US 11,718,638 B2
Compounds, compositions and methods for synthesis
David Charles Donnell Butler, Medford, MA (US); Christopher P. Hencken, Boston, MA (US); Naoki Iwamoto, Brighton, MA (US); Pachamuthu Kandasamy, Belmont, MA (US); Alvaro Andres Lanao, Boston, MA (US); Genliang Lu, Winchester, MA (US); Mamoru Shimizu, Arlington, MA (US); Sethumadhavan Divakaramenon, Lexington, MA (US); Chandra Vargeese, Schwenksville, PA (US); Gopal Reddy Bommineni, Belmont, MA (US); and Subramanian Marappan, Acton, MA (US)
Assigned to WAVE LIFE SCIENCES LTD., Singapore (SG)
Appl. No. 16/624,896
Filed by WAVE LIFE SCIENCES LTD., Singapore (SG)
PCT Filed Jun. 21, 2018, PCT No. PCT/US2018/038835
§ 371(c)(1), (2) Date Dec. 19, 2019,
PCT Pub. No. WO2018/237194, PCT Pub. Date Dec. 27, 2018.
Claims priority of provisional application 62/560,169, filed on Sep. 18, 2017.
Claims priority of provisional application 62/523,175, filed on Jun. 21, 2017.
Prior Publication US 2022/0356204 A1, Nov. 10, 2022
Int. Cl. C07H 21/04 (2006.01); C07H 19/06 (2006.01); C07C 213/00 (2006.01); C07C 215/20 (2006.01); C07C 215/44 (2006.01); C07D 207/08 (2006.01); C07D 211/22 (2006.01); C07F 7/08 (2006.01); C07F 9/6564 (2006.01)
CPC C07H 21/04 (2013.01) [C07C 213/00 (2013.01); C07C 215/20 (2013.01); C07C 215/44 (2013.01); C07D 207/08 (2013.01); C07D 211/22 (2013.01); C07F 7/083 (2013.01); C07F 7/0812 (2013.01); C07F 9/6564 (2013.01); C07H 19/06 (2013.01); C07C 2601/14 (2017.05)] 20 Claims
 
1. A compound having the structure of formula V-b:

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or a salt thereof, wherein:
PL is P;

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 is of such a structure that

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 is a compound of formula I-e or a salt thereof:

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wherein:
L8-H is the —OH shown in formula I-e;
t is 1;
Ring A is an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
each of R1, R2, R3, R4, and R5 is independently —H, -Ls-R, halogen, —CN, —NO2,
Ls-Si(R)3, —OR, —SR, or —N(R)2;
R6 is —H;
—NHR5 is —NR5R6 shown in formula I-e;
each Ls is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C1-30 aliphatic group and a C1-30 heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-6 alkylene, C1-6 alkenylene, —C≡C—, a bivalent C1-C6 heteroaliphatic group having 1-5 heteroatoms, —C(R′)2—, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′)3]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, —OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or —OP(OR′)[B(R′)3]O—, and one or more carbon atoms are optionally and independently replaced with CyL;
each -Cy- is independently an optionally substituted bivalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
each CyL is independently an optionally substituted tetravalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O)2R;
BA is an optionally substituted group selected from a natural nucleobase moiety and a modified nucleobase moiety;
each Rs is independently —H, halogen, —CN, —N3, —NO, —NO2, -Ls-R′, -Ls-Si(R)3, -Ls-OR′, -Ls-SR′, -Ls-N(R′)2, —O-Ls-R′, —O-Ls-Si(R)3, —O-Ls-OR′, —O-Ls-SR′, or —O-Ls-N(R′)2;
Ring As is

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 wherein each of R2s and R4s is independently Rs;
R5s is Rs;
each R is independently —H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms, C6-30 aryl, C6-30 arylaliphatic, C6-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
two R groups are optionally and independently taken together to form a covalent bond, or:
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms; or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.