# US 2025/0145587 A1 · Bromodomain inhibitors

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- Number: US 2025/0145587 A1
- Document ID: US20250145587A1
- Status: Published application
- Kind: A1
- Application number: 18/733,551
- Filed: 2024-06-04
- Published: 2025-05-08
- Earliest claimed: 2016-10-14
- Assignees: AbbVie Inc.
- Applicants: AbbVie Inc.
- Inventors: Andrew Bogdan; Steven Fidanze; Keith McDaniel; John Pratt; Le Wang
- Web page: https://patentgrep.com/patent/US20250145587A1

## CPC

- A61P 31/18: for HIV
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 213/64: attached in position 2 or 6
- C07D 213/69: Two or more oxygen atoms
- C07D 213/76: to which a second hetero atom is attached (nitro radicals C07D213/61)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides for compounds of formula (I) wherein R1, Y, X1, X2, R2, R3, R4, R5, R6, and m have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising compounds of formula (I).

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
R1 is C1-C3 alkyl;
Y is N or C(RY) wherein RY is hydrogen or C1-C3 alkyl;
m is 0, 1, 2, 3, or 4;
R2 is G1A, —N(Ra)S(O)2Rb, —N(Ra)C(O)Rb, or —N(Ra)C(O)ORb;
Ra, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C2-C6 alkylenyl)-ORx wherein Rx is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
Rb, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, G1B, or —(C1-C6 alkylenyl)-ORj;
G1A is formula (i)
wherein
Z1 is C(O) or C(Re)(Rf);
Z2 is a bond, O, —(C(Rg)(Rh))p—C(Rm)(Rn)— wherein the left end of the moiety is attached to Z1, or N(Ri) wherein Ri is hydrogen, C1-C3 alkyl, or cyclopropyl;
wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 independently selected Rs groups;
p is 0 or 1;
Rc, Rd, Re, Rf, Rg, Rh, Rm, and Rn, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cyclopropyl; wherein the cyclopropyl, at each occurrence, is optionally substituted with 1, 2, 3, or 4 independently selected Rs groups; or
Rc and Rm together with the carbon atoms to which they are attached, form a C3-C6 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocycle; wherein the C3-C6 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected Rs groups; or
Rc and Ri together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocycle; wherein the 4-6 membered monocyclic heterocycle is optionally substituted with 1, 2, 3, or 4 independently selected Rs groups; or
Rc and Rd together with the carbon atoms to which they are attached, form a C3-C6 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocycle; wherein the C3-C6 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected Rs groups;
G1B is oxetanyl, cyclopropyl, cyclobutyl, or cyclopentyl; wherein each G1B is optionally substituted with 1, 2, 3, or 4 Rt groups; wherein each Rt is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl;
each R3 is independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, —CN, —OR3a, —N(R3a)2, —C(O)R3a, cyclopropyl, or cyclobutyl; wherein each R3a is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
R4 is phenyl or monocyclic heteroaryl; wherein each R4 is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH;
R5 is hydrogen, halogen, —CN, C1-C6 haloalkyl, or C1-C6 alkyl;
R6 is —(C1-C3 alkylenyl)n-S(O)2—R6a or —N(R6b)—SO2—R6c;
n is 0 or 1;
R6a and R6c are each independently C1-C6 alkyl, C1-C6 haloalkyl, or cyclopropyl; wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl;
R6b is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
X1 and X2 are C(R7) or
one of X1 and X2 is N and the other is C(R7);
R7, at each occurrence, is independently hydrogen or halogen;
Rs, at each occurrence, is independently C1-C6 alkyl, halogen, or C1-C6 haloalkyl;
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and
Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is G1A.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is —N(Ra)S(O)2Rb.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is —N(Ra)C(O)Rb.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is —N(Ra)C(O)ORb.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R4 is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH.

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R4 is monocyclic heteroaryl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH.

### Claim 8 (depends on 1)

The compound of claim 1 of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R2 is G1A; and
R4 is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH.

### Claim 9 (depends on 1)

The compound of claim 1 of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R2 is —N(Ra)C(O)Rb; and
R4 is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH.

### Claim 10 (depends on 1)

The compound of claim 1 of formula (I-a) or a pharmaceutically acceptable salt thereof,
R2 is —N(Ra)C(O)ORb; and
R4 is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —S(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), and —(C1-C6 alkylenyl)-OH.

### Claim 11 (depends on 1)

The compound of claim 1 of formula (I-a) or a pharmaceutically acceptable salt thereof,
wherein R1, Y, X1, X2, R2, R3, R4, R5, R6, and m are as set forth in claim 1.

### Claim 12 (depends on 1)

The compound of claim 1 of formula (I-b) or a pharmaceutically acceptable salt thereof,
wherein R1, Y, X1, X2, R2, R3, R4, R5, R6, and m are as set forth in claim 1.

### Claim 13 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Y is C(RY);
X1 is N or C(R7); and
X2 is C(R7).

### Claim 14 (depends on 13)

The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein
X1 and X2 are C(R7).

### Claim 15 (depends on 13)

The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein
X1 is N and X2 is C(R7).

### Claim 16 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]acetamide;
N-[cis-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]acetamide;
methyl [trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]carbamate;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]methanesulfonamide;
tert-butyl [trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]carbamate;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-2,2,2-trifluoroacetamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]propanamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-2,2-dimethylpropanamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-2-methoxyacetamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-1-methylcyclopropane-1-carboxamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]cyclopropanecarboxamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-3-methyloxetane-3-carboxamide;
N-[trans-4-({5-[2-(2,6-dimethylphenoxy)-5-(ethanesulfonyl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-3,3-difluorocyclobutane-1-carboxamide;
N-{trans-4-[(5-{5-[(ethanesulfonyl)amino]-2-[4-(2-hydroxypropan-2-yl)-2,6-dimethylphenoxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]cyclohexyl}acetamide;
methyl {trans-4-[(5-{5-[(ethanesulfonyl)amino]-2-[4-(2-hydroxypropan-2-yl)-2,6-dimethylphenoxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]cyclohexyl}carbamate;
methyl {trans-4-[(5-{5-[(ethanesulfonyl)amino]-2-(4-fluoro-2,6-dimethylphenoxy)phenyl}-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]cyclohexyl}carbamate;
methyl [trans-4-({5′-[(ethanesulfonyl)amino]-2′-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-6-oxo[1,6-dihydro[3,3′-bipyridine]]-4-yl}oxy)cyclohexyl]carbamate;
methyl {trans-4-[(5-{2-(4-fluoro-2,6-dimethylphenoxy)-5-[(methanesulfonyl)methyl]phenyl}-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]cyclohexyl}carbamate;
5-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-1-methyl-4-{[trans-4-(2-oxopyrrolidin-1-yl)cyclohexyl]oxy}pyridin-2(1H)-one; and
N-[trans-4-({5-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)cyclohexyl]-N-methylacetamide.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

### Claim 19 (depends on 18)

The method of claim 18 wherein the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

### Claim 20 (depends on 1)

A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

### Claim 21 (depends on 1)

A method for treating an acquired immunodeficiency syndrome (AIDS) in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

### Claim 22 (depends on 1)

A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, and diabetic neuropathy.

### Claim 23 (depends on 1)

A method of contraception in a male subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

### Claim 24 (depends on 1)

A method for treating an acute kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced kidney disease.

### Claim 25 (depends on 1)

A method of treating a chronic kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis.