# US 10,501,438 B2 · Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals

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- Number: US 10,501,438 B2
- Document ID: US10501438B2
- Status: Granted
- Kind: B2
- Application number: 15/751,800
- Filed: 2016-08-11
- Published: 2018-08-16
- Granted: 2019-12-10
- Earliest claimed: 2015-08-11
- Assignees: Neomed Institute
- Applicants: NEOMED Institute
- Inventors: Guillaume Jacquemot; Malken Bayrakdarian; Shawn Johnstone; Jeffrey S. Albert; Andrew Griffin
- Web page: https://patentgrep.com/patent/US10501438B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This application relates to aryl-substituted dihydroquinolinones of formula (I), compositions comprising them and their uses in the treatment of diseases and conditions in which inhibition of a bromodomain is indicated. For example, the application relates to aryl-substituted dihydroquinolinones and to their use as bromodomain inhibitors. The present application is also related to the treatment or prevention of proliferative disorders, auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, including tumors and/or cancers.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
A is —CH2;
R1 is hydrogen or methyl;
R2 and R5 independently represent hydrogen, halogen, —CH3, —C(Ra)(Rb)(Rc), —N(Rd)(Re) or —O(Rf),
wherein
Ra is hydrogen or C1-C6 alkyl;
Rb is hydrogen, hydroxyl or C1-C6 alkyl;
Rc is C3-C6 cycloalkyl, C6-C10 aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C3-C6 cycloalkyl)C1-C6 alkyl, (3-7 membered heterocycloalkyl)C1-C6 alkyl, (C6-C10 aryl)C1-C6 alkyl or (5-10 membered heteroaryl)C1-C6 alkyl, —O(Rg) or —N(Rg)(Rh);
Rd is hydrogen or C1-C6 alkyl;
Re is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C3-C6 cycloalkyl)C1-C6 alkyl, (3-7 membered heterocycloalkyl)C1-C6 alkyl, (C6-C10 aryl)C1-C6 alkyl, (5-10 membered heteroaryl)C1-C6 alkyl, keto(C6-C10 aryl) or keto(5-10 membered heteroaryl);
Rf is C1-C6 alkyl, C3-C6cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, (C3-C6 cycloalkyl)C1-C6 alkyl, (3-7 membered heterocycloalkyl)C1-C6 alkyl, (C6-C10 aryl)C1-C6 alkyl or (5-10 membered heteroaryl)C1-C6 alkyl;
Rg is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C3-C6 cycloalkyl)C1-C6 alkyl, (3-7 membered heterocycloalkyl)C1-C6 alkyl, (C6-C10 aryl)C1-C6 alkyl or (5-10 membered heteroaryl)C1-C6 alkyl;
Rh is hydrogen, C1-C4 alkyl, —C(O)(R6); —C(O)NH2, —C(O)NH(R6) or —C(O)N(R6)(R6′);
one of R3 and R4 represents a group of formula (II), provided that when R3 is a group of formula (II), then R4 has the same definition than R2 and R5, and when R4 is a group of formula (II), then R3 has the same definition than R2 and R5;
the group of formula (II) has the following structure:
wherein:
X1, X2 and X3 are each independently N or C, wherein when X1, X2 or X3 is N, then the R7, R8 or R10 attached thereto is absent, provided that at least two of X1, X2 and X3 are C;
R7 and R10 are each independently hydrogen, halogen, CN, linear or branched C1-C6alkyl, C3-C6cycloalkyl, OR6, SR6, NHR6, N(R6)(R6′), NHC(O)R6 or N(R6)C(O)R6′;
R8 is halogen, CN, linear or branched C1-C6alkyl, C3-C6cycloalkyl, OR6, SR6, NHR6, N(R6)(R6′), NHC(O)R6 or N(R6)C(O)R6′;
R6 and R6′, which are the same or different, represent a C1-C6 alkyl group;
R9 is a C1-C3alkyl or C3-C5cycloalkyl group;
each alkyl group is linear or branched and optionally substituted with 1 to 3 groups being halogen, CN, alkoxy or haloalkoxy, and each of cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy;
and
when R3 is the group of formula (II), one of R2, R4 and R5 is —C(Ra)(Rb)(Rc), —N(Rd)(Re) or —O(Rf) and the other two of R2, R4 and R5 are independently hydrogen, halogen or —CH3; or
when R4 is the group of formula (II), one of R2, R3 and R5 is —C(Ra)(Rb)(Rc), —N(Rd)(Re) or —O(Rf) and the other two of R2, R3 and R5 are independently hydrogen, halogen or —CH3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2, R3, R4 or R5 represent —O(Ra)(Rb)(Rc), —C(Ra)(Rb)O(Rg), —C(Ra)(Rb)N(Rg)(Rh), —N(Rd)(Re) or —O(Rf), wherein:
Ra is H;
Rb is H or methyl;
Rc is a group benzyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl or tetrahydropyranyl, each group Rc being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy;
Rd is hydrogen or methyl;
Re is a group cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, or tetrahydropyranyl, each of these groups being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy, or Re is a group —CH(Rh)(C3-C6 aryl) or —CH(Rh)(5-10 membered heteroaryl);
Rf is C3-C6 cycloalkyl, C6-C10 aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, —CH(Rh)(C3-C6 cycloalkyl), —CH(Rh)(C3-C6 aryl), —CH(Rh)(3-7 membered heterocycloalkyl) or —CH(Rh)(5-10 membered heteroaryl);
Rg is a group methyl, ethyl, propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl or tetrahydropyranyl, each group Rg being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy;
Rh is hydrogen, linear or branched C1-C4 alkyl or —(CO)R6 with R6 being a C1-C3 alkyl group; and
wherein each of cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2, R3, R4 or R5 represent —C(Ra)(Rb)(Rc), —C(Ra)(Rb)O(Rg), —C(Ra)(Rb)N(Rg)(Rh), —N(Rd)(Re) or —O(Rf), wherein:
Ra is H;
Rb is H or methyl;
Rc is a group phenyl, benzyl, piperidinyl, tetrahydropyranyl or pyridyl;
Rd is hydrogen or methyl;
Re is cyclohexyl, phenyl, benzyl, pyridyl, tetrahydropyranyl, —CH2(pyridyl) or —CH(CH3)(pyridyl);
Rf is phenyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, —CH2(pyridyl), —CH(CH3)(pyridyl), —CH2(pyrazinyl), —CH2(pyrimidinyl), —CH2(tetrahydropyranyl), —CH2(cyclopentyl), —CH2(cyclohexyl), —CH2(oxazolyl) or —CH2(thiazolyl);
Rg is ethyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl;
Rh is hydrogen, methyl or acetyl;
wherein each of Rc, Re, Rf and Rg is optionally substituted by 1 to 3 groups being halogen, CN, C1-C6 alkyl or C1-C6 alkoxy.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2, R3, R4 or R5 represent a group:

