Hydrazinyl-pyrrolo compounds and methods for producing a conjugate

1. A conjugate of formula (IIIa):

wherein:

m is 0 or 1;

R 1 is selected from hydrogen and alkyl;

R 2 and R 3 are each alkyl;

X 1 is C or N, wherein if X 1 is N, then Y 1 is absent;

X 2 , X 3 and X 4 are each C;

Y 1 , if present, Y 2 , Y 3 and Y 4 are each hydrogen;

L is a linker represented by -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) 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 T 1 , T 2 , T 3 , T 4 and T 5 and V 1 , V 2 , V 3 , V 4 and V 5 are selected from the following table:

T 1

V 1

T 2

V 2

T 3

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(EDA) w

(C 1 -C 12 )alkylene

—CO—

(EDA) w

—CO—

(CR 13 OH) h

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CO—

(EDA) w

—CO—

(CR 13 OH) h

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CO—

(EDA) w

—CO—

(CR 13 OH) h

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

MABO

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CO—

(AA) p

—NR 11 —

(PEG) n

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

MABC

(C 1 -C 12 )alkylene

—CONR 11 —

substituted

—NR 11 —

(PEG) n

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CONR 11 —

(PEG) n

—CO—

(AA) p

(C 1 -C 12 )alkylene

—CONR 11 —

(C 1 -C 12 )

—

(CR 13 OH) h

alkylene

(C 1 -C 12 )alkylene

—CO—

P4A

—CO—

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CO—

P4A

—CO—

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CO—

P4A

—CO—

(C 1 -C 12 )

alkylene

(C 1 -C 12 )alkylene

—CO—

P4A

—CO—

(C 1 -C 12 )

alkylene

V 3

T 4

V 4

T 5

V 5

—CO—

—

—

—

—

—NR 11 —

—

—

—

—

—

—

—

—

—

—CONR 11 —

(C 1 -C 12 )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

—

—SO 2 —

(AA) p

—

—

—

—

PABC—

—

—

—

(AA) p

—

PABC

—

—

—

—CONR 11 —

(PEG) n

—CO—

—

—

—CO—

MABC—

—

—

—

(AA) p—

—CO—

MABC

—

(AA) p

—

—

—

—

—

—

—CO—

MABO

—

—

—

—CO—

PABO

—

—

—

—CO—

PABC

—

—

—

—

(AA) p

—

—

—

—CO—

—

—

—

—

—

PABC

—

—NR 11 —

—

—CONR 11 —

—

—

—

—

—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;

R 11 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;

R 13 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 R 14 is independently selected from hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, aryl, and substituted aryl;

each R 15 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 R 16 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;

W 1 is a drug; and

W 2 is an antibody.

2. 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 R 12 is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl and a substituted aryl, wherein any two adjacent R 12 groups may be cyclically linked to form a piperazinyl ring; and

R 13 is selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl.

3. 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.

4. The conjugate of claim 1 , wherein m is 1.

5. The conjugate of claim 1 , wherein X 1 , X 2 , X 3 and X 4 are each C.

6. The conjugate of claim 1 , wherein the drug comprises a maytansinoid.

7. The conjugate of claim 6 , wherein the maytansinoid is deacyl maytansine.

8. The conjugate of claim 1 , wherein the conjugate is of the formula:

9. A pharmaceutical composition comprising:

a conjugate of claim 1 ; and

a pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9 , wherein the conjugate is of the formula:

11. 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 .

12. The method of claim 11 , wherein the conjugate is of the formula:

13. A method of treating cancer by administering to a patient having said cancer a therapeutically effective amount of the conjugate of claim 1 .

14. The method of claim 13 , wherein the cancer is carcinoma, sarcoma, leukemia, or lymphoma.

15. 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.

16. 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.

17. 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.

18. 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.

19. The method of claim 13 , wherein the cancer is a solid tumor.

20. 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.

21. The method of claim 13 , wherein the cancer is multiple myeloma.