# US 12,006,331 B2 · Therapeutic compounds and methods

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,006,331 B2
- Document ID: US12006331B2
- Status: Granted
- Kind: B2
- Application number: 17/862,963
- Filed: 2022-07-12
- Published: 2023-04-20
- Granted: 2024-06-11
- Earliest claimed: 2021-07-15
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Samantha Alyson Green; Jessica Marie Grandner; Steven Thomas Staben; Neri Amara; Vishva M. Dixit; Elisia Villemure
- Web page: https://patentgrep.com/patent/US12006331B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/12: Aerosols; Foams {(A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015)}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 47/02: Inorganic compounds
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- 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)
- 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

The invention provides a compound of formula (I): or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 have any of the values described in the specification, as well as compositions comprising a compound of formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compounds are agonists of glycolytic enzyme phosphofructokinase-1 liver type and are useful for treating diseases associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type, such as cancer, diabetes, sepsis, and septic shock.

## Claims

### Claim 1

A compound of formula (I):
or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein:
R1 is —NRaRb or a 5-10 membered heteroaryl that is optionally substituted with one or more groups Rc;
R2 is a 6-10 membered aryl that is optionally substituted with one or more groups Rr; or R2 is a 5-10 membered heteroaryl that is that is optionally substituted with one or more groups Rs; or R2 is a 3-10 membered heterocycle that is that is optionally substituted with one or more groups Rz;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkynylcarbonyl, 3-6 membered heterocycle, or a 5-6 membered heteroaryl that is optionally substituted with one or more groups Rf; wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkynylcarbonyl, and 3-6 membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, (C2-C6)alkenyl, (C2-C6)alkynyl, C(═O)NRmRn, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected form the group consisting of halo, hydroxy, cyano, —NRmRn, and —C(═O)NRmRn;
Rb is H or (C1-C6)alkyl;
each Rc is independently selected from the group consisting of cyano, —NRdRe, —C(═O)NRdRe, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)alkanoyl, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)alkanoyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, and cyano;
Rd and Re are each independently selected from the group consisting of H and (C1-C6)alkyl; or Rd and Re are taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
each Rf is independently selected from the group consisting of halo, hydroxy, cyano, —NRgRh, —C(═O)NRgRh, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRgRh, —C(═O)NRgRh, and cyano;
Rg and Rh are each independently selected from the group consisting of H and (C1-C6)alkyl; or Rg and Rh taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rm is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
Rn is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
each Rr is independently selected from the group consisting of halo, hydroxy, cyano, —NRtRu, —C(═O)NRtRu, —S(O)2NRtRu, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, —N(H)S(O)2Rx, —S(O)2Rx, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, and (C2-C6)alkynyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, —S(O)2NRtRu, —S(O)2Rx, and cyano;
each Rs is independently selected from the group consisting of halo, cyano, —NRvRw, —C(═O)NRvRw, —S(O)2NRvRw, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, 3-6 membered heterocycle, and —S(O)2Ry, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, 3-6 membered heterocycle, and (C1-C6)alkylthio, is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, S(O)2NRvRw, —S(O)2Ry, and cyano;
Rt and Ru are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C2-C6)alkynylcarbonyl; or Rt and Ru taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rv and Rw are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)alkanoyl; or Rv and Rw taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rx is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
Ry is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo; and
each Rz is independently selected from the group consisting of oxo, halo, hydroxy, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, S(O)2NRvRw, —S(O)2Ry, cyano, and oxo;
provided the compound is not:

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
R1 is —NRaRb or a 5-10 membered heteroaryl that is optionally substituted with one or more groups Rc;
R2 is a phenyl that is optionally substituted with one or more groups Rr; or R2 is a 5-9 membered heteroaryl that is that is optionally substituted with one or more groups Rs; or R2 is a 9-membered heterocycle that is that is optionally substituted with one or more groups Rz;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C2-C6)alkynylcarbonyl, 3-6 membered heterocycle, or a 5-membered heteroaryl that is optionally substituted with one or more groups Rf; wherein each (C1-C6)alkyl and (C3-C6)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C2-C6)alkynyl, C(═O)NRmRn, and (C1-C6)alkyl that is optionally substituted with one or more hydroxy;
Rb is H or (C1-C6)alkyl;
each Rc is independently selected from the group consisting of cyano, —NRdRe, and (C1-C6)alkyl that is optionally substituted with one or more cyano;
Rd and Re are each H;
each Rf is independently selected from the group consisting of halo, hydroxy, cyano, —C(═O)NRgRh, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy and carboxy;
Rg and Rh are each H;
Rm is H;
Rn is H;
each Rr is independently selected from the group consisting of halo, hydroxy, cyano, —NRtRu, —C(═O)NRtRu, —S(O)2NRtRu, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, —N(H)S(O)2Rx, —S(O)2Rx, and (C2-C6)alkynyl, wherein each (C1-C6)alkyl and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, —NRtRu, —C(═O)NRtRu, and cyano;
each Rs is independently selected from the group consisting of halo, cyano, —NRvRw, —C(═O)NRvRw, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, 3-6 membered heterocycle, and —S(O)2Ry, wherein each (C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and —NRtRu;
Rt and Ru are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C2-C6)alkynylcarbonyl; or Rt and Ru taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rv and Rw are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)alkanoyl;
Rx is (C1-C6)alkyl;
Ry is (C1-C6)alkyl; and
each Rz is independently selected from the group consisting of oxo and (C1-C6)alkyl;
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R1 is —NRaRb.

### Claim 4 (depends on 3)

The compound, prodrug, or pharmaceutically acceptable salt of claim 3, wherein Ra is acetyl.

### Claim 5 (depends on 3)

The compound, prodrug, or pharmaceutically acceptable salt of claim 3, wherein Ra is selected from the group consisting of:

### Claim 6 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R1 is a 5-membered heteroaryl that is optionally substituted with one or more groups Rc.

### Claim 7 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R1 is selected from the group consisting of:

### Claim 8 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R2 is a 5-9 membered heteroaryl that is optionally substituted with one or more groups Rs, or phenyl that is optionally substituted with one or more groups Rr.

### Claim 9 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R2 is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R2 is:
and Rr (C2-C6)alkynyl that is substituted with hydroxy.

### Claim 11 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, wherein R2 is selected from the group consisting of:

### Claim 12 (depends on 1)

The compound, prodrug, or pharmaceutically acceptable salt of claim 1, which is selected from the group consisting of:
and prodrugs and pharmaceutically acceptable salts thereof.

### Claim 13 (depends on 1)

The prodrug of claim 1, which is a compound of formula (I) that comprises a hydroxy group that has been converted to a prodrug group that increases the aqueous solubility of the compound; or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The prodrug or pharmaceutically acceptable salt of claim 13, wherein the hydroxy group has been converted to a prodrug group selected from the group consisting of: a phosphate,

### Claim 15 (depends on 1)

The prodrug or pharmaceutically acceptable salt of claim 1 that is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 16

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound, prodrug, or pharmaceutically acceptable salt as described in claim 1 and a pharmaceutically acceptable excipient.