# US 11,028,051 B2 · Tetrahydroquinoline-based bromodomain inhibitors

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- Number: US 11,028,051 B2
- Document ID: US11028051B2
- Status: Granted
- Kind: B2
- Application number: 16/468,657
- Filed: 2017-12-12
- Published: 2020-03-12
- Granted: 2021-06-08
- Earliest claimed: 2016-12-13
- Assignees: St. Jude Children's Research Hospital
- Applicants: St. Jude Children's Research Hospital
- Inventors: R. Kip Guy; P. Jake Slavish; William Robert Shadrick; Brandon M. Young; Vincent A. Boyd; Nagakumar Bharatham; Jeanine E. Price; Anang Shelat
- Web page: https://patentgrep.com/patent/US11028051B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 215/42: attached in position 4
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/06: Antipsoriatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- C07D 215/44: with aryl radicals attached to said nitrogen atoms
- C07D 215/46: with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In one aspect, compounds and compositions that modulate a bromodomain and methods of making and using same are disclosed. The disclosed compounds and compositions can be useful for disorders associated with inhibition of a bromodomain such as, for example, cancer. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

## Claims

### Claim 1

A compound having a structure represented by a formula:
wherein R1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 deuterated alkyl;
wherein R2 is C1-C4 alkyl;
wherein R3a is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Cy2, —(C1-C6 alkyl)Cy2, —(C1-C6 alkyl)Ar4, —C(O)(C1-C6 alkyl), —C(O)(CH2)mCy2, —C(O)(CH2)mAr4, —C(O)(C1-C4 alkyl)CCH, —CO2(C1-C6 alkyl), and amine protecting group, and wherein R3b is selected from —C(O)(unsubstituted C1-C6 alkyl), —C(O)(CH2)mCy2, —C(O)(CH2)mAr4, —C(O)(C1-C4 alkyl)CCH, and -CO2(C1-C6 alkyl);
wherein m, when present, is selected from 0, 1, 2, and 3;
wherein Cy2, when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar4, when present, is selected from aryl and heteroaryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
or wherein each of R3a and R3b are optionally covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heteroaryl and are substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar1 is selected from aryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein R4a is selected from hydrogen, C1-C4 alkyl, and amine protecting group and wherein R4b is selected from C4-C8 alkyl, —(CH2)nCy1, —(CH2)oAr2, and —COR6;
wherein each of n and o, when present, is selected from 0, 1, 2, and 3;
wherein Cy1, when present, is selected from cycloalkyl, five-membered heterocycle, and six-membered heterocycle and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar2, when present, is selected from aryl and 5- to 12-membered heteroaryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, —NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 aminoalkyl, C3-C6 cycloalkyl, —COR21, —CO2R21, —CONR22aR22b, —(CH2)qNR22aR22b, —SO2NR22aR22b, —NR23C(O)R24, —NR23(CH2)q(C3-C6 cycloalkyl), —NR23(CH2)q(heterocycloalkyl), and 3- to 5-membered heterocycloalkyl;
wherein q, when present, is selected from 0, 1, 2, 3, and 4;
wherein each occurrence of R21, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, —COR30, —(C1-C4 alkyl)OC(O)(C1-C4 alkyl), and —(C1-C6 alkyl)NHC(O)A;
wherein A has a structure:
wherein each occurrence of R30, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
wherein each occurrence of each of R22a and R22b, when present, is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and —COR30;
wherein R23, when present, is selected from hydrogen and C1-C4 alkyl;
wherein R24, when present, is selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkyl (C1-C4 alkoxy), C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-4 alkylamino(C1-C4 alkyl), (C1-C4)(C1-C4) dialkylamino(C1-C4 alkyl), —(CH2)r(C3-C6 cycloalkyl), and —(CH2)s(C3-C6 heterocycloalkyl);
wherein r, when present, is selected from 0, 1, 2, and 3;
wherein R6, when present, is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and —(CH2)sCy3;
wherein s, when present, is selected from 0, 1, and 2; and
wherein Cy3, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
or wherein each of R4a and R4b is hydrogen,
provided that when o is 0 and Ar2 is monoaryl then Ar2 is substituted with at least one non-hydrogen group,
or a pharmaceutically acceptable salt thereof.

