Facially Amphiphilic Compounds, Compositions, And Uses Thereof In Treating Cancer

1 . A method for treating or reducing cancer, or inhibiting growth of a cancer cell, or inhibiting tumor growth, or reducing spread or metastasis of cancer in an animal in need thereof comprising administering to the animal an effective amount of a compound or pharmaceutically acceptable salt thereof; wherein the compound or pharmaceutically acceptable salt administered is a compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:

X 1 is O, S, S(═O), or S(═O) 2 ;

R 1 and R 2 are, independently, halo, C 1-4 alkyl, C 1-4 alkoxy, CN, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

R 3 and R 4 are, independently, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or 1,2,3,6-tetrahydropyridin-4-yl, each substituted with R 5 and optionally substituted with R 6 ;

each R 5 is independently —(CH 2 ) t1 —NH 2 , —(CH 2 ) t2 —NH—(CH 2 ) t3 —NH 2 , —(CH 2 ) t4 —NHC(═NH)NH 2 , —S—(CH 2 ) t5 —NH 2 , —O—(CH 2 ) t6 —NH 2 , —(CH 2 ) t7 —NH 2 , or NR 7 R 8 ;

each R 6 is independently halo, OH, C 1-4 alkyl, C 1-4 alkoxy, CN, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

R 7 and R 8 , together with the N atom to which they are attached, form pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, or piperazin-1-yl, each optionally substituted with 1 or 2 C 1-4 alkyl;

m is 0 or 1;

n is 0 or 1;

each t1 is independently 2 or 3;

each t2 is independently 1, 2, or 3;

each t3 is independently 2 or 3;

each t4 is independently 2 or 3;

each t5 is independently 2 or 3;

each t6 is independently 2 or 3; and

each t7 is independently 2 or 3;

or the compound or pharmaceutically acceptable salt administered is a compound of Formula II:

or pharmaceutically acceptable salt thereof, wherein:

R 11 and R 14 are, independently, H, Cl, CN, methyl, CH 2 F, CHF 2 , or CF 3 ;

R 12 and R 15 are, independently, —S—(CH 2 ) t11 —NH 2 , —O—(CH 2 ) t12 —NH 2 , —O—R 17 , —S—(CH 2 ) t13 —NHC(═NH)NH 2 , or —(CH 2 ) t14 —NH 2 ;

R 13 and R 16 are, independently, —NH 2 , —NH—(CH 2 ) m13 —NH 2 , —NHC(═NH)NH 2 , or —NH—(CH 2 ) m14 —NHC(═NH)NH 2 ;

each R 17 is independently pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with 1 or 2 C 1-4 alkyl;

each of t11, t12, t13, and t14 is independently 2 or 3;

each of m11 and m12 is independently 3, 4, or 5;

each of m13 and m14 is independently 1, 2, 3, 4, or 5;

or the compound or pharmaceutically acceptable salt administered is a compound of Formula III:

or pharmaceutically acceptable salt thereof, wherein:

R 51 and R 54 are, independently, H, Cl, CN, methyl, CH 2 F, CHF 2 , or CF 3 ;

R 52 and R 55 are, independently, —S—(CH 2 ) t51 —NH 2 or —(CH 2 ) t52 —NH 2 ;

R 53 and R 56 are, independently, —NH 2 , —NH—(CH 2 ) m53 —NH 2 , —NHC(═NH)NH 2 , or —NH—(CH 2 ) m54 —NHC(═NH)NH 2 ;

each of t51 and t52 is independently 2 or 3;

each of m51 and m52 is independently 3, 4, or 5; and

each of m53 and m54 is independently 1, 2, 3, 4, or 5;

or the compound or pharmaceutically acceptable salt administered is a compound of Formula IV or IVa:

or pharmaceutically acceptable salt thereof, wherein:

R 71 and R 74 are, independently, H, Cl, CN, methyl, CH 2 F, CHF 2 , or CF 3 ;

R 72 and R 75 are, independently, —S—(CH 2 ) t71 —NH 2 , —(CH 2 ) t72 —NH 2 , or —O—(CH 2 ) t73 —NH 2 ;

R 73 and R 76 are, independently, —S—(CH 2 ) t74 —NH 2 , —(CH 2 ) t75 —NH 2 , or —O—(CH 2 ) t76 —NH 2 ;

t71 and t74 are independently 2 or 3;

t72 and t75 are independently 2 or 3; and

t73 and t76 are independently 2 or 3.

2 . The method of claim 1 wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a compound Formula Ia:

or pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are, independently, Cl, Br, methyl, CH 2 F, CHF 2 , or CF 3 ;

each R 5 is independently —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —S—(CH 2 ) 2 —NH 2 , —O—(CH 2 ) 3 —NH 2 , or piperazin-1-yl;

each R 6 is independently, Cl, Br, methyl, CH 2 F, CHF 2 , or CF 3 ;

Y 1 is N or CH;

Y 2 is N or CH;

m is 0 or 1;

n is 0 or 1;

q1 is 0 or 1; and

q2 is 0 or 1.

3 . The method of claim 2 wherein the compound of Formula Ia or pharmaceutically acceptable salt thereof is a compound Formula Ia-1:

or pharmaceutically acceptable salt thereof.

4 . The method of claim 3 wherein the compound of Formula Ia-1 or pharmaceutically acceptable salt thereof is a compound of Formula Ia-1-1:

or pharmaceutically acceptable salt thereof.

5 . The method of claim 2 wherein the compound of Formula Ia or pharmaceutically acceptable salt thereof is a compound selected from:

or pharmaceutically acceptable salt thereof.

6 . The method of claim 1 wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a compound Formula Ib:

or pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are, independently, Cl, Br, methyl, CH 2 F, CHF 2 , or CF 3 ;

each R 5 is independently —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —S—(CH 2 ) 2 —NH 2 , —O—(CH 2 ) 3 —NH 2 , or piperazin-1-yl;

each R 6 is independently, Cl, Br, methyl, CH 2 F, CHF 2 , or CF 3 ;

Y 1 is N or CH;

Y 2 is N or CH;

m is 0 or 1;

n is 0 or 1;

q1 is 0 or 1; and

q2 is 0 or 1.

7 . The method of claim 6 wherein the compound of Formula Ib or pharmaceutically acceptable salt thereof is a compound Formula Ib-1:

or pharmaceutically acceptable salt thereof.

8 . The method of claim 7 wherein the compound of Formula Ib-1 or pharmaceutically acceptable salt thereof is a compound of Formula Ib-1-1:

or pharmaceutically acceptable salt thereof.

9 . The method of claim 6 wherein the compound of Formula Ib or pharmaceutically acceptable salt thereof is a compound that is

or pharmaceutically acceptable salt thereof.

10 . The method of claim 1 wherein the compound of Formula II or pharmaceutically acceptable salt thereof is a compound that is:

or pharmaceutically acceptable salt thereof.

11 . The method of claim 1 wherein the compound of Formula III or pharmaceutically acceptable salt thereof is a compound that is:

or pharmaceutically acceptable salt thereof.

12 . The method of claim 1 wherein the compound of Formula IV or IVa, or pharmaceutically acceptable salt thereof, is a compound that is:

or pharmaceutically acceptable salt thereof.

13 . The method of claim 1 wherein the cancer is selected from leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovary cancer, breast cancer, prostate cancer, and kidney cancer.