# US 11,306,102 B2 · 1,3-di-substituted ketene compound and application thereof

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- Number: US 11,306,102 B2
- Document ID: US11306102B2
- Status: Granted
- Kind: B2
- Application number: 16/634,827
- Filed: 2018-06-29
- Published: 2021-04-29
- Granted: 2022-04-19
- Earliest claimed: 2017-07-31
- Assignees: BeBetter Med Inc.
- Applicants: Bebetter Med Inc.
- Inventors: Xiong Cai; Changgeng Qian; Chunqiang Ye; Qijie He
- Web page: https://patentgrep.com/patent/US11306102B2

## CPC

- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 495/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 13/12: of the kidneys
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 323/22: containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 263/56: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 307/80: Radicals substituted by oxygen atoms
- C07D 307/82: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D 307/83: Oxygen atoms
- C07D 307/85: attached in position 2
- C07D 317/54: Radicals substituted by oxygen atoms
- C07D 327/04: Five-membered rings
- C07D 327/06: Six-membered rings
- C07D 333/54: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 333/56: Radicals substituted by oxygen atoms
- C07D 333/62: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Provided are a 1,3-di-substituted ketene compound having a structure as represented by formula (I) and an application thereof. Such a type of compound primarily activates peroxisome proliferator-activated receptor (PPAR) α, and also activates PPPAδ and PPPAγ. The compound may be used to treat various diseases associated with PPAR regulation and control abnormality, such as non-alcoholic fatty liver disease, and especially in treating non-alcoholic hepatitis, and may potentially be used in the treatment of diseases comprising diabetes, obesity, fibrotic diseases, cardiovascular diseases (comprising heart failure, atherosclerosis, and so on), kidney diseases (comprising chronic kidney disease, renal failure, and so on), and brain degenerative diseases (comprising Alzheimer's disease and so on), having great application value.

## Claims

### Claim 1

A 1,3-disubstituted ketene compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:
wherein R1 and R2 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C1-C6 alkoxy, and hydroxyl;
R3 and R4 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C1-C6 alkoxy, and hydroxyl, and R3 and R4 are not H at the same time; or R3 and R4 are bonded to form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring;
R5 is selected from the group consisting of OR6 and NR7R8;
Q is a single bond or CR7R8;
R6, R7, and R8 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkylmethyl;
W, W1, and Y are each independently selected from the group consisting of O and S;
ring A is selected from the group consisting of the following structures,
where X1, X2, X3, X4, X5, X6, and X7 are each independently selected from the group consisting of CR9, CR12, and N, and at least one of X1, X2, X3, and X4 is CR12;
R9 is selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C4 alkylamino-substituted C1-C6 alkyl, aryl, heteroaryl, nitro, cyano, —OR, —N(R)2, —SR, —C(O)OR, —C(O)N(R)2, —C(O)R, —S(O)R, —S(O)2R, —S(O)2N(R)2, and —N(R)C(O)R;
R10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, and C1-C4 alkylamino-substituted C1-C6 alkyl;
R11 is selected from the group consisting of H, —SR, —OR, —N(R)2, C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkylmethyl;
R12 is selected from the group consisting of H, —SR, —OR, —N(R)2, C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkylmethyl;
n is 0, 1, or 2; and
each of R is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, and C1-C4 alkylamino-substituted C1-C6 alkyl.

### Claim 2 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein the compound has a structure represented by formula (II):

### Claim 3 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein ring A is selected from the group consisting of the following structures,

### Claim 4 (depends on 3)

The 1,3-disubstituted ketene compound of claim 3 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein ring A is selected from the group consisting of the following structures,

### Claim 5 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R9 is selected from the group consisting of H, methyl, ethyl, isopropyl, and trifluoromethyl.

### Claim 6 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R12 is selected from the group consisting of H, —SR, —OR, —N(R)2, and C1-C6 alkyl, where R is selected from the group consisting of H and C1-C6 alkyl.

### Claim 7 (depends on 6)

The 1,3-disubstituted ketene compound of claim 6 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R12 is selected from the group consisting of SR and OR, where R is C1-C6 alkyl.

### Claim 8 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R1 and R2 are both methyl or chlorine.

### Claim 9 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, and halogen; or R3 and R4 are bonded to form a 3-8 membered carbocyclic ring.

### Claim 10 (depends on 9)

The 1,3-disubstituted ketene compound of claim 9 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R3 and R4 are C1-C6 alkyl.

### Claim 11 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R5 is OR6, where R6 is selected from the group consisting of H and C1-C6 alkyl.

### Claim 12 (depends on 11)

The 1,3-disubstituted ketene compound of claim 11 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R5 is OR6, where R6 is H.

### Claim 13 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein Y is O.

### Claim 14 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R1 and R2 are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, and halogen;
R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, and halogen; or R3 and R4 are bonded to form a 3-8 membered carbocyclic ring;
R5 is OR6, where R6 is selected from the group consisting of H and C1-C6 alkyl;
Y is selected from the group consisting of O and S;
ring A is selected from the group consisting of the following structures,
where R9 is selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C4 alkylamino-substituted C1-C6 alkyl, nitro, cyano, —OR, —N(R)2, —SR, —C(O)OR, —C(O)N(R)2, —C(O)R, —S(O)R, —S(O)2R, —S(O)2N(R)2, and —N(R)C(O)R;
R11 is selected from the group consisting of H, —SR, —OR, —N(R)2, and C1-C6 alkyl;
R12 is selected from the group consisting of H, —SR, —OR, —N(R)2, and C1-C6 alkyl;
n is 0, 1, or 2; and
each of R is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, and halogen-substituted C1-C6 alkyl.

### Claim 15 (depends on 14)

The 1,3-disubstituted ketene compound of claim 14 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein R1 and R2 are each independently selected from the group consisting of C1-C3 alkyl, halogen, and C1-C3 alkoxy;
R3 and R4 are each independently C1-C6 alkyl;
R5 is OR6, where R6 is H;
Y is O;
ring A is selected from the group consisting of the following structures,
where R9 is selected from the group consisting of H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, —OR, —N(R)2, —SR, —C(O)OR, —C(O)N(R)2, —C(O)R, —S(O)R, —S(O)2R, —S(O)2N(R)2, and —N(R)C(O)R;
R12 is selected from the group consisting of H, —SR, —OR, and C1-C6 alkyl;
n is 0 or 1; and
each of R is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, and halogen-substituted C1-C6 alkyl.

### Claim 16 (depends on 1)

The 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,
wherein the 1,3-disubstituted ketene compound is selected from the group consisting of the following structures,

### Claim 17 (depends on 1)

A method of preventing or treating a disease associated with abnormal regulation of PPAR, comprising administering the 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof to a subject in need thereof,
wherein the disease associated with abnormal regulation of PPAR is selected from the group consisting of a disease associated with abnormal metabolism of lipid and glucose, a disease associated with inflammation and abnormal fibrosis, a cardiovascular disease, a kidney disease, and a degenerative brain disease.

### Claim 18 (depends on 17)

The method of claim 17, wherein the disease associated with abnormal metabolism of lipid and glucose is diabetes or obesity,
the disease associated with inflammation and abnormal fibrosis is nonalcoholic fatty liver disease, nonalcoholic hepatitis, or cholestatic liver disease,
the cardiovascular disease is atherosclerosis or heart failure,
the kidney disease is renal failure or chronic kidney disease, and
the degenerative brain disease is Alzheimer's disease.

### Claim 19 (depends on 1)

A pharmaceutical composition for preventing or treating a disease associated with abnormal regulation of PPAR, comprising the 1,3-disubstituted ketene compound of claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.