Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activities

1. A compound of Formula I,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,

wherein

X is halogen;

Z1 and Z2 are CR2;

Z3 is CH;

each R1 is independently and individually halogen, H, C1-C6 alkyl, branched C3-C7 alkyl, C3-C7 cycloalkyl, or —CN;

each R2 is individually and independently H, halogen, C1-C6 alkyl, or cyano;

R3 is —C(O)R4, —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl, wherein

aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl; and

with the proviso that when R3 is —C(O)—C4-C6-heterocyclyl, the heterocyclyl does not have a N bonding hand to —C(O);

R4 is C3-C8 cycloalkyl, C1-C7 alkyl, —(CH 2 ) p —CN, —(CH 2 ) p —OR6, —(CH 2 ) p —NR6(R7), —(CH 2 ) p —SO 2 —C1-C6-alkyl, —(CH 2 ) p —C6-C10-aryl, —(CH 2 ) p —C5-C6-heteroaryl, or —(CH 2 ) p —C4-C6-heterocyclyl, wherein

each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl; and

aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl;

each R6 and R7 is individually and independently H, C1-C6 alkyl, or C3-C8 branched alkyl;

each cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with —(R25) m ;

each R25 is individually and independently C1-C6 alkyl, branched C3-C8 alkyl, halogen, —(CH 2 ) m —CN, —(CH 2 ) m —OR6, —(CH 2 ) m —NR6(R7), —(CH 2 ) m —SO 2 —C1-C6-alkyl, —(CH 2 ) m —C(O)NR6(R7), —(CH 2 ) m —C(O)—C4-C6-heterocyclyl, or —(CH 2 ) m —C4-C6-heterocyclyl, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;

each m is individually and independently 0, 1, 2, or 3; and

p is 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is a compound of Formula Ic,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and wherein n is 0, 1, or 2.

3. The compound of claim 2 , wherein R3 is —C(O)R4.

4. The compound of claim 3 , wherein R4 is C3-C8 cycloalkyl, C1-C7 alkyl, —(CH 2 ) p —CN, —(CH 2 ) p —OR6, —(CH 2 ) p —NR6(R7), —(CH 2 ) p —SO 2 —C1-C6-alkyl, or —(CH 2 ) p —C4-C6-heterocyclyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl.

5. The compound of claim 3 , wherein R4 is C3-C8 cycloalkyl or C1-C7 alkyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl.

6. The compound of claim 2 , wherein R3 is —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl.

7. A compound of claim 1 selected from the group consisting of N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-5-chloro-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide, N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate, N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and pharmaceutically acceptable salts and tautomers thereof.

8. A compound of claim 1 selected from N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

9. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

10. The composition of claim 9 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

11. The compound N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition, comprising the compound of claim 11 and a pharmaceutically acceptable carrier.

13. The composition of claim 12 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

14. The compound N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition, comprising the compound of claim 14 and a pharmaceutically acceptable carrier.

16. The composition of claim 15 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

17. The compound N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt, thereof.

18. A pharmaceutical composition, comprising the compound of claim 17 and a pharmaceutically acceptable carrier.

19. The composition of claim 18 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.