# US 10,246,463 B2 · Hypoxia-inducible factor 1 (HIF-1) inhibitors

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- Number: US 10,246,463 B2
- Document ID: US10246463B2
- Status: Granted
- Kind: B2
- Application number: 15/563,851
- Filed: 2016-04-06
- Published: 2018-04-05
- Granted: 2019-04-02
- Earliest claimed: 2015-04-07
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Inventors: Kirk R. Gustafson; Martin J. Schnermann; Susanna T. S. Chan; Paresma R. Patel; William D. Figg; James B. McMahon
- Web page: https://patentgrep.com/patent/US10246463B2

## CPC

- C07D 487/16: Peri-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Embodiments of small molecule inhibitors of hypoxia inducible factor 1 (HIF-1) and pharmaceutical compositions thereof are disclosed. The disclosed compounds suppress HIF-1 activity by inhibiting the interaction between the HIF-1 α subunit and transcriptional co-activator protein p300. Embodiments of methods for making and using the small molecule inhibitors are also disclosed.

## Claims

### Claim 1

A compound having a chemical structure according to Formula I or a pharmaceutically acceptable salt thereof
wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements;
R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl; or
R1 and R2 together are ═O or ═S;
each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2;
m is 0, 1, or 2;
R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur; and
each Ra independently is hydrogen or alkyl,
wherein the compound is not a naturally occurring compound.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has a chemical structure according to Formula II:
wherein:
n is 0, 1, 2, 3, or 4; and
each R6 independently is aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl, halo, —ORa, —SRa, —COORa, or —C(O)N(Ra)2, where each Ra independently is hydrogen or alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 0.

### Claim 4 (depends on 2)

The compound of claim 2, wherein n is 0.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
(i) R1 is hydroxyl, lower alkoxy, lower aliphatic, alicyclic, or aryl; or
(ii) R2 is aryl or heteroaryl; or
(iii) both (i) and (ii).

### Claim 6 (depends on 1)

The compound of claim 1, wherein:
R1 is:
wherein Rb is hydrogen, halo, aliphatic, heteroaliphatic, —ORa, —SRa, —C(O)ORa, or —C(O)N(Ra)2; and
Rc is hydrogen, aliphatic, or heteroaliphatic;
optionally wherein R2 is:

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is:
wherein Rb is hydrogen, halo, aliphatic, heteroaliphatic, —ORa, —SRa, —C(O)ORa, or —C(O)N(Ra)2;
Rc is hydrogen, aliphatic, or heteroaliphatic;
each Rd independently is —ORa, hydrogen, halo, aliphatic, heteroaliphatic, amido, —SRa, or aryl; and
x is 0, 1, 2, or 3.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is:

### Claim 9

A pharmaceutical composition comprising:
(i) at least one compound or pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I or a pharmaceutically acceptable salt thereof
wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl; or R1 and R2 together are ═O or ═S,
each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
m is 0, 1, or 2,
R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
each Ra independently is hydrogen or alkyl; and
(ii) at least one pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, further comprising a second therapeutic agent.

### Claim 11 (depends on 1)

A method of making a compound according to claim 1, comprising:
(i) heating compound A, wherein R′ is hydrogen or R3, with 1,1-dimethoxy-N,N′-dimethylmethanamine to form an intermediate
(ii) refluxing a solution comprising the intermediate and guanidine hydrochloride to form compound B
(iii) hydrogenating compound B with a catalyst comprising Pd/C to form compound C
(iv) oxidizing R2—C(O)CH2X to form R2—C(O)C(O)H, where X is halo;
(v) if R2 is —OH or —SH, heating compound C with the R2—C(O)C(O)H to form compound D where A is O or S; or if R2 is other than —OH or —SH, heating compound C with the R2—C(O)C(O)H, followed by addition of an oxidant to form compound E
and
(vi) optionally reacting compound E with a nucleophile comprising R1 to form compound F

### Claim 12 (depends on 11)

The method of claim 11, wherein:
R4 and R5 together with the carbon atoms to which they are bound define an optionally substituted phenyl ring; or
R′ is hydrogen; or
R1 is hydroxyl, lower alkoxy, lower aliphatic, alicyclic, or aryl; or
R2 is aryl or heteroaryl; or
any combination thereof.

### Claim 13 (depends on 11)

The method of claim 11, wherein the nucleophile comprising R1 is R1H.

### Claim 14

A method for inhibiting hypoxia-inducible factor 1 (HIF-1) activity, comprising contacting a cell with an effective amount of a compound or pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I
wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl; or R1 and R2 together are ═O or ═S,
each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
m is 0, 1, or 2,
R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
each Ra independently is hydrogen or alkyl.

### Claim 15 (depends on 14)

The method of claim 14, further comprising contacting the cell with a second therapeutic agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the second therapeutic agent is an anticancer agent, an antimalarial agent, or an anti-inflammatory agent.

### Claim 17

A method, comprising administering to a subject a therapeutically effective amount of:
(i) a compound, or a pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I
wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl; or R1 and R2 together are ═O or ═S,
each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
m is 0, 1, or 2,
R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
each Ra independently is hydrogen or alkyl, or
(ii) a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

### Claim 18 (depends on 17)

The method of claim 17, wherein the subject has a solid tumor, malaria, or an inflammatory condition mediated by HIF-1.

### Claim 19 (depends on 18)

The method of claim 18, wherein administering comprises:
administering to the subject a pharmaceutical composition comprising (i) the compound or pharmaceutically acceptable salt thereof, (ii) a second therapeutic agent, and (iii) at least one pharmaceutically acceptable carrier; or
separately administering in any order to the subject (i) the compound or pharmaceutically acceptable salt thereof and (ii) a second therapeutic agent.

### Claim 20 (depends on 18)

The method of claim 18, wherein the inflammatory condition is a malignant tumor, intestinal inflammation, lung inflammation, ischemia, atherosclerosis, myocardial infarction, rheumatoid arthritis, or a healing wound.

### Claim 21 (depends on 11)

The method of claim 11, wherein:
heating compound C with the R2—C(O)C(O)H to form compound D comprises heating at 50-70° C. for several hours; and
heating compound C with the R2—C(O)C(O)H, followed by addition of an oxidant to form compound E comprises heating compound C with the R2—C(O)C(O)H for 50-70° C. for 15-60 minutes.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is not eudistidine A, eudistidine B, or eudistidine C: