Methods and compositions for inhibiting the interaction of menin with MLL proteins

1. A method of treating a menin-mediated disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula II-A:

or a pharmaceutically acceptable salt thereof, wherein:

X 2 is CR 2 or N;

X 5 is S;

X 6 is CR 3 or N;

L 3 is a carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;

L 2 is a bond, carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;

m is an integer from 0 to 12;

B is selected from B-I, B-II, B-III, and B-IV;

wherein B is connected at any ring atom to L 2 ;

B-I is

B-II is

B-III is

B-IV is

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently CR 7 , N, or NR 9 ;

Z 5 is C or N;

each of Z 6 , Z 7 , and Z 8 is independently CR 8 , N, NR 9 , O, or S;

each of Z 9 , Z 10 , and Z 11 is independently CR 10 , CR 11 R 12 , NR 13 , O, or S;

n is an integer from 0 to 6;

each of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclyl alkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino;

each of R A and R B is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino,

wherein two R A groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring; and

R 14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino,

wherein the disease or condition comprises a leukemia, a lymphoma, a hematologic malignancy, a solid tumor cancer, prostate cancer, pancreatic cancer, lung cancer, skin cancer, breast cancer, liver cancer, a brain tumor, or diabetes.

2. The method of claim 1 , wherein R 14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl.

3. The method of claim 2 , wherein R 14 is hydroxyl, alkylamino, or amino.

4. The method of claim 1 , wherein X 6 is CR 3 and R 3 in X 6 is selected from H, halo, amino, carboxyl, and alkyl.

5. The method of claim 1 , wherein L 3 is carbonyl, O, S, or —NR 5 —.

6. The method of claim 1 , wherein L 2 is C 1 -C 4 alkylene.

7. The method of claim 1 , wherein X 2 is N.

8. The method of claim 1 , wherein R 1 is haloalkyl.

9. The method of claim 1 , wherein m is 0 and n is 1 or 2.

10. The method of claim 1 , wherein R 5 is H or alkyl.

11. The method of claim 1 , wherein B is B-II.

12. The method of claim 11 , wherein B-II is

13. The method of claim 1 , comprising B-II, wherein:

Z 1 and Z 2 are CR 7 ;

Z 5 is C;

Z 6 is NR B ; and

Z 7 and Z 8 are CR 8 .

14. The method of claim 1 , comprising B-II, wherein:

Z 1 is CCH 3 ;

Z 2 and Z 8 are CH;

Z 5 is C;

Z 6 is NR B ; and

Z 7 is CCN.

15. The method of claim 1 , comprising an R B selected from:

wherein:

G is selected from a bond, alkylene, heteroalkylene, C 3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, wherein G is optionally substituted with one or more R 32 groups;

V is absent or selected from a C 3-12 carbocycle, and 3- to 12-membered heterocycle; wherein V is optionally substituted with one or more R 32 groups;

each of R 21 and R 32 is, at each occurrence, independently selected from:

H, halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , and —CN;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 carbocycle and 3- to 10-membered heterocycle;

wherein two R 32 on the same carbon atom can come together to form a C 3-10 carbocycle or 3- to 10-membered heterocycle;

wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle of R 32 is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 20 is, at each occurrence, independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 30 , —SR 30 , —N(R 30 ) 2 , —N(R 30 )C(O)R 30 , —C(O)R 30 , —C(O)OR 30 , —C(O)N(R 30 ) 2 , —OC(O)R 30 , —S(O) 2 R 30 , —S(O) 2 N(R 30 ) 2 , —N(R 30 )S(O) 2 R 30 , —NO 2 , —P(O)(OR 30 ) 2 , —P(O)(R 30 ) 2 , —OP(O)(OR 30 ) 2 , and —CN; and

3- to 10-membered heterocycle and C 3-10 carbocycle; and

R 30 is, at each occurrence, independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

16. The method of claim 15 , wherein V is selected from:

any one of which is optionally substituted with one or more R 32 groups.

17. The method of claim 15 , wherein G is alkylene optionally substituted with one or more R 32 groups.

18. The method of claim 15 , wherein:

X 5 is S;

X 6 is CR 3 , wherein R 3 in X 6 is selected from H, halo, amino, carboxyl, and alkyl;

L 2 is C 1 -C 4 alkylene;

L 3 is carbonyl, O, S, or —NR 5 —;

B is

Z 1 and Z 2 are CR 7 ;

Z 5 is C;

Z 6 is NR B ;

Z 7 and Z 8 are CR 8 ;

R 1 is haloalkyl;

R 14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl; and

V is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which optionally substituted with one or more R 32 groups.

19. The method of claim 18 , wherein R 14 is hydroxyl, alkylamino, or amino.

20. The method of claim 1 , further comprising administering a second therapeutic agent to the subject.

21. The method of claim 1 , wherein the disease or disorder is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, chronic myelogenous leukemia, acute monocytic leukemia, hairy cell leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, mixed lineage leukemia, T-cell prolymphocyte leukemia, T-cell lymphoma, and Burkitt lymphoma.

22. The method of claim 1 , wherein the disease or disorder is selected from AML, ALL, mixed lineage leukemia, and leukemia having a Partial Tandem Duplication of MLL.

23. A method of inhibiting the interaction of menin and one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication, comprising contacting menin with an effective amount of a compound of Formula II-A:

or a pharmaceutically acceptable salt thereof, wherein:

X 2 is CR 2 or N;

X 5 is S;

X 6 is CR 3 or N;

L 3 is a carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;

L 2 is a bond, carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;

m is an integer from 0 to 12;

B is selected from B-I, B-II, B-III, and B-IV;

wherein B is connected at any ring atom to L 2 ;

B-I is

B-II is

B-III is

B-IV is

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently CR 7 , N, or NR 9 ;

Z 5 is C or N;

each of Z 6 , Z 7 , and Z 8 is independently CR 8 , N, NR 9 , O, or S;

each of Z 9 , Z 10 , and Z 11 is independently CR 10 , CR 11 R 12 , NR 13 , O, or S;

n is an integer from 0 to 6;

each of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino;

each of R A and R B is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino,

wherein two R A groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring; and

R 14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino.

24. The method of claim 23 , wherein:

X 5 is S;

X 6 is CR 3 , wherein R 3 in X 6 is selected from H, halo, amino, carboxyl, and alkyl;

L 2 is C 1 -C 4 alkylene;

L 3 is carbonyl, O, S, or —NR 5 —;

B is

Z 1 and Z 2 are CR 7 ;

Z 5 is C;

Z 6 is NR B ;

Z 7 and Z 8 are CR 8 ;

R 1 is haloalkyl; and

R 14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl.