MACROCYCLIC COMPOUNDS AND METHODS OF USE
The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. The compounds have a general Formula I′: wherein the variables of Formula I′ are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.
1 . A compound of Formula (I′):
or a pharmaceutically acceptable salt of said compound, wherein;
Z is C—H, C-halogen, C—CN, C—C 1-4 alkyl, C—C 1-4 haloalkyl, C—C 1-4 alkoxy, C—C 1-4 haloalkoxy, C—C 3-7 cycloalkyl or N;
Q is CH, C-halogen, C—C 1-4 alkyl, C—C 1-4 haloalkyl or N;
B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
each R x is independently hydroxyl, halogen, oxo, cyano, —N(R z ) 2 , C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 5-7 membered heteroaryl, —S(O) 2 —C 1-4 alkyl, —S(O) 2 N(R z ) 2 , —C(O)R z , —C(O)OR z , —C(O)N(R z ) 2 , —C 1-4 alkylene-C(O)—C 1-4 alkyl, —C 1-4 alkylene-C(O)N(R z ) 2 , C 1-4 alkylene-S(O) 2 —C 1-4 alkyl, or —S—C 1-4 alkyl;
L is a bond, C 1-6 alkylene, —O—C 1-6 alkylene, —S—C 1-6 alkylene, NR z , O or S, wherein each C 1-6 alkylene, —O—C 1-6 alkylene and —S—C 1-6 alkylene chain is substituted with 0-2 occurrences of R 2 ;
-L 1 -L 2 - is -L 2 , —N(R z )C(O)-L 2 , —C(O)-L 2 -, —OC(O)-L 2 , —C(O)O-L 2 , —OC(O)—O-L 2 , —OC(S)—O-L 2 , —O-L 2 , —N(R z )C(O)O-L 2 , —OC(O)N(R z )-L 2 , —N(R z )-L 2 , —S(O) 2 -L 2 , —S-L 2 , alkylene-OC(O)-L 2 , —C 1-4 alkylene-O-L 2 , —C 1-4 alkylene-S(O) 2 -L 2 , —C 1-4 alkylene-S-L 2 , —C 1-4 alkylene-S(O)-L 2 , —O-5-6 membered heteroaryl-L 2 , —C 1-4 alkylene-5-6 membered heteroaryl-L 2 , —C 1-4 hydroxyalkylene-5-6-membered heteroaryl-L 2 or a 5-6 membered heteroaryl-L 2 ;
L 2 is C 1-6 alkylene, C 1-6 alkylene-O—, C 1-6 alkylene-O—C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-7 cycloalkylene, C 1-4 alkylene-C 3-7 cycloalkylene, C 1-4 haloalkylene-C 3-7 cycloalkylene, C 3-7 cycloalkylene-C 1-4 alkylene, C 1-6 hydroxyalkylene or C 1-6 haloalkylene;
R 1 is hydrogen, hydroxyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R 5 ;
R 2 is halogen, hydroxyl, C 1-4 alkyl or two R 2 on the same or adjacent carbon atoms can be taken together to form a C 3-7 cycloalkyl;
A is 5-10 membered heteroaryl and is substituted with q occurrences of R 6 ;
R 4 is hydrogen, hydroxyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl or cyano;
each R 5 independently is halogen, cyano, oxo, -T-R y , hydroxyl, —N(R z ) 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or —O—C 2-4 alkynyl;
each R 6 independently is halogen, hydroxyl, cyano, —N(R z ) 2 , —C(O)R z , —C(O)OR z , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl or C 3-6 cycloalkyl or two R 6 taken together on adjacent carbon atoms form a C 3-7 cycloalkyl;
T is C 1-4 alkylene, —S(O) 2 —, —C(O)—, —C 1-4 alkylene-C(O)—, C 1-4 alkylene-S(O) 2 — or —S—;
R y is halogen, oxo, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, cyano or —N(R z ) 2 ; and
each R z is hydrogen or C 1-4 alkyl.
2 . The compound or salt of claim 1 , wherein the compound is a compound of Formula (I):
or a pharmaceutically acceptable salt of said compound, wherein;
X is N, CH 2 , O, S, S(O), S(O)(NR z ) or S(O) 2 ;
Z is C—H, C-halogen, C—CN, C—C 1-4 alkyl, C—C 1-4 haloalkyl, C—C 1-4 alkoxy, C—C 1-4 haloalkoxy, C—C 3-7 cycloalkyl or N;
Q is CH, C-halogen, C—C 1-4 alkyl, C—C 1-4 haloalkyl or N;
n is 0, 1, 2, or 3;
m is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
each R x is hydroxyl, halogen, oxo, cyano, —N(R z ) 2 , C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-7 membered heteroaryl, -T-R y or two R x taken together with the same carbon or adjacent carbon atoms can form C 3-7 cycloalkyl, a 3-7 membered heterocycloalkyl, wherein each C 3-7 cycloalkyl or 3-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of R y or two R x taken together can form a bridged ring where the bridge is selected from one of the following: —C 1-4 alkylene, —C 1-4 alkylene-O—C 1-4 alkylene-, —O—, —S— or —C 1-4 alkylene-S—C 1-4 alkylene- and wherein each C 1-4 alkylene is further substituted with 0-2 occurrences of R y ;
L is a bond, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, —O—C 1-6 alkylene, —S—C 1-6 alkylene, NR z , O or S, wherein each C 1-6 alkylene, —O—C 1-6 alkylene and —S—C 1-6 alkylene chain is substituted with 0-2 occurrences of R 2 ;
-L 1 -L 2 - is -L 2 , —N(R z )C(O)-L 2 , —C(O)-L 2 -, —OC(O)-L 2 , —C(O)O-L 2 , —OC(O)—O-L 2 , —OC(S)—O-L 2 , —O-L 2 , —N(R z )C(O)O-L 2 , —OC(O)N(R z )-L 2 , —N(R z )-L 2 , —S(O) 2 -L 2 , —S-L 2 , alkylene-OC(O)-L 2 , —C 1-4 alkylene-O-L 2 , —C 1-4 alkylene-S(O) 2 -L 2 , —C 1-4 alkylene-S-L 2 , —C14 alkylene-S(O)-L 2 , —O-5-6 membered heteroaryl-L 2 , —C 1-4 alkylene-5-6 membered heteroaryl-L 2 , —C 1-4 hydroxyalkylene-5-6-membered heteroaryl-L 2 or a 5-6 membered heteroaryl-L 2 ;
L 2 is C 1-6 alkylene, C 1-6 alkylene-O—, C 1-6 alkylene-O—C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-7 cycloalkylene, C 1-4 alkylene-C 3-7 cycloalkylene, C 1-4 haloalkylene-C 3-7 cycloalkylene, C 3-7 cycloalkylene-C 14 alkylene, C 1-6 hydroxyalkylene or C 1-6 haloalkylene;
R 1 is hydrogen, hydroxyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R 5 ;
R 2 is halogen, hydroxyl, C 1-4 alkyl or two R 2 on the same or adjacent carbon atoms can be taken together to form a C 3-7 cycloalkyl;
A is 5-10 membered heteroaryl and is substituted with q occurrences of R 6 ;
R 4 is hydrogen, hydroxyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl or cyano;
each R 5 independently is halogen, cyano, oxo, -T-R y , hydroxyl, —N(R z ) 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or —O—C 2-4 alkynyl;
each R 6 independently is halogen, hydroxyl, cyano, —N(R z ) 2 , —C(O)R 2 , —C(O)OR 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl or C 3-6 cycloalkyl or two R 6 taken together on adjacent carbon atoms form a C 3-7 cycloalkyl;
T is C 1-4 alkylene, —S(O) 2 —, —C(O)—, —C 1-4 alkylene-C(O)—, C 1-4 alkylene-S(O) 2 — or —S—;
R y is halogen, oxo, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, cyano or —N(R z ) 2 ; and
each R z is hydrogen or C 1-4 alkyl.
3 . The compound or salt of claim 2 , wherein Z is N and Q is CH or Z is C—F and Q is CH.
4 . The compound or salt of claim 2 , wherein L is-O-methylene-, —O-ethylene-, —O-n-propylene or —O-isopentanylene and L is substituted with 0-2 occurrences of R 2 .
5 . The compound or salt according to claim 2 , wherein -L-R 1 is
methoxy or methyl.
6 . The compound or salt of claim 5 , wherein -L-R 1 is
7 - 8 . (canceled)
9 . The compound or salt of claim 1 , wherein n is 1 and m is 1 or n is 1 and m is 2 or n is 2 and m is 1.
10 . The compound or salt of claim 9 , wherein X is O.
11 . The compound or salt of claim 1 , wherein B-L 1 is
12 . The compound or salt of claim 11 , wherein B-L 1 is
13 . The compound or salt of claim 1 , wherein X is CH 2 .
14 . The compound or salt of claim 13 , wherein n is 0 and m is 1; n is 1 and m is 0; n is 1 and m is 1; n is 1 and m is 2 or n is 2 and m is 1.
15 . The compound or salt of claim 14 , wherein
16 . The compound or salt of claim 15 , wherein B-L 1 is
17 . The compound or salt of claim 1 , wherein B-L 1 is
18 . The compound or salt of claim 17 , wherein B-L 1 is
19 - 22 . (canceled)
23 . The compound or salt of claim 22 , wherein A-L 2 is
24 . The compound or salt of claim 23 , wherein A-L 2 is
25 . The compound or salt of claim 1 , wherein -L 1 -L 2 - is —O—C(O)—O-L 2 .
26 . The compound or salt of claim 25 , wherein L 2 is ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propenylene, trans-2-propenylene or —CH 2 -cyclopropylene.
27 . The compound or salt of claim 26 , wherein -L 1 -L 2 - is
28 - 29 . (canceled)
30 . The compound or salt of claim 1 , wherein -L 1 -L 2 - is a —C 1-4 hydroxyalkylene-5-6 membered heteroaryl-L 2 .
31 . The compound or salt of claim 30 , wherein -L 1 -L 2 - is
32 . The compound or salt of claim 31 , wherein L 2 is ethylene.
33 . The compound or salt of claim 32 , wherein -L 1 -L 2 - is
34 . The compound or salt of claim 1 , wherein -L 1 -L 2 - is —C 1-4 alkylene-O-L 2 .
35 . The compound or salt of claim 34 , wherein -L 1 -L 2 - is -methylene-O-L 2 .
36 . The compound or salt of claim 35 , wherein L 2 is n-butylene, 2,2-difluoro-n-butylene, trans-2-butenylene, cis-2-butenylene, 3-methyl-n-butylene, -ethylene-cyclopropylene- or ethylene-O-methylene.
37 . The compound or salt of claim 36 , wherein -L 1 -L 2 - is
38 . (canceled)
39 . The compound or salt of claim 34 , wherein -L 1 -L 2 - is ethylene-O-L 2 .
40 . The compound or salt of claim 39 , wherein L 2 is ethylene, n-propylene or methylene-cyclopropylene.
41 . The compound or salt of claim 40 , wherein -L 1 -L 2 - is
42 . (canceled)
43 . The compound or salt of claim 1 , wherein -L 1 -L 2 - is —NR z —C(O)—O-L 2 .
44 . The compound or salt of claim 43 , wherein R z is hydrogen or methyl.
45 . The compound or salt of claim 43 or 44 , wherein L z is n-propylene, ethylene, —CH 2 -cyclopropylene.
46 . The compound or salt of claim 45 , wherein -L 1 -L 2 - is
47 - 51 . (canceled)
52 . The compound or salt of claim 1 , wherein -L 1 -L 2 - is —C(O)—.
53 . The compound or salt of claim 52 , wherein L 2 is n-propylene, -methylene-O-n-propylene or n-butylene.
54 . The compound or salt of claim 53 , wherein -L 1 -L 2 - is
55 . (canceled)
56 . The compound or salt of claim 1 , wherein R 4 is C 1-4 alkyl or halogen.
57 . The compound or salt of claim 56 , wherein R 4 is fluorine.
58 . The compound or salt of claim 1 , wherein the compound is:
Compound
or
59 . (canceled)
60 . The compound or salt of claim 1 , wherein the compound is:
Compound
or
61 . (canceled)
62 . A pharmaceutical composition comprising the compound or salt according of claim 1 and a pharmaceutically acceptable excipient.
63 - 69 . (canceled)
70 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according of claim 1 or a pharmaceutical composition according to claim 62 .
71 . (canceled)
72 . The method according to claim 70 , wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
73 . The method according to claim 70 , wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
74 . The method according to claim 73 , wherein the cancer is non-small cell lung cancer.
75 . The method according to claim 73 , wherein the cancer is colorectal cancer.
76 . The method according to claim 73 , wherein the cancer is pancreatic cancer.
77 . (canceled)