# US 2016/0355501 A1 · Nitrogenous heterocyclic derivatives and their application in drugs

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- Number: US 2016/0355501 A1
- Document ID: US20160355501A1
- Status: Published application
- Kind: A1
- Application number: 15/034,546
- Filed: 2014-12-19
- Published: 2016-12-08
- Earliest claimed: 2013-12-19
- Assignees: Sunshine Lake Pharma Co., Ltd.
- Applicants: Sunshine Lake Pharma Co., Ltd.
- Inventors: Jiancun Zhang; Xiaojun WANG; Yingjun ZHANG; Runfeng LIN; Yi YU; Liang CHEN; Jihua LIN
- Web page: https://patentgrep.com/patent/US20160355501A1

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- 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 35/00: Antineoplastic agents
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: 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

The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.

## Claims

### Claim 1

A compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein, each of Q1 and Q2 is independently N or CH;
X is N or CH;
J is —O—, —C(═S)—, —(CH2)m—O—, —C(═O)—, —C(═O)O—, —S(═O)t—, —(CH2)m—N(R6)—, —N(R6)—, —S(═O)tN(R6)—, —CH═CH—, —N(R6)C(═O)— or —(CH2)m—;
each R1 is independently —Y—R5, wherein each Y is independently —O—, —C(═S)—, —(CH2)m—O—, —C(═O)—, —C(═O)O—, —S(═O)t—, —(CH2)m—N(R6)—, —N(R6)—, —S(═O)tN(R6)—, —CH═CH—, —N(R6)C(═O)— or —(CH2)m—;
each R1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxy, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, alkenyl, alkynyl, nitro, mercapto, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, alkyl-O—C(═O)—, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy, haloalkoxy or cycloalkylalkyl;
each of R2 and R3 is independently H, F, Cl, Br, I, cyano, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
each R4 is independently H, hydroxy, carboxy, amino, F, Cl, Br, I, cyano, nitro, mercapto, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
each R5 is independently bridged heterobicyclyl, bridged bicyclyl, fused bicyclyl, fused heterobicyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
each R6 is independently H, hydroxy, amino, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, aryl, arylalkyl or heteroaryl;
each t is independently 0, 1 or 2;
each m is independently 1, 2, 3 or 4;
each of n and p is independently 0, 1, 2, 3 or 4; and
k is 1, 2, 3 or 4;
wherein each of —(CH2)m—O—, —(CH2)m—N(R6)—, —N(R6)—, —S(═O)tN(R6)—, —CH═CH—, —N(R6)C(═O)—, —(CH2)m—, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, alkyl-O—C(═O)—, aryl, aryloxy, heteroaryloxy, haloalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, bridged heterobicyclyl, bridged bicyclyl, fused bicyclyl, fused heterobicyclyl, alkylamino and alkylthio is independently and optionally substituted with one or more substituents independently selected from H, oxo (═O), F, Cl, Br, I, alkyl —O—C(═O)—, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, nitro, amino, alkylamino, mercapto, alkylthio, aryl, aryloxy, heteroaryl, heteroaryloxy and haloalkoxy.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
each R5 is independently C5-12 bridged heterobicyclyl, C5-12 bridged bicyclyl, C5-12 fused bicyclyl, C5-12 fused heterobicyclyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-9 heteroaryl, C1-9 heteroaryl-C1-4-alkyl, C2-10 heterocyclyl, C2-10 heterocyclyl-C1-4-alkyl, C3-10 cycloalkyl or C3-10 cycloalkyl-C1-4-alkyl; and
each R6 is independently H, hydroxy, amino, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl, C6-10 aryl-C1-4-alkyl or C1-9 heteroaryl;
wherein each of —(CH2)m—O—, —(CH2)m—N(R6)—, —N(R6)—, —S(═O)tN(R6)—, —CH═CH—, —N(R6)C(═O)—, —(CH2)m—, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C5-12 bridged heterobicyclyl, C5-12 bridged bicyclyl, C5-12 fused bicyclyl, C5-12 fused heterobicyclyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-9 heteroaryl, C1-9 heteroaryl-C1-4-alkyl, C2-10 heterocyclyl, C2-10 heterocyclyl-C1-4-alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C1-4 alkylamino and C1-4 alkylthio is independently and optionally substituted with one or more substituents independently selected from H, oxo (═O), F, Cl, Br, I, C1-4 alkyl-O—C(═O)—, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, cyano, nitro, amino, C1-4 alkylamino, mercapto, C1-4 alkylthio, C6-10 aryl, C6-10 aryloxy, C1-9 heteroaryl, C1-9 heteroaryloxy and C1-4 haloalkoxy.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein:
each R1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C2-4 alkenyl, C2-4 alkynyl, nitro, mercapto, C1-4 hydroxyalkoxy, C14 hydroxyalkyl, C1-4 aminoalkoxy, C1-4 alkyl-O—C(═O)—, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-9 heteroaryl, C1-9 heteroaryl-C1-4-alkyl, C2-10 heterocyclyl, C2-10 heterocyclyl-C1-4-alkyl, C3-10 cycloalkyl, C6-10 aryloxy, C1-9 heteroaryloxy, C1-4 haloalkoxy or C3-10 cycloalkyl-C1-4-alkyl;
each of R2 and R3 is independently H, F, Cl, Br, I, cyano, carboxy, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 hydroxyalkyl, C1-6 aminoalkoxy, C1-6 haloalkoxy, C6-10 aryl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl, C1-9 heteroaryl-C1-6-alkyl, C2-10 heterocyclyl, C2-10 heterocyclyl-C1-6-alkyl, C3-10 cycloalkyl or C3-10 cycloalkyl-C1-6-alkyl; and
