# US 12,215,090 B2 · Agents and methods for treating dysproliferative diseases

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- Number: US 12,215,090 B2
- Document ID: US12215090B2
- Status: Granted
- Kind: B2
- Application number: 16/970,918
- Filed: 2019-02-18
- Published: 2020-12-17
- Granted: 2025-02-04
- Earliest claimed: 2018-02-19
- Assignees: Memorial Sloan Kettering Cancer Center; Tri-Institutional Therapeutics Discovery Institute, Inc.
- Applicants: Memorial Sloan-kettering Cancer Center
- Inventors: Yoshiyuki Fukase; Mark Duggan; Hans-Guido Wendel; Kamini Singh
- Web page: https://patentgrep.com/patent/US12215090B2

## CPC

- C07D 307/93: condensed with a ring other than six-membered
- A61P 35/00: Antineoplastic agents
- C07F 9/65517: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Compounds are described with the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and n are defined as anywhere herein, which are useful for the treatment of cancer and other dysproliferative diseases.

## Claims

### Claim 1

A compound represented by formula (I)
wherein
R1, R3, and R5 are each independently H, alkyl, —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2—P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2—P(O)(O-alkyl)(O-alkyl), or (CO)-alkyl, or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2—P(O)(OH)(O-alkyl), and
wherein at least one of R1, R3, and R5 is H, —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2—P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2—P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2—P(O)(OH)(O-alkyl);
R2 and R4 are each independently H, alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
R6 is alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
R7 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
R8 and R9 are each independently H, OH, alkyl, halo, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, or NH(CO)-alkyl;
R10 is H, alkyl, (CO)-alkyl, or (CO)NRaRb;
R11 and R12 are each independently H, OH, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxy, or heteroaryloxy;
Ra and Rb are each H or alkyl, or Ra and Rb, together with the nitrogen atom they are attached, form a heterocycloalkyl group; and
n is an integer from 0 to 4,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R11 is H.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R11 and R12 both are H.

### Claim 4 (depends on 2)

The compound of claim 2, wherein R11 is H and R12 is alkyloxy or cycloalkyloxy.

### Claim 5 (depends on 2)

The compound of claim 2, wherein R11 is H and R12 is OMe.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3 is H, —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2—P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2—P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2—P(O)(OH)(O-alkyl).

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R5 is H, —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2—P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2—P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2—P(O)(OH)(O-alkyl).

### Claim 9 (depends on 1)

The compound of claim 1, wherein R5 is H.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R5 is —P(O)(OH)(OH) or —CH2—P(O)(OH)(OH), or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is H, —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2—P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2—P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2—P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2—P(O)(OH)(O-alkyl).

### Claim 12 (depends on 1)

The compound of claim 1, wherein R1 is H.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 is alkyl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R1 is methyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2 and R4 are H and n is 0.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R10 is H.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R8 is H and R9 is OH.

### Claim 18 (depends on 1)

The compound of claim 1, wherein said compound of formula (I) is represented by a compound of formula (II)

### Claim 19 (depends on 18)

The compound of claim 18, wherein R12 is H or OMe.

### Claim 20 (depends on 1)

The compound of claim 1, wherein said compound of formula (I) is represented by a compound of formula (III)

### Claim 21 (depends on 20)

The compound of claim 20, wherein R12 is OMe.

### Claim 22 (depends on 20)

The compound of claim 20, wherein R12 is H.

### Claim 23 (depends on 1)

The compound of claim 1, wherein said compound of formula (I) is represented by a compound of formula (IV)
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The compound of claim 23, wherein R12 is alkyloxy or cycloalkyloxy.

### Claim 25 (depends on 23)

The compound of claim 23, wherein R12 is OMe.

### Claim 26 (depends on 1)

The compound of claim 1, wherein said compound of formula (I) is represented by a compound of formula (V)

### Claim 27 (depends on 1)

The compound of claim 1, wherein said compound of formula (I) is represented by a compound of formula (VI)

### Claim 28 (depends on 1)

The compound of claim 1, wherein said compound is

### Claim 29 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically-acceptable excipient, diluent or carrier.

### Claim 30 (depends on 29)

A method for treating or intervening in the recurrence of a cancer or dysproliferative disease in a subject comprising administering to the subject a pharmaceutical composition of claim 29.

### Claim 31 (depends on 30)

The method of claim 30 wherein the cancer is T-cell acute lymphoblastic leukemia, small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, neuroblastoma, pancreatic cancer, transformed follicular lymphoma, mantel cell lymphoma, breast cancer, ovarian cancer, hepatocellular carcinoma, non-small cell lung cancer, gastric cancer, Ewing sarcoma or lung adenocarcinoma.