and Y 2 is CR 4B1 .

10. The method of claim 9 , wherein the compound has the formula:

wherein

R 3A is hydrogen, —CX 3A 3 , —CHX 3A 2 , —CH 2 X 3A , —C(O)NH 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; and each X 3A is independently —F, —Cl, —Br, or —I.

11. The method of claim 9 , wherein the compound has the formula:

12. The method of claim 9 , wherein the method is inhibiting the level of Rev protein activity, inhibiting HIV virion formation in an HIV infected cell, inhibiting HIV viral shedding from an HIV infected cell, inhibiting HIV proliferation, or treating an HIV infection.

13. The method of claim 9 , wherein the method is inhibiting the level of HIV Vpu activity in a cell or modulating an HIV Vpu gene.

14. A compound having the following formula:

15. A compound of claim 2 , having the formula:

16. The method of claim 9 , wherein the method is treating an HIV infection.

17. The method of claim 9 wherein R 3A is hydrogen and R 2 is hydrogen.

18. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 , 14 , or 15 and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition of claim 18 , further comprising an anti-viral agent.

20. The pharmaceutical composition of claim 19 , wherein the anti-viral agent is an human immunodeficiency virus (HIV) reverse transcriptase inhibitor, human immunodeficiency virus (HIV) protease inhibitor, human immunodeficiency virus (HIV) integrase inhibitor, human immunodeficiency virus (HIV) fusion inhibitor, or human immunodeficiency virus (HIV) entry inhibitor.