US 12,465,653 B2
Thienoazepine immunoconjugates, and uses thereof
Romas Kudirka, Redwood City, CA (US); and Brian Safina, Redwood City, CA (US)
Assigned to BOLT BIOTHERAPEUTICS, INC., Redwood City, CA (US)
Filed by BOLT BIOTHERAPEUTICS, INC., Redwood City, CA (US)
Filed on Mar. 6, 2023, as Appl. No. 18/118,105.
Application 18/118,105 is a division of application No. 17/078,467, filed on Oct. 23, 2020, granted, now 11,654,199.
Claims priority of provisional application 62/984,184, filed on Mar. 2, 2020.
Claims priority of provisional application 62/926,333, filed on Oct. 25, 2019.
Prior Publication US 2023/0338571 A1, Oct. 26, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/68 (2017.01); C07K 16/28 (2006.01)
CPC A61K 47/6803 (2017.08) [A61K 47/6849 (2017.08); A61K 47/6889 (2017.08); C07K 16/2827 (2013.01)] 30 Claims
OG exemplary drawing
 
1. An immunoconjugate comprising an antibody covalently attached to one or more 5-aminothienoazepine moieties by a linker, and having Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
Ab is the antibody;
p is an integer from 1 to 8;
TAZ is the 5-aminothienoazepine moiety having the formula:

OG Complex Work Unit Chemistry
R1, R2, R3, and R4 are independently selected from the group consisting of H, C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are independently and optionally substituted with one or more groups selected from;
—(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-N(R5)2;
—(C1-C12 alkyldiyl)-OR5;
—(C3-C12 carbocyclyl);
—(C3-C12 carbocyclyl)-*;
—(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-NR5—*;
—(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-N(R5)2;
—(C3-C12 carbocyclyl)-NR3—C(═NR5)NR5—*;
—(C6-C20 aryl);
—(C6-C20 aryl)-*;
—(C6-C20 aryldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-(C2-C20 heterocyclyldiyl)-*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-NR5—C(═NR5a)N(R5)—*;
—(C2-C20 heterocyclyl);
—(C2-C20 heterocyclyl)-*;
—(C2-C9 heterocyclyl)-(C1-C12 alkyldiyl)-NR5—*;
—(C2-C9 heterocyclyl)-(C1-C12 alkyldiyl)-N(R5)2;
—(C2-C9 heterocyclyl)-C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
—(C2-C9 heterocyclyl)-NR5—C(═NR5a)NR5a—*;
—(C2-C9 heterocyclyl)-NR5—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C2-C9 heterocyclyl)-(C6-C20 aryldiyl)-*;
—(C1-C20 heteroaryl);
—(C1-C20 heteroaryl)-*;
—(C1-C20 heteroaryl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C20 heteroaryl)-(C1-C12 alkyldiyl)-N(R5)2;
—(C1-C20 heteroaryl)-NR5—C(═NR5a)N(R5)—*;
—(C1-C20 heteroaryl)-N(R5)C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
—C(═O)—*;
—C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
—C(═O)—(C2-C20 heterocyclyldiyl)-*;
—C(═O)N(R5)2;
—C(═O)N(R5)—*;
—C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)R5;
—C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)N(R5)2;
—C(═O)NR5—(C1-C12 alkyldiyl)-N(R5)CO2R3;
—C(═O)NR5—(C1-C12 alkyldiyl)-N(R5)C(═NR5a)N(R5)2;
—C(═O)NR5—(C1-C12 alkyldiyl)-NR5C(═NR5a)R5;
—C(═O)NR5—(C1-C8 alkyldiyl)-NR5(C2-C8 heteroaryl);
—C(═O)NR5—(C1-C20 heteroaryldiyl)-N(R5)—*;
—C(═O)NR5—(C1-C20 heteroaryldiyl)-*;
—C(═O)NR5—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
—C(═O)NR5—(C1-C20 heteroaryldiyl)-(C2-C20 heterocyclyldiyl)-C(═O)NR5—(C1-C12 alkyldiyl)-NR5—*;
—N(R5)2;
—N(R5)—*;
—N(R5)C(═O)R5;
—N(R5)C(═O)—*;
—N(R5)C(═O)N(R5)2;
—N(R5)C(═O)N(R5)—*;
—N(R5)CO2R5;
—NR5C(═NR5a)N(R5)2;
—NR5C(═NR5a)N(R5)—*;
—NR5C(═NR5a)R5;
—N(R5)C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
—N(R5)—(C2-C5 heteroaryl);
—N(R5)—S(═O)—(C1-C12 alkyl);
—O—(C1-C12 alkyl);
—O—(C1-C12 alkyldiyl)-N(R5)2;
—O—(C1-C12 alkyldiyl)-N(R5)—*;
—S(═O)2—(C2-C20 heterocyclyldiyl)-*;
—S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
—S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-NR5—*; and
—S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-OH;
or R2 and R3 together form a 5- or 6-membered heterocyclyl ring;
X1, X2, X3, and X4 are independently selected from the group consisting of a bond, C(═O), C(═O)N(R5), O, N(R5), S, S(O)2, and S(O)2N(R5);
R5 is selected from the group consisting of H, C6-C20 aryl, C3-C12 carbocyclyl, C6-C20 aryldiyl, C1-C12 alkyl, and C1-C12 alkyldiyl, or two R5 groups together form a 5- or 6-membered heterocyclyl ring;
R5a is selected from the group consisting of C6-C20 aryl and C1-C20 heteroaryl;
where the asterisk * indicates the attachment site of L, and where one of R1, R2, R3 and R4 is attached to L;
L is the linker selected from the group consisting of:
—C(═O)—(PEG)-;
—C(═O(PEG)-C(═O)—;
—C(═O)—(PEG)-O—;
—C(═O(PEG)-C(═O)—(PEP)-;
—C(═O(PEG)-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
—C(═O(PEG)-C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O(PEG)-C(═O)N(R5)—(C1-C12 alkyldiyl)-(MCgluc)-;
—C(═O(PEG)-C(═O)-(MCgluc)-;
—C(═O(PEG)-C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-;
—C(═O(PEG)-C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)—(PEG)-N(R5)—;
—C(═O(PEG)-N(R5)C(═O)—;
—C(═O(PEG)-N(R5)—(PEG)-C(═O)—(PEP)-;
—C(═O)—(PEG)-N*(R5)2(EG)-C(═O)—(PEP)-;
—C(═O(PEG)-C(═O)—N(R5)CH(AA1)C(═O)-(PEG)-C(═O)—(PEP)-;
—C(═O(PEG)-C(═O)—N(R5)CH(AA1)C(═O)—N(R5)—(C1-C12 alkyldiyl)-;
—C(═O(PEG)-SS—(C1-C12 alkyldiyl)-OC(═O)—;
—C(═O(PEG)-SS—(C1-C12 alkyldiyl)-C(═O)—;
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—(PEP)-;
—C(═O)C1-C12 alkyldiyl)-C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-;
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-N(R5)—C(═O);
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O—(PEG)-C(═O)-(MCgluc)-;
—C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O—(PEG)-C(═O)-(MCgluc)-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-; and
-(succinimidyl)-(CH2)m—C(═O)—(PEP)—N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
PEG has the formula: —(CH2CH2O)n—(CH2)m—; m is an integer from 1 to 5, and n is an integer from 2 to 50;
PEP has the formula:

OG Complex Work Unit Chemistry
where AA1 and AA2 are independently selected from an amino acid side chain, or AA1 or AA2 and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment;
R6 is selected from the group consisting of C6-C20 aryldiyl and C1-C20 heteroaryldiyl, substituted with —CH2O—C(═O)— and optionally with:

OG Complex Work Unit Chemistry
and
MCgluc is selected from the groups:

OG Complex Work Unit Chemistry
where q is 1 to 8, and AA is an amino acid side chain; and
alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH═CH2, —C═CH, —C═CCH3, —CH2CH2CH3, —CH(CH3), —CH2CH(CH3), —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)OH, —CH(OH)CH(CH3), —C(CH3)CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)CN, —CH2CN, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3), —CO2K, —COCH3, —CO2CH3, —CO2C(CH3), —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3), —C(CH3)CONH2, —NH2, —NHCH3, —N(CH3), —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)CONH2, —N(CH3)CH2CH2S(O)2CH3, —NHC(═NH)H, —NHC(═NH)CH3, —NHC(═NH)NH2, —NHC(═O)NH2, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —CH2CH2OCH3, —OCH2CH2OH, —CH2CH2N(CH3), —O(CH2CH2O), —(CH2)˜CO2H, —O(CH2CH2O)nH, —OCH2F, —OCHF2, OCF3, —OP(OXOH)2, —S(O)2N(CH3), —SCH3, —S(O)2CH3, and —S(O)3H.