each R4 is independently H, hydroxy, carboxyl, amino, F, Cl, Br, I, cyano, nitro, mercapto, C1-4 alkyl, C1-6 haloalkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-9 heteroaryl, C1-9 heteroaryl-C1-6-alkyl, C2-10 heterocyclyl, C2-10 heterocyclyl-C1-6-alkyl, C3-10 cycloalkyl or C3-10 cycloalkyl-C1-6-alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1 having formula (II), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein, each of Q1 and Q2 is independently N or CH;
J is —O— or —(CH2)m—; and
Y is —O—, —(CH2)m—O—, —(CH2)m—N(R6)—, —N(R6)— or —(CH2)m—.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein,
each Y is independently —O—, —(CH2)m—O—, —(CH2)m—N(R6)—, —N(R6)— or —(CH2)m—;
each R5 is independently
wherein, each E1, E2, E3 and E4 is independently N or CR7;
each T, T1 and T2 is independently —NR8—, —O—, —S— or —CR7R7a—;
each R7 and R7a is independently H, F, Cl, Br, I, C1-4 alkyl-O—C(═O)—, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, cyano, nitro, amino, C1-4 alkylamino, mercapto, C1-4 alkylthio, C6-10 aryl, C6-10 aryloxy, C1-9 heteroaryl, C1-9 heteroaryloxy or C1-4 haloalkoxy;
wherein, each R5 is independently and optionally substituted with one or more substituents independently selected from H, oxo (═O), F, Cl, Br, I, C1-4 alkyl —O—C(═O)—, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, cyano, nitro, amino, C1-4 alkylamino, mercapto, C1-4 alkylthio, C6-10 aryl, C6-10 aryloxy, C1-9 heteroaryl, C1-9 heteroaryloxy and C1-4 haloalkoxy;
each R6 is independently H, hydroxy, amino, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl, C6-10 aryl-C1-4-alkyl or C1-9 heteroaryl; and
each R8 is independently H, C1-4 alkyl-O—C(═O)—, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, amino, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl or C1-9 heteroaryl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein,
each R5 is independently
wherein, each R9 is independently H, oxo (═O), F, Cl, Br, I, C1-4 alkyl-O—C(═O)—, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, cyano, nitro, amino, C1-4 alkylamino, mercapto, C1-4 alkylthio, C6-10 aryl, C6-10 aryloxy, C1-9 heteroaryl, C1-9 heteroaryloxy or C1-4 haloalkyloxy; and
each q is independently 0, 1, 2, 3, 4, 5, 6 or 7.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein,
each R9 is independently H, oxo (═O), F, Cl, Br, I, methyl-O—C(═O)—, ethyl-O—C(═O)—, propyl-O—C(═O)—, butyl-O—C(═O)—, tert-butyl —O—C(═O)—, isopropyl-O—C(═O)—, methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, ethenyl, 3-propenyl, propenyl, C2-4 alkynyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, chloromethyl, trifluoroethyl, 1-fluoroethyl, cyano, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, mercapto, methylthio, ethylthio, propylthio, C6-10 aryl, phenoxy, C1-9 heteroaryl, C1-9 heteroaryloxy, trifluoroethoxy or trifluoromethoxy.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein,
each R1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxyl, methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloroethyl, methoxy, propoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, C2-4 alkenyl, C2-4 alkynyl, nitro, mercapto, C1-4hydroxyalkoxy, C1-4 hydroxyalkyl, C1-4aminoalkoxy, C1-4 alkyl-O—C(═O)— or phenyl;
each of R2 and R3 is independently H, F, Cl, Br, I, cyano, carboxyl, hydroxy, methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, chloromethyl, trifluoroethyl, 1-chloroethyl, methoxy, ethoxy, propoxy, C1-4hydroxyalkoxy, C1-4 hydroxyalkyl, C1-4aminoalkoxy, trifluoromethoxy, 1-chloroethoxy, phenyl or phenyl-C1-4-alkyl; and
each R4 is independently H, F, Cl, Br, I, cyano, carboxyl, hydroxy, methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, chloromethyl, trifluoroethyl, 1-chloroethyl, methoxy, ethoxy, propoxy, C1-4 hydroxyalkoxy, C1-4 hydroxyalkyl, C1-4 aminoalkoxy, trifluoromethoxy, 1-chloroethoxy, phenyl or phenyl-C1-4-alkyl.

### Claim 9 (depends on 1)

The compound according to claim 1 having one of the following structures:
or a stereoisomer a geometric isomer, a tautomer an N-oxide, a solvate, a hydrate, a metabolite, a ester, pharmaceutically acceptable salt or a prodrug thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14

(canceled)

### Claim 15 (depends on 1)

A method of preventing, managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with the compound according to claim 1.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the tissue or organ fibrosis is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, post-surgery adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, dermatosclerosis, multiple sclerosis, pancreatic fibrosis, liver cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.

### Claim 17 (depends on 10)

A method of preventing, managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with the pharmaceutical composition according to claim 10.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the tissue or organ fibrosis is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, post-surgery adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, dermatosclerosis, multiple sclerosis, pancreatic fibrosis, liver cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.