Multicyclic compounds and uses thereof

1. A compound represented by Structural Formula IA:

or a pharmaceutically acceptable salt thereof, wherein:

W is —Y(CR 4a R 4b ) n R 2 or Y′;

Y is *N(R 5a )C(R 6 )N(R 5b )—;

Y′ is

“*” represents a portion of Y or Y′ directly adjacent to [C(R 3a )(R 3b )] m ;

R 5a and R 5b are independently hydrogen or (C 1 -C 4 )alkyl;

R 6 is ═O or ═NR 7 ;

R 7 is hydrogen, alkyl, or CN;

is a 3-18-membered heterocyclyl;

R 2 is 5-18-membered heteroaryl or 6-18-membered aryl;

each of R 3a and R 3b is independently selected from hydrogen and (C 1 -C 4 )alkyl;

m is 1 or 2;

n is 0 or 1;

each of R 4a and R 4b , if present, is independently selected from hydrogen, (C 1 -C 4 )alkyl, and (C 3 -C 6 )cycloalkyl;

A is

wherein:

“†” represents the point of attachment of A to the remainder of the molecule;

one “ ” represents a single bond and the other “ ” represents a double bond;

X 1 is —O—, —S— or —N(R 10a )— and X 2 is —C(R 11a )— or —N—; or

X 1 is —N— and X 2 is —N(R 12a )—, wherein:

R 10a is hydrogen or (C 1 -C 4 )alkyl;

R 11a is hydrogen, deuterium, (C 1 -C 4 )alkyl or halo; and

R 12a is hydrogen or (C 1 -C 4 )alkyl;

each R 1 is independently (C 3 -C 12 )carbocyclyl, 3-15-membered heterocyclyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, —O-halo(C 1 -C 4 )alkyl, cyano, sulfonate, —S(O) 0-2 (C 1 -C 4 )alkyl, —O—(C 3 -C 12 )carbocyclyl, and —O-(3-15-membered)heterocyclyl;

R 8 is a C 3 -C 18 carbocyclyl or a 3-18-member heterocyclyl; and

t is 1, 2 or 3;

wherein each aryl, heteroaryl, carbocyclyl, heterocyclyl, alkyl or cycloalkyl is optionally and independently substituted.

2. The compound of claim 1 , represented by Structural Formula III-IV:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from each R 1 is independently (C 3 -C 12 )carbocyclyl, 3-15-membered heterocyclyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, —O-halo(C 1 -C 4 )alkyl, —O—(C 3 -C 12 )carbocyclyl, —O-(3-15-membered)heterocyclyl;

R 8 is optionally substituted (C 3 -C 12 )carbocyclyl and optionally substituted 3-15-membered heterocyclyl; and

each carbocyclyl, heterocyclyl, aryl, heteroaryl and alkyl is optionally and independently substituted.

3. The compound of claim 2 , wherein Y is —N(R 5a )C(O)N(R 5b )—.

4. The compound of claim 2 , represented by Structural Formulas V-VIII:

or a pharmaceutically acceptable salt thereof, wherein:

m is 1 or 2.

5. The compound of claim 2 , wherein R 2 is optionally substituted phenyl or optionally substituted 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

6. The compound of claim 5 , wherein R 2 is optionally substituted and is selected from pyridinyl, isoxazolyl, thiazolyl, pyridazinyl, and phenyl.

7. The compound of claim 5 , wherein R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from amino, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl.

8. The compound of claim 2 , represented by Structural Formula XIII-XVI:

or a pharmaceutically acceptable salt thereof, wherein:

m is 1 or 2.

9. The compound of claim 1 , represented by Structural Formula XXXIII-XXXIV:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from (C 3 -C 12 )carbocyclyl, 3-15-membered heterocyclyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, —O-halo(C 1 -C 4 )alkyl, —O—(C 3 -C 12 )carbocyclyl, —O-(3-15-membered)heterocyclyl;

R 8 is optionally substituted (C 3 -C 12 )carbocyclyl and optionally substituted (3-15-membered)heterocyclyl; and

each carbocyclyl, heterocyclyl and alkyl is optionally and independently substituted.

10. The compound of claim 9 , represented by Structural Formula XXXV or XXXVI:

or a pharmaceutically acceptable salt thereof, wherein:

m is 1 or 2.

11. The compound of claim 10 , wherein

is selected from

12. The compound of claim 1 , wherein R 1 is selected from halogen, halo(C 1 -C 4 )alkyl, optionally substituted (C 1 -C 4 )alkyl, optionally substituted —O-halo(C 1 -C 4 )alkyl and optionally substituted —O—(C 1 -C 4 )alkyl.

13. The compound of claim 1 , wherein R 1 is independently selected from optionally substituted (C 3 -C 12 )carbocyclyl, optionally substituted (3-15-membered)heterocyclyl, optionally substituted —O—(C 3 -C 12 )carbocyclyl, optionally substituted —O-(3-15-membered)heterocyclyl.

