# US 10,946,023 B2 · Therapeutically active compounds and their methods of use

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- Number: US 10,946,023 B2
- Document ID: US10946023B2
- Status: Granted
- Kind: B2
- Application number: 16/167,725
- Filed: 2018-10-23
- Published: 2019-04-25
- Granted: 2021-03-16
- Earliest claimed: 2013-07-11
- Assignees: Agios Pharmaceuticals, Inc.
- Applicants: Agios Pharmaceuticals, Inc.
- Inventors: Zenon D. Konteatis; Janeta Popovici-Muller; Jeremy Travins; Robert Zahler; Zhenwei Cai; Ding Zhou
- Web page: https://patentgrep.com/patent/US10946023B2

## CPC

- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/506: not condensed and containing further heterocyclic rings
- 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 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 251/18: with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
- C07D 251/48: Two nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- 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

Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.

## Claims

### Claim 1

A method for preparing a compound of formula (Ia) wherein:
ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH-S(O)2-(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —CN, —S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with —OH, —NH2, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;
R2 and R5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(O)-NH2, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R6)-C1-C6 alkyl), —(C0-C6 alkylene)-Q and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2CL, C(O)CH3, C(O)CF3, CN, or CO2H;
Q is selected from carbocyclyl and heterocyclyl, and of which is substituted woth 0-3 instances of halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, —C(O)-C1-C4 alkyl, and CN; wherein
R1 and R2 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1C4 alkyl; or
R4 and R5 are optionally taken together to form a carbocyclyl, or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl;
R7 and R8 are H;
comprising a reaction between

### Claim 2 (depends on 1)

The method of claim 1 wherein the reaction takes place between 40-120 ° C.

### Claim 3 (depends on 1)

The method of claim 1 wherein
is prepared by a method comprising a reaction between

### Claim 4 (depends on 3)

The method of claim 3 wherein the reaction takes place between 20-50 ° C.

### Claim 5 (depends on 1)

The method of claim 1 wherein
is prepared by a method comprising a reaction between

### Claim 6 (depends on 5)

The method of claim 5 wherein the reaction takes place in the presence of a palladium catalyst and a base.

### Claim 7 (depends on 6)

The method of claim 6 wherein the palladium catalyst is Pd(PPh3)4.

### Claim 8 (depends on 7)

The method of claim 7 wherein the base is K2CO3.

### Claim 9

A method for preparing a compound of Formula (Ia) wherein:
ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH-S(O)2-(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —CN, —S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with —OH, —NH2, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;
R2 and R5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(O)-NH2, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), —(C0-C6 alkylene)-Q and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2CL, C(O)CH3,C(O)CF3, CN, or CO2H;
Q is selected from carbocyclyl and heterocyclyl, and of which is substituted with 0-3 instances of halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, —C(O)-C1-C4 alkyl, and CN; wherein
R1 and R2 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl; or
R4 and R5 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl;
R7 and R8 are H;
comprising a reaction between

### Claim 10 (depends on 9)

The method of claim 9 wherein the reaction takes place in the presence of a palladium catalyst and a base.

### Claim 11 (depends on 10)

The method of claim 10 wherein the palladium catalyst is Pd(PPh3)4.

### Claim 12 (depends on 11)

The method of claim 11 wherein the base is K2CO3.

### Claim 13 (depends on 9)

The method of claim 9 wherein
is prepared by a method comprising a reaction between

### Claim 14 (depends on 13)

The method of claim 13 wherein the reaction takes place between 30-60 ° C.

### Claim 15 (depends on 13)

The method of claim 13 wherein
is prepared by a method comprising a reaction between

### Claim 16 (depends on 15)

The method of claim 15 wherein the reaction takes place between 20-60 ° C.

### Claim 17 (depends on 16)

The method of claim 16 wherein the reaction takes place in the presence of a base.

### Claim 18 (depends on 17)

The method of claim 17 wherein the base is selected from CsF, NaHCO3, Na2CO3, DIPEA, TEA, pyridine or a combination thereof.

### Claim 19 (depends on 18)

The method of claim 18 wherein the base is a mixture of CsF and DIPEA.

### Claim 20 (depends on 3)

The method of claim 3 wherein
is prepared by a method comprising a reaction between
and POCl3.

### Claim 21 (depends on 20)

The method of claim 20 wherein the reaction takes place at 80-110 ° C.

### Claim 22 (depends on 21)

The method of claim 21 wherein
is prepared by a method comprising a reaction between
in the presence of a base.

### Claim 23 (depends on 22)

The method of claim 22 wherein the base is an alkoxide base dissolved in the corresponding alcohol.

### Claim 24 (depends on 23)

The method of claim 23 wherein the alkoxide is sodium ethoxide dissolved in ethanol.

### Claim 25 (depends on 22)

The method of claim 22 wherein the reaction takes place at 20-110° C.

### Claim 26 (depends on 20)

The method of claim 20 wherein the reaction additionally takes place in the presence of PCl5.

### Claim 27 (depends on 1)

The method of claim 1 wherein R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 is independently substituted with 0-3 instances of —OH, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2; and
R2 and R5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(0)-NH2, —(C1-C6 alkyl)-CO2H, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:
any alkyl or alkylene moiety present in R2 and R5 is substituted with 0-3 instances of —OH, —O(C1-C4 alkyl), —CO2H, or halo; and
any terminal methyl moiety present in R2 and R5 can be replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H;
R1 and R2 can be taken together to form a carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH and —C(O)C1-C4 alkyl; or
R4 and R5 can be taken together to form a carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH and —C(O)C1-C4 alkyl;

### Claim 28 (depends on 1)

The method of claim 1 wherein ring A is:
wherein R9 is selected from hydrogen, halo, and —C1-C4 haloalkyl; each Xa is independently N or C-R9a, provided that when one Xa is N, then the other two Xa are both C-R9a; and R9a is selected from hydrogen, halo, and —C1-C4 haloalkyl.

### Claim 29 (depends on 1)

The method of claim 1 wherein ring A is
wherein R9 is selected from hydrogen, halo, and —C1-C4 haloalkyl.

### Claim 30 (depends on 1)

The method of claim 1 wherein R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, and —CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently substituted with 0-1 instances of —OH, —NH2, —CN, —O-C1-C4 alkyl; and R2 and R5 are each independently selected from —(C1-C6 alkyl) and —(C0-C6 alkylene)-Q.

### Claim 31 (depends on 1)

The method of claim 1 wherein Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, =O, fluoro, chloro, and bromo.

### Claim 32 (depends on 31)

The method of claim 31 wherein Q is cyclopropyl.

### Claim 33 (depends on 1)

The method of claim 1 wherein R1 and R2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, azetidinyl, any of which is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —OH, —C(O)CH3, fluoro, and chloro.

### Claim 34 (depends on 1)

The method of claim 1 wherein R4 and R5 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, or azetidinyl, any of which is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —OH, —C(O)CH3, fluoro, and chloro.

### Claim 35 (depends on 1)

The method of claim 1 wherein the compound is