# US 8,785,454 B2 · Heterocyclic compounds and uses thereof

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- Number: US 8,785,454 B2
- Document ID: US8785454B2
- Status: Granted
- Kind: B2
- Application number: 13/289,540
- Filed: 2011-11-04
- Published: 2012-12-27
- Granted: 2014-07-22
- Earliest claimed: 2009-05-07
- Assignees: Intellikine LLC
- Applicants: Pingda Ren; Yi Liu; Liansheng Li; Troy Edward Wilson
- Inventors: Pingda Ren; Yi Liu; Liansheng Li; Troy Edward Wilson
- Web page: https://patentgrep.com/patent/US8785454B2

## CPC

- C07D 473/34: attached in position 6, e.g. adenine
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- 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 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the isoquinolone entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described herein.

## Claims

### Claim 1

A compound of Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein
W1 is N or CR5, W2 is N or CR6, W3 is N or CR7, W4 is N or CR8, wherein no more than two N atoms are adjacent;
R1 is -(L)n—R1;
L is —S—, —N(R2)—, —C(R3)2—, or —O—;
n is 0 or 1;
R1′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R4, R5, R6, R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
X is absent or is —(CH(R10)) z— and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R9)—, —C(═O)—, —N(R9)—C(═O)—, —N(R9)—C(═O)NH—,)—N(R9)C(R102—, or —C(═O)—(CHR10)z—;
each instance of R2 and R9 is independently hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heterocycloalkyl, C2-C10heteroalkyl, aryl, or heteroaryl;
each instance of R3 and R10 is independently hydrogen, alkyl, aryl, heteroaryl, or halo; and
Wd is
wherein each instance of Ra is independently hydrogen or alkyl;
R11 is H, alkyl, halo, amino, amido, hydroxyl, or alkoxy, and
R12 is H, alkyl, cyano, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocyloalkyl, cycloalkyl, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amino.

### Claim 2

A compound of Formula I-B:
or a pharmaceutically acceptable salt thereof, wherein
W1 is N or CR5, W2 is N or CR6, W3 is N or CR7, W4 is N or CR8, wherein no more than two N atoms are adjacent;
R1 is —(L)n—R1′;
L is —S—, —N(R2)—, —C(R3)2—, or —O—;
n is 0or 1;
R1′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R5, R6, R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
X is absent or is —(CH(R10))z— and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R9)—, —C(═O)—, —N(R9)—C(═O)—, —N(R9)—C(═O)NH—,—N(R9)C(R102—,or —C(═O)—(CHR10)z—;
each instance of R2 and R9 is independently hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heterocycloalkyl, C2-C10heteroalkyl, aryl, or heteroaryl;
each instance of R3 and R10 is independently hydrogen, alkyl, aryl, heteroaryl or halo; and
Wd is
wherein each instance of Ra is independently hydrogen or alkyl;
R11 is H, alkyl, halo, amino, amido, hydroxyl, or alkoxy, and
R12 is H, alkyl, cyano, alkynyl, alkenyl , halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amino.

### Claim 3 (depends on 1, 2)

The compound of claim 1 or 2 wherein
W1 is N, W2 is CR6, W3 is CR7, W4 is CR8;
W1 is CR5, W2 is N, W3 is CR7, W4 is CR8;
W1 is CR5, W2 is CR6, W3 is N, W4 is CR8;
W1 is N, W2 is CR6, W3 is N, W4 is CR8;
W1 is N, W2 is N, W3 is CR7, W4 is CR8;
W1 is N, W2 is CR6, W3 is CR7, W4 is N;
W1 is CR5, W2 is N, W3 is N, W4 is CR8;
W1 is CR5, W2 is N, W3 is CR7, W4 is N;
W1 is CR5, W2 is CR6, W3 is N , W4 is N ; or
W1 is CR5, W2 is CR6, W3 is CR7, w4 is CR8.

### Claim 4 (depends on 1)

The compound of claim 1 wherein the compound of Formula I-A is a compound of Formula XV-A:

### Claim 5 (depends on 2)

The compound of claim 2 wherein the compound of Formula I-B is a compound of Formula XV-B:

### Claim 6 (depends on 1, 2)

The compound of claim 1 or 2 wherein n is 0 and R1′ is hydrogen, amino, alkoxy, alkyl, heterocycloalkyl, aryl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

### Claim 7 (depends on 1, 2)

The compound of claim 1 or 2 wherein n is 1 and R1′ is amino, alkoxy, alkyl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

### Claim 8 (depends on 7)

The compound of claim 7 wherein n is 1 and R1′ is alkyl which is substituted with heterocycloalkyl or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

### Claim 9 (depends on 1, 2)

The compound of claim 1 or 2 wherein R8 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, sulfonamido, halo, cyano, hydroxy, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

### Claim 10 (depends on 1, 2)

The compound of claim 1 or 2 wherein R8 is hydrogen or alkyl.

### Claim 11 (depends on 10)

The compound of claim 10 wherein R8 is alkyl substituted with one or more fluoro.

### Claim 12 (depends on 1, 2)

The compound of claim 1 or 2 wherein X is —CH2—, —CH(CH3)—, —CH(C6H5)—,or —CH(CH2CH3)—.

### Claim 13 (depends on 12)

The compound of claim 12 wherein —CH(CH3)—or —CH(CH2CH3)—has either a predominately (S) stereochemical configuration or a predominately (R) stereochemical configuration.

### Claim 14 (depends on 1, 2)

The compound of claim 1 or 2 wherein Y is absent, —O—, —N(R9)—, —N(R9)C(R10)2—, or —S(═O)2—.

### Claim 15 (depends on 14)

The compound of claim 14 wherein R9 and R19 are independently hydrogen, methyl, or ethyl.

### Claim 16 (depends on 15)

The compound of claim 15 wherein the compound is a compound of Formula I-A, when R1 is alkyl, X is —(CH(R10))z—, z is 1, and Y is —N(R9)—, then R9 is hydrogen.

### Claim 17 (depends on 1, 2)

The compound of claim 1 or 2 wherein Y is —N(CH2CH3)CH2—or —N(CH3)CH2—.

### Claim 18 (depends on 1, 2)

The compound of claim 1 or 2 wherein X-Y is —CH2—N(CH3)—, or —CH2—N(CH2CH3)—.

### Claim 19 (depends on 1, 2)

The compound of claim 1 or 2 wherein Wd is of Formula XIV:
wherein R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amido.

### Claim 20 (depends on 1, 2)

The compound of claim 1 or 2 wherein R11 is amino.

### Claim 21 (depends on 1, 2)

The compound of claim 1 or 2 wherein R12 is a monocyclic heteroaryl, a bicyclic heteroaryl, or a heterocycloalkyl.

### Claim 22 (depends on 1, 2)

The compound of claim 1 or 2 wherein R12 is hydrogen.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula XIX-A:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula XXI-A:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1, 2)

A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or 2.

### Claim 26 (depends on 25)

The composition of claim 25 wherein the composition is a liquid, solid, semi-solid, gel, or an aerosol form.

### Claim 27 (depends on 2)

The compound of claim 2, wherein the compound is a compound of Formula XIX-B:
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 2)

The compound of claim 2, wherein the compound is a compound of Formula XXI-B:
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 1)

The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 29)

The compound of claim 29, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 1)

The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 31)

The compound of claim 31, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 31)

The compound of claim 31, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 2)

The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 35 (depends on 34)

The compound of claim 34, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 1)

The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 2)

The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 1)

The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 2)

The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.