# US 10,479,770 B2 · Phosphatidylinositol 3-kinase inhibitors

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- Number: US 10,479,770 B2
- Document ID: US10479770B2
- Status: Granted
- Kind: B2
- Application number: 15/711,875
- Filed: 2017-09-21
- Published: 2018-03-29
- Granted: 2019-11-19
- Earliest claimed: 2016-09-23
- Assignees: Gilead Sciences, Inc.
- Applicants: Gilead Sciences, Inc.
- Inventors: Jayaraman Chandrasekhar; Devan Naduthambi; Leena Patel; Stephane Perreault; Gary Phillips; Kassandra F. Sedillo; Nicholas Alexander Till; Jennifer Anne Treiberg; William J. Watkins; Julian A. Codelli; Joshua J. Van Veldhuizen
- Web page: https://patentgrep.com/patent/US10479770B2

## CPC

- C07D 235/08: Radicals containing only hydrogen and carbon atoms
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present application provides the compounds of formula I or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein t, R1, R2, R3, R4, and R6 are as described herein.

## Claims

### Claim 1

A compound having the structure of formula (I):
wherein: R1 is selected from:
n is 1, 2, 3 or 4;
s is 1, 2 or 3;
t is 1 or 2;
each X1, X2, X3, X4, X5, X6 and X7 is independently selected from C and N;
R2 is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R2 is optionally substituted with one to four R101;
R3 is selected from halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —N(Ra)C(O)NRaRb, —OC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Ra, —N(Ra)C(O)NRaRb, —OC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Ra, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R3 is optionally substituted with one to four R102;
R4 is selected from 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R4 is optionally substituted with one to four R103;
each R5 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —N(Ra)C(O)NRaRb, —N(Ra)C(O)NRaRb, —OC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Ra, —OC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Ra, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R5 is optionally substituted with one to four R104;
each R6 is independently hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
each R7 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rg, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R7 is optionally substituted with one to four R100;
each Ra and Rb is independently selected from hydrogen, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
wherein each C1-6 alkyl, C2-6 alkynyl of Ra and Rb, C2-6 alkynyl, is optionally substituted with one to four R200;
each R100, R101, R102, R103 and R104 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Rc, —C(O)ORc, —C(O)NRcRd, —N(Rc)C(O)Rd, —N(Rc)C(O)NRcRd, —N(Rc)C(O)NRcRd, —OC(O)NRcRd, —NRcS(O)2NRcRd, —NRcS(O)2Rc, —OC(O)NRcRd, —NRcS(O)2NRcRd, —NRcS(O)2Rc, —S(O)NRcRd, —S(O)2NRcRd, —S(O)Rc, —S(O)2Rg, —NRcRd, —ORc, —SRd, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R100, R101, R102, R103 and R104 is optionally substituted with one to four R201, and
each Rc and Rd is independently selected from hydrogen, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R200 and R201 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)Re, —C(O)ORe, —C(O)NReRf, —N(Re)C(O)Rf, —S(O)NReRf, —S(O)2NReRf, NReRf, —ORe, —SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl,
each Re and Rf is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; and
each Rg is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of Rg is optionally substituted with one to four R200,
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 2 (depends on 1)

The compound of claim 1 having the structure of formula IA:
wherein t, R1, R2, R4, and R6 are as defined in claim 1;
represents a single or double bond;
X12 is N or C;
each X8, X9, X10 and X11 is independently selected from S, O, CR10 and NR11;
wherein each R10 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;
wherein each R11 is independently selected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; or
one R10 and one R11 group, together with the atoms to which they are attached form a five, six or seven membered fused, or bridged ring,
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 3 (depends on 1)

The compound of claim 1 having the structure of formula IB:
wherein m is 1, 2 or 3;
each R14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl,
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 4 (depends on 2)

The compound of claim 2 having the structure of formula IC:
wherein m is 1, 2 or 3;
each R14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl,
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is selected from:
k is 1 or 2;
each R13 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R4 is selected from:
m is 1, 2 or 3;
each R14 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)Ra, —C(O)ORb, —C(O)NRaRb, —N(Ra)C(O)Rb, —S(O)NRaRb, —S(O)2NRaRb, —S(O)Rc, —S(O)2Rg, —NRaRb, —ORa, —SRb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl;
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is selected from:
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is selected from:
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R3 is selected from:
or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
Compound
Image
2-1
2-2
2-3
3-1
3-2
4-1
4-2
4-3
4-4
5-1
5-2
5-3
5-4
5-5
5-6
5-7
5-8
5-9
5-10
5-11
5-12
5-13
6-1
6-2
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof, and at least one pharmaceutically acceptable vehicle.

### Claim 12 (depends on 1)

A kit comprising the compound of claim 1, or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof, and a label and/or instructions for use.

### Claim 13

A compound selected from:
Compound
Image
5-14
5-15
or a pharmaceutically acceptable salt thereof.