# US 2021/0276956 A1 · Quinoline-based compounds and methods of inhibiting cdk8/19

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- Number: US 2021/0276956 A1
- Document ID: US20210276956A1
- Status: Published application
- Kind: A1
- Application number: 17/330,279
- Filed: 2021-05-25
- Published: 2021-09-09
- Earliest claimed: 2018-08-21
- Assignees: University of South Carolina; Senex Biotechnology, Inc.
- Applicants: University of South Carolina; Senex Biotechnology, Inc.
- Inventors: Igor Roninson; Campbell McInnes; Mengqian Chen; Li Zhang; Jing Li
- Web page: https://patentgrep.com/patent/US20210276956A1

## CPC

- C07D 215/46: with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 215/18: Halogen atoms or nitro radicals
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 215/42: attached in position 4
- C07D 215/44: with aryl radicals attached to said nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted qunioline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.

## Claims

### Claim 1

A compound of Formula 1B
wherein R1 is —CN, NO2, a halogen, an amino, or a halo-substituted alkyl;
wherein R3 comprises a substituted or unsubstituted, branched or unbranched C1-C6 alkylene; and
wherein R4 comprises —C(O)NRARB where—
RA and RB groups on the same nitrogen are taken together with their intervening atoms to form a substituted or unsubstituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur; or
each RA and RB are independently selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a substituted or unsubstituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R4 comprises
and
wherein—
D is —N(RC)— and RC is a substituted, branched or unbranched C1-C6 alkyl or
D is —S(═O)(═NRD)— and RD is hydrogen or a substituted or unsubstituted, branched or unbranched C1-C6 alkyl, —S—, or —S(O)—.

### Claim 3 (depends on 2)

The compound of claim 2, wherein D is —N(RC)— and RC is an oxo substituted C1-C6 alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein RC is —C(O)CH3 or —C(O)OC(CH3)3.

### Claim 5 (depends on 2)

The compound of claim 2, wherein D is —N(RC)— and RC is a hydroxyl substituted C1-C6 alkyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein RC is —(CH2)3OH.

### Claim 7 (depends on 2)

The compound of claim 2, wherein D is —N(RC)— and RC is an amino substituted C1-C6 alkyl.

### Claim 8 (depends on 5)

The compound of claim 5, wherein RC is —(CH2)3NH2.

### Claim 9 (depends on 2)

The compound of claim 2, wherein D is —S(═O)(═NRD)— and RD is hydrogen or the substituted or unsubstituted, branched or unbranched C1-C6 alkyl, —S—, or —S(O)—.

### Claim 10 (depends on 9)

The compound of claim 9, wherein D is —S(═O)(═NRD)— and RD is hydrogen.

### Claim 11 (depends on 1)

The compound of claim 1, wherein each RA and RB are independently selected from hydrogen, the substituted or unsubstituted alkyl, the substituted or unsubstituted cycloalkyl, the substituted or unsubstituted phenyl, the substituted or unsubstituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a substituted or unsubstituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 12 (depends on 11)

The compound of claim 11, wherein at least one of RA and RB is the substituted or unsubstituted alkyl.

### Claim 13 (depends on 11)

The compound of claim 11, wherein the at least one substituted or unsubstituted alkyl is —CH3, an amino substituted C1-C6 alkyl, or a —NHC(O)OC(CH3)3 substituted alkyl.

### Claim 14 (depends on 11)

The compound of claim 11, wherein at each of RA and RB is the substituted or unsubstituted alkyl.

### Claim 15 (depends on 14)

The compound of claim 14, wherein one or both of RA and RB are independently selected from is —CH3, an amino substituted C1-C6 alkyl, of a —NHC(O)OC(CH3)3 substituted alkyl.

### Claim 16 (depends on 1)

A method for the treatment of a subject having a CDK8-associated disease, disorder, or condition or a CDK19-associated disease, disorder, or condition comprising administering a pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1.

### Claim 17 (depends on 16)

The method of claim 16, wherein the CDK8-associated disease or disorder or the CDK19-associated disease or disorder is a selected from breast cancer, prostate cancer, leukemia, or kidney cancer.

### Claim 18 (depends on 16)

The method of claim 16, wherein R4 comprises
and
wherein—
D is —N(RC)— and RC is a substituted, branched or unbranched C1-C6 alkyl or
D is —S(═O)(═NRD)— and RD is hydrogen or a substituted or unsubstituted, branched or unbranched C1-C6 alkyl, —S—, or —S(O)—.

### Claim 19 (depends on 16)

The method of claim 16, wherein at least one of RA and RB is the substituted or unsubstituted alkyl.

### Claim 20 (depends on 1)

A method for the inhibition of CDK8 or CDK19, the method comprising contacting CDK8 or CDK19 with an effective amount of the compound of claim 1.