# US 9,040,555 B2 · Antifibrotic compounds and uses thereof

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- Number: US 9,040,555 B2
- Document ID: US9040555B2
- Status: Granted
- Kind: B2
- Application number: 14/374,210
- Filed: 2013-01-26
- Published: 2014-12-18
- Granted: 2015-05-26
- Earliest claimed: 2012-01-26
- Assignees: Angion Biomedica Corp.
- Applicants: Bijoy Panicker; Rama K. Mishra; Dong Sung Lim; Lambertus J. W. M. Oehlen; Dawoon Jung
- Inventors: Bijoy Panicker; Rama K. Mishra; Dong Sung Lim; Lambertus J. W. M. Oehlen; Dawoon Jung
- Web page: https://patentgrep.com/patent/US9040555B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K 31/4353: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- C07D 401/02: containing two hetero rings
- C07D 401/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides compounds having the general structural formula (I), and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving abnormal or excessive fibrosis.

## Claims

### Claim 1

A compound as described in Formula (I) below:
or a pharmaceutically acceptable salt thereof or a prodrug thereof;
where in R1 is —COOR5;
R2 is H or a prodrug moiety, optionally a carbamate or amide;
R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
R5 is a lower alkyl group;
R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR8, NR8R9, or NCOR8 moieties;
R8 and R9 are independently H or a lower alkyl group;
A is N or CH, wherein one A is nitrogen; and
B is O or S.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R2 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R2 is a carbamate prodrug moiety or an amide prodrug moiety.

### Claim 4 (depends on 1)

The compound of claim 1 wherein R3 is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1 wherein R4 is phenyl.

### Claim 6 (depends on 1)

The compound of claim 1 wherein R5 is methyl.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R6 is methyl.

### Claim 8 (depends on 1)

The compound of claim 1 wherein R7 is methylpiperazinylmethyl.

### Claim 9 (depends on 1)

The compound of claim 1 having the structure in Formula (II) below:
or a pharmaceutically acceptable salt thereof or a prodrug thereof;
where in R1 is —COOR5;
R2 is H or a prodrug moiety, optionally a carbamate or amide;
R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
R5 is a lower alkyl group;
R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR8, NR8R9, or NCOR8 moieties;
R8 and R9 are independently H or a lower alkyl group; and
B is O or S.

### Claim 10 (depends on 9)

The compound of claim 9 selected from (Z)-methyl 3-(((4-((2-(ethyl(methyl)amino)-2-oxoethyl)(methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-((3-(dimethyl amino)-3-oxopropyl)(methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(1,1-dioxidothiomorpholino)-N-methylacetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(dimethylamino)-N-methylacetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate; and (Z)-methyl 3-(((4-(methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo [2,3-b]pyridine-6-carboxylate.

### Claim 11 (depends on 1)

The compound of claim 1 having the structure in Formula (III) below:
or a pharmaceutically acceptable salt thereof or a prodrug thereof;
where in R1 is —COOR5;
R2 is H or a prodrug moiety, optionally a carbamate or amide;
R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
R5 is a lower alkyl group;
R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COORS, NR8R9, or NCOR8 moieties;
R8 and R9 are independently H or a lower alkyl group; and
B is O or S.

### Claim 12 (depends on 11)

The compound of claim 11 selected from among (Z)-methyl 3-(((4-2-(ethyl(methyl)amino)-2-oxoethyl)(methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate; (Z)-methyl 3-(((4-((3-(dimethylamino)-3-oxopropyl)(methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(1,1-dioxidothiomorpho lino)-N-methylacetamido) phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(dimethylamino)-N-methylacetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate; and (Z)-methyl 3-(((4-(methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate.

### Claim 13 (depends on 1)

The compound of claim 1 having the structure in Formula (IV) below:
or a pharmaceutically acceptable salt thereof or a prodrug thereof;
where in R1 is —COOR5;
R2 is H or a prodrug moiety, optionally a carbamate or amide;
R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
R5 is lower alkyl group;
R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR8, NR8R9, or NCOR8 moieties;
R8 and R9 are independently H or a lower alkyl group; and
B is O or S.

### Claim 14 (depends on 13)

The compound of claim 13 selected from among (Z)-methyl 3-(((4-((2-(ethyl(methyl)amino)-2-oxoethyl)(methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro -1H-pyrrolo [3,2-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4((3-(dimethylamino)-3-oxopropyl) (methyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b ]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(1,1-dioxidothiomorpholino)-N-methylacetamido) phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(2-(dimethylamino)-N-methylacetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate; (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate; and (Z)-methyl 3-(((4-(methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H- pyrrolo[3,2-b]pyridine-6-carboxylate.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.