# US 12,215,080 B2 · Hydrazinyl-pyrrolo compounds and methods for producing a conjugate > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,215,080 B2 - Document ID: US12215080B2 - Status: Granted - Kind: B2 - Application number: 17/497,735 - Filed: 2021-10-08 - Published: 2022-05-19 - Granted: 2025-02-04 - Earliest claimed: 2013-11-27 - Assignees: Redwood Bioscience, Inc. - Applicants: Redwood Bioscience Inc. - Inventors: David Rabuka; Aaron Edward Albers; Romas Alvydas Kudirka; Albert W. Garofalo; Jesse M. McFarland - Web page: https://patentgrep.com/patent/US12215080B2 ## CPC - C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical - A61K 47/68031: {the drug being an auristatin} - A61K 47/68033: {the drug being a maytansine} - A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin} - A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin} - A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment} - C07D 405/12: linked by a chain containing hetero atoms as chain links - C07D 498/18: Bridged systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The present disclosure provides conjugate structures and hydrazinyl-pyrrolo compound structures used to produce these conjugates. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same. ## Claims ### Claim 1 A conjugate of formula (IIIa): wherein: m is 0 or 1; R1 is selected from hydrogen and alkyl; R2 and R3 are each alkyl; X1 is C or N, wherein if X1 is N, then Y1 is absent; X2, X3 and X4 are each C; Y1, if present, Y2, Y3 and Y4 are each hydrogen; L is a linker represented by -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-, wherein a, b and c are each 1, and d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 3 to 5; wherein T1, T2, T3, T4 and T5 and V1, V2, V3, V4 and V5 are selected from the following table: T1 V1 T2 V2 T3 (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CONR11— (PEG)n —CO— (EDA)w (C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h (C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12) alkylene (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h (C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12) alkylene (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12) alkylene (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CONR11— (PEG)n —CO— MABO (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n (C1-C12)alkylene —CONR11— (PEG)n —CO— MABC (C1-C12)alkylene —CONR11— substituted —NR11— (PEG)n (C1-C12) alkylene (C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p (C1-C12)alkylene —CONR11— (C1-C12) — (CR13OH)h alkylene (C1-C12)alkylene —CO— P4A —CO— (C1-C12) alkylene (C1-C12)alkylene —CO— P4A —CO— (C1-C12) alkylene (C1-C12)alkylene —CO— P4A —CO— (C1-C12) alkylene (C1-C12)alkylene —CO— P4A —CO— (C1-C12) alkylene V3 T4 V4 T5 V5 —CO— — — — — —NR11— — — — — — — — — — —CONR11— (C1-C12)alkylene —CO— — — —CO— — — — — — — — — — — MABO — — — — PABO — — — — PABC — — — —CO— (AA)p — — — —CO— (AA)p — — — —CO— (AA)p — — — —CO— (AA)p — — — —CO— (AA)p— — — — PABC— (AA)p —CO— (AA)p— — PABC— — (AA)p —CO— (AA)p— — — — PABO —CO— (AA)p — PABO — —SO2— (AA)p — — — — PABC— — — — (AA)p — PABC — — — —CONR11— (PEG)n —CO— — — —CO— MABC— — — — (AA)p— —CO— MABC — (AA)p — — — — — — —CO— MABO — — — —CO— PABO — — — —CO— PABC — — — — (AA)p — — — —CO— — — — — — PABC — —NR11— — —CONR11— — — — — —CO— (AA)p — PABO —CO— —CO— (AA)p — PABO — —CO— (AA)p — PABC — (AA)p —CO— (AA)p— — — — wherein: EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue; piperidin-4-amino (P4A) is MABC is MABO is PABC is PABO is w is an integer from 1 to 20; n is an integer from 1 to 30; p is an integer from 1 to 20; h is an integer from 1 to 12; R11 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; R13 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; each R14 is independently selected from hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, aryl, and substituted aryl; each R15 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; each R16 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; W1 is a drug; and W2 is an antibody. ### Claim 2 (depends on 1) The conjugate of claim 1, wherein: (PEG)n is where n is an integer from 1 to 30; EDA is an ethylene diamine moiety having the following structure: where q is an integer from 1 to 6 and r is 0 or 1; each R12 is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl and a substituted aryl, wherein any two adjacent R12 groups may be cyclically linked to form a piperazinyl ring; and R13 is selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl. ### Claim 3 (depends on 1) The conjugate of claim 1, wherein L is one of the following structures: wherein: each f is independently 0 or an integer from 1 to 12; each w is independently 0 or an integer from 1 to 20; each n is independently 0 or an integer from 1 to 30; each p is independently 0 or an integer from 1 to 20; each h is independently 0 or an integer from 1 to 12; each R is independently hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and each R′ is independently H, a sidechain group of an amino acid, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. ### Claim 4 (depends on 1) The conjugate of claim 1, wherein m is 1. ### Claim 5 (depends on 1) The conjugate of claim 1, wherein X1, X2, X3 and X4 are each C. ### Claim 6 (depends on 1) The conjugate of claim 1, wherein the drug comprises a maytansinoid. ### Claim 7 (depends on 6) The conjugate of claim 6, wherein the maytansinoid is deacyl maytansine. ### Claim 8 (depends on 1) The conjugate of claim 1, wherein the conjugate is of the formula: ### Claim 9 (depends on 1) A pharmaceutical composition comprising: a conjugate of claim 1; and a pharmaceutically acceptable excipient. ### Claim 10 (depends on 9) The pharmaceutical composition of claim 9, wherein the conjugate is of the formula: ### Claim 11 (depends on 1) A method of delivering a conjugate to a subject, the method comprising: administering to the subject an effective amount of a conjugate of claim 1. ### Claim 12 (depends on 11) The method of claim 11, wherein the conjugate is of the formula: ### Claim 13 (depends on 1) A method of treating cancer by administering to a patient having said cancer a therapeutically effective amount of the conjugate of claim 1. ### Claim 14 (depends on 13) The method of claim 13, wherein the cancer is carcinoma, sarcoma, leukemia, or lymphoma. ### Claim 15 (depends on 14) The method of claim 14, wherein the carcinoma is a carcinoma selected from the group consisting of esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma. ### Claim 16 (depends on 14) The method of claim 14, wherein the sarcoma is a sarcoma selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, and rhabdomyosarcoma. ### Claim 17 (depends on 14) The method of claim 14, wherein the leukemia is a leukemia selected from the group consisting of chronic myeloproliferative syndromes, acute myelogenous leukemias, chronic lymphocytic leukemias, and acute lymphoblastic leukemias. ### Claim 18 (depends on 14) The method of claim 14, wherein the lymphoma is a lymphoma selected from the group consisting of B-cell lymphomas, Hodgkin's lymphoma, and non-Hodgkin's B cell lymphoma. ### Claim 19 (depends on 13) The method of claim 13, wherein the cancer is a solid tumor. ### Claim 20 (depends on 19) The method of claim 19, wherein the solid tumor is selected from the group consisting of glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma. ### Claim 21 (depends on 13) The method of claim 13, wherein the cancer is multiple myeloma.