# US 11,433,071 B2 · Heterocyclylamines as PI3K inhibitors

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- Number: US 11,433,071 B2
- Document ID: US11433071B2
- Status: Granted
- Kind: B2
- Application number: 16/828,315
- Filed: 2020-03-24
- Published: 2020-10-15
- Granted: 2022-09-06
- Earliest claimed: 2011-09-02
- Assignees: Incyte Corporation; Incyte Holdings Corporation
- Applicants: Incyte Corporation; Incyte Holdings Corporation
- Inventors: Yun-Long Li; Wenqing Yao; Andrew P. Combs; Eddy W. Yue; Song Mei; Joseph Glenn; Thomas P. Maduskuie, Jr.; Richard B. Sparks; Brent Douty; Chunhong He
- Web page: https://patentgrep.com/patent/US11433071B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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 heterocyclylamine derivatives of Formula I: wherein the variables are defined herein, that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

## Claims

### Claim 1

A method of inhibiting or ameliorating a skin condition selected from psoriasis, skin rash, contact dermatitis, and eczema, in a patient, comprising administering to the patient a compound of Formula VIIa:
or a pharmaceutically acceptable salt thereof, wherein:
G is NH, n is 1, and V is O; or
G is NH, n is 0, and V is CH2; or
G is O, n is 0, and V is NH;
R1 is C1-3 alkyl;
R2 is halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, phenyl, or 5-6 membered heteroaryl; wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R4 is H, halo, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy;
R5 is halo, OH, CN, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, or cyclopropyl;
R6 is H, halo, OH, CN, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, or C1.4 haloalkoxy;
R8 is H, halo, —OH, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy2, —(C1-3 alkylene)-Cy2, ORa2, SRa2, C(═O)Rb2, C(═O)NRc2Rd2, C(═O)ORa2, OC(═O)Rb2, OC(═O)NRc2Rd2, NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, C(═NRW)Rb2, C(═NRe)NRc2Rd2, NRc2C(═NRe)NRc2Rd2, NRc2S(═O)Rb2 NRc2S(═O)2NRc2Rd2 S(═O)Rb2, S(═O)2Rb2, or S(═O)2NRc2Rd2; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R11 groups;
R10 is H or C1-4 alkyl;
each Re is independently selected from H, CN, OH, C1-4 alkyl, and C1-4 alkoxy;
each Cy2 is independently selected from C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or 9-10-membered bicyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R11 groups;
each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R11 groups;
or Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with —OH or C1-3 alkyl; and
each R11 is independently selected from OH, NO2, CN, halo, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, cyano-C1-3 alkyl, HO—C1-3 alkyl, C1-3 alkoxy-C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-3 alkylcarbonylamino, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(C1-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(C1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(C1-3 alkyl)aminocarbonylamino.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of Formula VIIa is a compound of Formula VIIb:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
G is NH;
n is 0;
V is CH2;
R2 is C1-3 alkoxy;
R4 is halo, CN, or C1-4 alkyl;
R5 is halo; and
R6 is H.

### Claim 4 (depends on 1)

The method of claim 1, wherein:
G is NH;
n is 1;
V is O;
R2 is C1-3 alkoxy;
R4 is halo, CN, or C1-4 alkyl;
R5 is halo; and
R6 is H.

### Claim 5 (depends on 1)

The method of claim 1, wherein:
G is O;
n is 0;
V is NH;
R2 is C1-3 alkoxy;
R4 is halo;
R5 is halo; and
R6 is H.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is selected from:
4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-one;
6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one;
4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;
4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile; and
4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one;
or a pharmaceutically acceptable salt thereof of any of the aforementioned.

### Claim 7 (depends on 4)

The method of claim 4, wherein the compound is 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one.

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound is (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound is (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one.

### Claim 17 (depends on 1)

The method of claim 1, wherein the skin condition is psoriasis.

### Claim 18 (depends on 1)

The method of claim 1, wherein the skin condition is skin rash.

### Claim 19 (depends on 1)

The method of claim 1, wherein the skin condition is contact dermatitis.

### Claim 20 (depends on 1)

The method of claim 1, wherein the skin condition is eczema.