### Claim 6 (depends on 1)

The compound of claim 1, wherein R2, R3, R4 or R5 represent a group:

### Claim 7 (depends on 1)

The compound of claim 1, wherein X1, X2 and X3 are all carbon atoms.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R9 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

### Claim 9 (depends on 7)

The compound of claim 7, wherein R7 and R10 are each hydrogen atoms and R8 is Cl, CN, NHR6 or a substituted or unsubstituted C1-C6alkyl or C3-C6cycloalkyl group.

### Claim 10 (depends on 1)

The compound of claim 1, having the following formula (IIIa), (IIIb) or (IIIc):
wherein A, R1, R2, R3, R5, R7, R8, R9 and R10 are as defined in claim 1,
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

### Claim 11 (depends on 1)

The compound of claim 1, having the following formula (IVa) (IVb) or (IVc):
wherein A, R1, R2, R4, R5, R7, R8, R9, R10 are as defined in claim 1,
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

### Claim 12 (depends on 1)

The compound of claim 1, having the following formula (IIId), (IIIe) or (IIIf):
wherein A, R1, R2, R3 and R5 are as defined in claim 1,
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

### Claim 13 (depends on 1)

The compound of claim 1, having the following formula (IVd), (IVe) or (IVf):
wherein A, R1, R2, R4 and R5 are as defined in claim 1,
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is selected from the following compounds

### Claim 15 (depends on 14)

The compound of claim 14, wherein the compound is selected from Compounds 1-29, 30-32, 34, 38, 39, 44, 46, 47, 48a, 48b, 52, 53, 54a, 54b, 55a, 55b, 57, 58, 61, 62, 67-73, 74a, 74b, 75-91, 92a, 92b and 93-101.

### Claim 16 (depends on 1)

The compound of claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A method for the treatment of rheumatoid arthritis, irritable bowel syndrome or psoriasis which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1.

### Claim 18 (depends on 14)

A method for the treatment of rheumatoid arthritis, irritable bowel syndrome or psoriasis which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 14.

### Claim 19 (depends on 17)

The method of claim 17, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A method for the treatment of cancer, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1, wherein the cancer is selected from the group consisting of bladder cancer, leukemia, lymphoma, brain cancer, central nervous system cancer, breast cancer, cervix cancer, colorectal cancer, colon cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and gastric cancer.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer is selected from the group consisting of breast cancer, bladder cancer, colon cancer, lung cancer, lymphoma, leukemia, mesothelioma, ovarian cancer and prostate cancer.

### Claim 22 (depends on 20)

The method of claim 20, wherein the cancer is prostate cancer.

### Claim 23 (depends on 14)

A method for the treatment of cancer, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 14, wherein the cancer is selected from the group consisting of bladder cancer, leukemia, lymphoma, brain cancer, central nervous system cancer, breast cancer, cervix cancer, colorectal cancer, colon cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and gastric cancer.

### Claim 24 (depends on 20)

The method of claim 20, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein the cancer is prostate cancer.