### Claim 2

A compound having a structure represented by a formula:
wherein R1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 deuterated alkyl;
wherein R2 is C1-C4 alkyl;
wherein R3a is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkyl)Cy2, —C(O)(C1-C6 alkyl), —C(O)Cy2, and amine protecting group; and R3b is selected from —C(O)(unsubstituted C1-C6 alkyl), and —C(O)Cy2;
wherein Cy2, when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
or wherein each of R3a and R3b are optionally covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heteroaryl and are substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar1 is selected from aryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein R4a is selected from hydrogen, C1-C4 alkyl, and amine protecting group and wherein R4b is selected from Cy1, Ar2, and —COR6;
wherein Cy1, when present, is selected from cycloalkyl, five-membered heterocycle, and six-membered heterocycle and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —OH, —CN, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;
wherein Ar2, when present, is selected from aryl and 5- to 12-membered heteroaryl and is substituted with 1-4 non-hydrogen groups independently selected from halogen, —OH, —CN, —NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 aminoalkyl, C3-C6 cycloalkyl, —COR21, —CO2R21, —CONR22aR22b, —NR22aR22b, —SO2NR22aR22b, and 3- to 5-membered heterocycloalkyl;
wherein each occurrence of R21, when present, is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and —COR30;
wherein each occurrence of each of R22a and R22b, when present, is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and —COR30;
wherein each occurrence of R30, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and
wherein R6, when present, is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy,
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the substituents on the carbons marked “a” and “b” are in a cis configuration.

### Claim 4 (depends on 2)

The compound of claim 2, wherein R4a is hydrogen and R4b is Ar2R5, wherein R5 is selected from halogen, —OH, —CN, —NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 aminoalkyl, C3-C6 cycloalkyl, —COR21, —CO2R21, —CONR22aR22b, —NR22aR22b, —SO2NR22aR22b, and 3- to 5-membered heterocycloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R4a is selected from hydrogen, C1-C4 alkyl, and amine protecting group and wherein R4b is selected from Cy1, Ar2, and —COR6.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R4b is selected from Cy1, Ar2, and —COR6.

### Claim 7 (depends on 2)

The compound of claim 2, wherein Ar1 is aryl substituted with 0 non-hydrogen groups.

### Claim 8 (depends on 2)

The compound of claim 2, having a structure represented by a formula:

### Claim 9 (depends on 2)

The compound of claim 2, having a structure represented by a formula:

### Claim 10 (depends on 2)

The compound of claim 2, having a structure represented by a formula:
wherein R5 is selected from halogen, —OH, —CN, —NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 aminoalkyl, C3-C6 cycloalkyl, —CORM, —CO2R21, —CONR22aR22b, —NR22aR22b, —SO2NR22aR22b, and 3- to 5-membered heterocycloalkyl.

### Claim 11 (depends on 2)

A pharmaceutical composition comprising the compound of claim 2.

### Claim 12 (depends on 2)

A method of treating a disorder for which a bromodomain is indicated in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 2.

### Claim 13 (depends on 12)

The method of claim 12, wherein the disorder is selected from an estrogen deficiency, inflammation, a metabolic disorder, adipogenesis, a vascular disease, acute myocardial infarction, addiction, biliary-driven liver regeneration, atherosclerosis, trypanosomiasis, pulmonary arterial hypertension, amyotrophic lateral sclerosis, psoriasis, rheumatoid arthritis, autosomal dominant polycystic kidney disease, acute graft-versus-host disease, a T-cell mediated inflammatory disease, septic shock, diabetic nephropathy, heart failure, moloney murine leukemia, an autoimmune disorder, idiopathic pulmonary fibrosis, respiratory syncytial virus, human immunodeficiency virus, and autoimmune encephalomyelitis.

### Claim 14 (depends on 12)

The method of claim 12, wherein the disorder is cancer.

### Claim 15 (depends on 2)

The compound of claim 2, wherein the compound has a structure represented by a formula:

### Claim 16

A compound selected from: