Macrocyclic heterocycles and uses thereof
The present disclosure provides compounds and pharmaceutically acceptable salt thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.
1. A compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
is selected from C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R 11 ;
is absent or selected from C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R 11a ;
L 1 is selected from a bond, C 1-6 alkylene, and C 1-6 haloalkylene;
L 2 is selected from C 5-25 alkylene, C 5-25 alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , or W 7 ;
W 2 is selected from N and C(R 2 );
W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O);
W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O);
W 5 is selected from N and C(R 5 );
W 7 is C(R 7 );
R 1 is C 1-3 alkyl optionally substituted with one or more R 11c ;
R 2 and R 8 are each independently selected from hydrogen, halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, —OR 12 , —SR 12 , —N(R 12 )(R 13 ), —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —N(R 14 )C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)OR 15 , —N(R 14 )S(O) 2 R 15 , —C(O)R 15 , —S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R 20 ;
R 3 , R 4 , R 5 , and R 7 are each independently selected from a bond to L 2 , hydrogen, halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, —OR 12 , —SR 12 , —N(R 12 )(R 13 ), —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —N(R 14 )C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)OR 15 , —N(R 14 )S(O) 2 R 15 , —C(O)R 15 , —S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R 20 ;
R 3b and R 4b are each independently selected from a bond to L 2 , hydrogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, —OR 12 , —SR 12 , —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —C(O)R 15 , —S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R 20 ;
R 11 and R 11a are each independently selected at each occurrence from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, —OR 12 , —SR 12 , —N(R 12 )(R 13 ), —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —N(R 14 )C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)OR 15 , —N(R 14 )S(O) 2 R 15 , —C(O)R 15 , —S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , —CH 2 S(O) 2 N(R 12 )(R 13 ), —CH 2 N(R 12 )S(O) 2 (R 13 ), and —P(O)(R 17 )(R 17a ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
R 11b is independently selected at each occurrence from halogen, oxo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, —OR 12 , —SR 12 , —N(R 12 )(R 13 ), —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —N(R 14 )C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)OR 15 , —N(R 14 )S(O) 2 R 15 , —C(O)R 15 , —S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , —CH 2 S(O) 2 N(R 12 )(R 13 ), —CH 2 N(R 12 )S(O) 2 (R 13 ), and —P(O)(R 17 )(R 17a ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
R 11c is independently selected at each occurrence from halogen, —OR 12 , and —N(R 12 )(R 13 );
R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
R 14 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
R 15 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
R 17 and R 17a are each independently selected at each occurrence from C 1-6 alkyl and C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one, two or three R 20 ; or R 17 and R 17a , together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle;
R 20 is independently selected at each occurrence from halogen, oxo, ═NH, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, —CH 2 —(C 3-10 carbocycle), 3- to 10-membered heterocycle, —CH 2 -(3- to 10-membered heterocycle), —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 ) C(O)N(R 22 )(R 23 ), —N(R 24 ) C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), —OCH 2 C(O)OR 22 , and —OC(O)R 25 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, —CH 2 -(C 3-10 carbocycle), 3- to 10-membered heterocycle, and —CH 2 -(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, ═NH, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 ) C(O)N(R 22 )(R 23 ), —N(R 24 ) C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), and —OC(O)R 25 ;
R 21 is independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl;
R 22 is independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl;
R 23 is independently selected at each occurrence from H and C 1-6 alkyl;
R 24 is independently selected at each occurrence from H and C 1-6 alkyl;
R 25 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 carbocycle, and 3- to 10-membered heterocycle; and
indicates a single or double bond such that all valences are satisfied.
2. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound, salt, or solvate of claim 1 , wherein R 1 is —CH 3 .
4. The compound, salt, or solvate of claim 1 , wherein R 3b is selected from hydrogen and —CH 3 .
5. The compound, salt, or solvate of claim 1 , wherein R 7 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and —N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R 20 .
6. The compound, salt, or solvate of claim 1 , wherein R 7 is selected from
7. The compound, salt, or solvate of claim 1 , wherein R 8 is hydrogen.
8. The compound, salt, or solvate of claim 1 , wherein
is selected from
9. The compound, salt, or solvate of claim 8 , wherein R 11 is selected from fluorine and —CH 3 .
10. The compound, salt, or solvate of claim 1 , wherein L 1 is C 1-3 haloalkylene.
11. The compound, salt, or solvate of claim 10 , wherein L 1 is selected from —CF 2 —, —CF 2 CH 2 —, and —CF 2 CH 2 CH 2 —.
12. The compound, salt, or solvate of claim 1 , wherein
is selected from absent, phenyl, and 4- to 8-membered heterocycle, wherein the phenyl and 4- to 8-membered heterocycle are optionally substituted with one or more R 11a .
13. The compound, salt, or solvate of claim 12 , wherein
is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH 3 .
14. The compound, salt, or solvate of claim 1 , wherein L 2 is selected from C 5-10 alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b .
15. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt or solvate thereof.
16. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt or solvate thereof.
17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
18. A method of inhibiting cell growth, comprising administering to a cell expressing SOS1 an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of said cells.
19. The method of claim 18 , wherein the cell is a cancer cell.
20. The method of claim 18 , further comprising administering an additional agent to the cell.
21. The method of claim 20 , wherein the additional agent is an inhibitor of one or more targets selected from MEK, EGFR, ALK, c-MET, ErbB2, PI3-kinase, SHP2, Bcr-Abl, and KRAS, or a mutant thereof.