# US 10,308,637 B2 · Therapeutic inhibitory compounds

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- Number: US 10,308,637 B2
- Document ID: US10308637B2
- Status: Granted
- Kind: B2
- Application number: 16/009,093
- Filed: 2018-06-14
- Published: 2019-01-03
- Granted: 2019-06-04
- Earliest claimed: 2015-07-01
- Assignees: Lifesci Pharmaceuticals, Inc.
- Applicants: LifeSci Pharmaceuticals, Inc.
- Inventors: Andrew McDonald; Shawn Qian
- Web page: https://patentgrep.com/patent/US10308637B2

## CPC

- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.

## Claims

### Claim 1

A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):
wherein,
Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl;
Ring B is an optionally substituted monocyclic heteroaryl ring selected from optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; or optionally substituted bicyclic heteroaryl ring selected from optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted 1H-pyrrolo[2,3-b]pyridinyl, optionally substituted benzoxazolyl, optionally substituted benzoisoxazolyl, or optionally substituted benzimidazolyl;
R12 is hydrogen;
R13 is selected from cyano, halo, hydroxy, azido, amino, nitro, —CO2H, —S(O)—R20, —S—R20, —S(O)2—R20, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O—, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkylamino, optionally substituted dialkylamino, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, —C(═NR22)—(NR21)2, or optionally substituted alkynyl;
R14 is selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, —CO2H, —S(O)—R20, —S—R20, —S(O)2—R20, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O—, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkylamino, optionally substituted dialkylamino, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, —C(═NR22)—(NR21)2, or optionally substituted alkynyl;
each R1 or R2 is independently selected from hydrogen, halo, hydroxy, amino, —CO2H, —S(O)—R20, —S—R20, —S(O)2—R20, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O—, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkylamino, optionally substituted dialkylamino, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, —C(═NR22)—(NR21)2, or optionally substituted alkynyl; or optionally, R1 and R2 are optionally substituted C1-C5 alkyl and join to form a ring; or optionally, R1 and R2 together form an oxo;
each R3 or R4 is independently selected from hydrogen, —CO2H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, —C(═NR22)—(NR21)2, or optionally substituted alkynyl; or optionally, R3 and R4 are optionally substituted C1-C5 alkyl and join to form a ring;
each R20 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
each R21 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
each R22 is selected from hydrogen, —CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R14 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R14 is independently selected from —S(O)—R20, —S—R20, —S(O)2—R20, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O—, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkylamino, optionally substituted dialkylamino, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, or —C(═NR22)—(NR21)2.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R14 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkynyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R14 is optionally substituted alkyl, or optionally substituted cycloalkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R13 is independently selected from —S(O)—R20, —S—R20, —S(O)2—R20, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O—, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkylamino, optionally substituted dialkylamino, —CO—R20, —CO2—R20, —CO(NR21)2, —SO2(NR21)2, or —C(═NR22)—(NR21)2.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R13 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkynyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R13 is optionally substituted alkyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R13 is optionally substituted cycloalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are hydrogen.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is optionally substituted alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are hydrogen.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted alkyl.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted alkoxy.

### Claim 21 (depends on 1)

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

### Claim 22 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from optionally substituted benzo[d]isoxazol-7-yl, optionally substituted 4-aminoquinazolin-5-yl, optionally substituted indol-5-yl; optionally substituted quinolin-3-yl; quinoxalin-2-yl; optionally substituted isoquinolin-1(2H)-on-2-yl; or optionally substituted quinolin-6-yl.

### Claim 23 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted quinolin-6-yl.

### Claim 24 (depends on 23)

The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl is substituted with at least one substituent selected from optionally substituted C1-C3 alkyl, halogen, —CN, —SO2Me, —SO2NH2, —CONH2, —CH2NHAc, —CO2Me, —CO2H, —CH2OH, —CH2NH2, —NH2, —OH, or —OMe.

### Claim 25 (depends on 23)

The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl is substituted at least at the 3-position.

### Claim 26 (depends on 25)

The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the quinolin-6-yl is selected from 3-chloroquinolin-6-yl, 3-methylquinolin-6-yl, 3-trifluoromethylquinolin-6-yl, 3-fluoroquinolin-6-yl, or 3-cyanoquinolin-6-yl.

### Claim 27 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted quinolin-3-yl.

### Claim 28 (depends on 27)

The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-3-yl is substituted at least at the 6-position or the 7-position.

### Claim 29 (depends on 27)

The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-3-yl is substituted with at least one substituent selected from optionally substituted C1-C3 alkyl, halogen, —CN, —SO2Me, —SO2NH2, —CONH2, —CH2NHAc, —CO2Me, —CO2H, —CH2OH, —CH2NH2, —NH2, —OH, or —OMe.

### Claim 30 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted pyridinyl.

### Claim 31 (depends on 30)

The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted pyridinyl is an optionally substituted aminopyridinyl.

### Claim 32 (depends on 31)

The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted aminopyridinyl is an optionally substituted 6-aminopyridin-3-yl.

### Claim 33 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from optionally substituted quinol-3-yl; and Ring B is selected from an optionally substituted 6-aminopyridin-3-yl.

### Claim 34 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted indolyl.

### Claim 35 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted indazolyl.

### Claim 36 (depends on 34)

The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted indolyl is an optionally substituted indol-5-yl.

### Claim 37 (depends on 35)

The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted indazolyl is an optionally substituted indazol-5-yl.

### Claim 38 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 1H-pyrrolo[2,3-b]pyridinyl.

### Claim 39 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from optionally substituted quinolyl; and Ring B is selected from an optionally substituted indolyl, an optionally substituted indazolyl, and an optionally substituted 1H-pyrrolo[2,3-b]pyridinyl.

### Claim 40 (depends on 1)

A pharmaceutical composition comprising a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 41 (depends on 1)

A method of inhibiting kallikrein enzyme comprising contacting the kallikrein enzyme with a compound of Formula (I) as described in claim 1.

### Claim 42 (depends on 1)

A method for treating angioedema in a patient in need thereof comprising administering to the patient a composition comprising a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.