14. The compound of claim 1 , wherein R 1 is optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.

15. The compound of claim 1 , wherein R 1 is

wherein:

each of D 1 and D 2 is independently —N— or —C(H)—, wherein no more than one of D 1 and D 2 is —N—;

each R 60 , if present, is independently halo, cyano, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy; and

q′ is 0, 1, 2 or 3.

16. The compound of claim 1 , wherein R 8 is optionally and independently substituted with 1, 2 or 3 substituents and is phenyl or a 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

17. The compound of claim 16 , wherein R 8 is substituted with 1, 2 or 3 substituents independently selected from halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, C(O)(C 1 -C 4 )alkyl, C(S)(C 1 -C 4 )alkyl, C(O)(C 0 -C 4 alkylene)NR 10 R 11 , C(S)(C 0 -C 4 alkylene)NR 10 R 11 , —S(O) 2 NR 10 R 11 and C(O)NR 12 NR 10 R 11 , wherein:

R 10 and R 11 are each independently hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted (C 3 -C 7 )carbocyclyl, or optionally substituted (3-15-membered)heterocyclyl; or

R 10 and R 11 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (3-15-membered)heterocyclyl; and

R 12 is hydrogen or optionally substituted (C 1 -C 4 )alkyl.

18. The compound of claim 17 , wherein R 8 is substituted with one substituent selected from C(O)(C 0 -C 1 alkylene)NR 10 R 11 , or C(S)(C 0 -C 1 alkylene)NR 10 R 11 , wherein R 10 and R 11 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (3-15-membered)heterocyclyl; and is further optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl.

19. The compound of claim 18 , wherein R 8 is:

phenyl or pyridinyl substituted at the para position relative to its attachment point with one substituent selected from —C(O)NR 10 R 11 or —C(S)NR 10 R 11 , wherein R 10 and R 11 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (3-15-membered)heterocyclyl; and

further optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl or (C 1 -C 4 )haloalkyl.

20. The compound claim 17 , wherein the heterocyclyl formed by R 10 and R 11 taken together with the nitrogen atom to which they are commonly attached is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy.

21. A compound represented by Structural Formula XXI-XXIV:

or a pharmaceutically acceptable salt thereof, wherein:

m′ is 1 or 2;

R 1a is selected from (C 3 -C 12 )carbocyclyl, 3-15-membered heterocyclyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, —O-halo(C 1 -C 4 )alkyl, —O—(C 3 -C 12 )carbocyclyl, —O-(3-15-membered)heterocyclyl;

Z 5 is —N— or —C(H)—;

R 20 is C(O)(C 0 -C 1 alkylene)NR 10 R 11 , C(S)(C 0 -C 1 alkylene)NR 10 R 11 , wherein:

R 10 and R 11 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (3-15-membered)heterocyclyl;

each R 21 , if present, is independently halo;

R7 is hydrogen, alkyl or —CN; and

q is 0, 1, 2, 3 or 4 when A is —C(H)— and 0, 1, 2 or 3 when A is —N—.

22. The compound of claim 21 , represented by Structural Formula XXV-XXVIII:

or a pharmaceutically acceptable salt thereof, wherein:

each of Z 6 and Z 7 is independently —N— or —C(H)—, wherein no more than one of Z 6 and Z 7 is nitrogen;

each R 22 , if present, is independently halo, cyano, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy; and

q′ is 0, 1, 2 or 3.

23. The compound of claim 21 , wherein R 20 is C(O)NR 10 R 11 or C(S)NR 10 R 11 , wherein R 10 and R 11 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (3-15-membered)heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

24. The compound of claim 21 , wherein the heterocyclyl formed by R 10 and R 11 taken together with the nitrogen atom to which they are commonly attached is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy.

25. The compound of claim 22 , represented by Structural Formula XXIX-XXXII:

or a pharmaceutically acceptable salt thereof.

26. A compound represented by any one of the structural formulas below

Cpd.

No.

Structure

Compound Name

100

1-((6-aminopyridin- 3-yl)methyl)-3-((5- (4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)benzofuran-2- yl)methyl)urea

101

1-(6-aminopyridin-3-yl)-3- ((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)- 7-(4-fluorophenyl) benzofuran-2- yl)methyl)urea

102

N-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)benzofuran- 2-yl)methyl)- 1,3-dihydro-2H- pyrrolo[3,4-c]pyridine- 2-carboxamide

118

(E)-1-(6-aminopyridin-3- yl)-2-cyano-3-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl) benzofuran-2- yl)methyl)guanidine

119

(Z)-1-((6-aminopyridin- 3-yl)methyl)-2- cyano-3-((5-(4-(4,4- difluoropiperidine- 1-carbonyl)phenyl)-7-(4- fluorophenyl)benzofuran-2- yl)methyl)guanidine

103

3-(6-aminopyridin-3-yl)- N-((5-(4-(4,4-difluoro- piperidine-1-carbonyl) phenyl)-7-(4-fluorophenyl) benzofuran-2-yl) methyl)azetidine- 1-carboxamide

104

1-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)benzofuran- 2-yl)methyl)-3-(pyridin- 3-ylmethyl)urea

105

N-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7- (trifluoromethyl) benzofuran-2-yl) methyl)-1,3-dihydro- 2H-pyrrolo [3,4-c]pyridine-2- carboxamide

106

N-((5-(4-(3,3- difluoroazetidine-1- carbonyl)phenyl)-7- (trifluoromethyl) benzofuran-2-yl) methyl)-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2- carboxamide

120

N-((5-(4-(4,4- difluoropiperidine-1- carbonyl)-4″-fluoro- [1,1′:3′,1″-terphenyl]-4′- yl)furan-2-yl)methyl)- 1,3-dihydro-2H-pyrrolo [3,4-c] pyridine-2-carboxamide

107

N-(2-(5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)benzofuran- 2-yl)ethyl)- 1,3-dihydro-2H-pyrrolo [3,4-c]pyridine- 2-carboxamide

121

N-(2-((4-(4,4-difluoro- piperidine-1-carbonyl)- 4″-fluoro-[1,1′:3′,1″- terphenyl]-4′-yl)oxy) ethyl)-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine- 2-carboxamide

108

N-((7-(2,4-difluoro- phenyl)-5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl) benzofuran-2- yl)methyl)-1,3- dihydro-2H-pyrrolo [3,4-c]pyridine-2- carboxamide

109

N-((5-(4-(4,4-difluoro- piperidine-1-carbonyl) phenyl)-7-(4- fluorophenyl)benzo- furan-2-yl)methyl)- N-methyl-1,3-dihydro- 2H-pyrrolo[3,4- c]pyridine-2-carboxamide

110

N-((5-(5-(4,4-difluoro- piperidine-1-carbonyl) pyridin-2-yl)-7-(4- fluorophenyl)benzo- furan-2-yl)methyl)- 1,3-dihydro-2H-pyrrolo [3,4-c]pyridine-2- carboxamide

122

N-((5-(4-(4,4-difluoro- piperidine-1-carbonyl) phenyl)-7-(4-fluoro- phenyl)-2,3-dihydro- benzofuran-2-yl)methyl)- 1,3-dihydro-2H-pyrrolo [3,4-c]pyridine- 2-carboxamide

111

N-((5-(4-(4,4-difluoro- piperidine-1-carbonyl) phenyl)-7-(4- fluorophenyl)benzo [b]thiophen-2- yl)methyl)-1,3-dihydro- 2H-pyrrolo[3,4- c]pyridine-2-carboxamide

112

1-((6-aminopyridin-3- yl)methyl)-3-((7- (2,4-difluorophenyl)- 5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl) benzofuran-2- yl)methyl)urea

113

1-((6-aminopyridin-3- yl)methyl)-3-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7- (trifluoromethyl) benzofuran-2- yl)methyl)urea

114

1-((6-aminopyridin-3- yl)methyl)-3-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)benzo [b]thiophen-2- yl)methyl)urea

115

6-amino-N-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)- 7-(4-fluorophenyl) benzofuran-2-yl)methyl)- 1,3-dihydro-2H-pyrrolo [3,4-c]pyridine-2- carboxamide

116

1-((6-aminopyridin-3- yl)methyl)-3-((5-(5-(4,4- difluoropiperidine-1- carbonyl)pyridin-2-yl)- 7-(4-fluorophenyl) benzofuran-2- yl)methyl)urea

123

1-((6-aminopyridin-3- yl)methyl)-3-((5-(4-(4,4- difluoropiperidine-1- carbonyl)phenyl)-7-(4- fluorophenyl)-2,3- dihydrobenzofuran-2- yl)methyl)urea

124

1-((6-aminopyridin-3-yl) methyl)-3-(2-((4-(4,4- difluoropiperidine-1- carbonyl)-4″-fluoro- [1,1′:3′,1″-terphenyl]- 4′-yl)oxy)ethyl)urea

125

1-((6-aminopyridin-3- yl)methyl)-3-((5-(4-(4,4- difluoropiperidine-1- carbonyl)-4″-fluoro- [1,1′:3′,1″-terphenyl]-4′-yl) furan-2-yl)methyl)urea

117

1-((6-aminopyridin-3-yl) methyl)-3-((5-(4-(3,3- difluoroazetidine-1- carbonyl)phenyl)-7- (trifluoromethyl) benzofuran-2- yl)methyl)urea

or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising:

(a) a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and

(b) a pharmaceutically acceptable carrier.

28. A method of treating cancer, an inflammatory disease, or an autoimmune system disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lymphoma, leukemia, multiple myeloma, cervical cancer, ovarian cancer, osteosarcoma, prostate cancer, breast cancer, colorectal cancer, lung cancer, glioma, liver cancer, and pancreatic cancer.

29. The method of claim 28 , wherein the cancer is non-Hodgkin lymphoma.

30. The method of claim 29 , wherein the non-Hodgkin lymphoma is selected from histiocytic lymphoma, mantle cell lymphoma, Burkett lymphoma, and diffuse large B-cell lymphoma.

31. The method of claim 28 , wherein the leukemia is selected from chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, erythroleukemia, T-cell leukemia, and B-cell leukemia.