Quinazoline-pyridine derivatives for the treatment of cancer-related disorders

Inventors: Manmohan Reddy Leleti (Dublin, CA); Dillon Harding Miles (Berkeley, CA); Jay Patrick Powers (Pacifica, CA); Brandon Reid Rosen (San Mateo, CA); Ehesan Ul Sharif (Menlo Park, CA); Rhiannon Thomas-Tran (San Jose, CA)

Assignee: ARCUS BIOSCIENCES, INC.

A61K31/517 A61K31/4709 A61K31/704 A61K33/243 A61K39/3955 A61K45/06 C07D401/14 C07D405/14

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Quick Facts

Patent No.: US 11,045,472
App. No.: 16/610,812
Granted: Jun 29, 2021
Kind: B2

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Abstract

Compounds of Formula I that inhibit at least one of the A 2A and A 2B adenosine receptors, and compositions containing compounds of Formula I and methods for synthesizing compounds of Formula I, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by the adenosine A 2A receptor and/or the adenosine A 2B receptor.

Claims (60)

1. A compound represented by Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

the subscript m is 0 or 1, indicating a pyridine when m is 0 or a pyridine N-oxide when m is 1;

G 1 is N or CR 3a ;

G 2 is N or CR 3b ;

R 3a and R 3b are each independently H or C 1-3 alkyl;

R 1a and R 1b are each independently selected from the group consisting of

i) H,

ii) C 1-8 alkyl optionally substituted with from 1-3 R 5 substituents,

iii) —X 1 —O—C 1-8 alkyl optionally substituted with from 1-3 R 5 substituents,

iv) —C(O)—R 6 ,

v) Y optionally substituted with 1-3 R 7 substituents,

vi) —X 1a —Y optionally substituted with 1-3 R 7 substituents; and

vii) R 1a and R 1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with from 1-3 R 8 substituents, wherein the heterocycloalkyl has 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S;

each Y is C 3-8 cycloalkyl or 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S;

R 2 and R 4 are each independently H or C 1-3 alkyl;

each X 1 is C 1-6 alkylene;

each R 5 is independently selected from the group consisting of hydroxyl, C 3-8 cycloalkyl, phenyl, —O-phenyl, —C(O)OR a and oxo;

each R 6 is C 1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl, and —O—C 1-8 alkyl;

each R 7 is independently selected from the group consisting of C 1-8 alkyl, hydroxyl, —O—C 1-8 alkyl, oxo, and C(O)OR a ;

each R 8 is independently selected from the group consisting of C 1-8 alkyl, hydroxyl, and oxo; the subscript n is 0, 1, 2 or 3;

each R 9 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, —O—C 1-8 alkyl, —X 1 —O—C 1-8 alkyl, —O—X 1 —O—C 1-8 alkyl, —X 1 —O—X 1 —O—C 1-8 alkyl, —C(O)OR a , halogen, cyano, phenyl, —NR b R c , Y, —X 1 —C 3-8 cycloalkyl, and —X 2 —Z, wherein X 2 is selected from the group consisting of C 1-6 alkylene, —C 1-6 alkylene-O—, —C 1-4 alkylene-O—C 1-4 alkylene-, —C(O)—, and S(O) 2 —, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each of said R 9 substituents is optionally substituted with 1-3 R 11 ;

each of R 10a , R 10b , R 10c and R 10d is independently selected from the group consisting of H, C 1-8 alkyl, halo, cyano, —O—C 1-8 alkyl, —X 1 —O—C 1-8 alkyl, —O—X 1 —O—C 1-8 alkyl, —S(O) 2 -C 1-6 alkyl, and —C(O)NR d R e , wherein each of said R 10a-d substituents is optionally substituted with 1-3 R 12 ;

each R 11 is independently selected from the group consisting of hydroxyl, oxo, halo, cyano, —NR d R e , —C(O)OR a , phenyl, C 3-8 cycloalkyl, and C 1-4 alkyl optionally substituted with C(O)OR a ;

each R 12 is independently selected from the group consisting of halo, cyano, hydroxy, —C(O)OR a ; and

each R a is H or C 1-6 alkyl;

each R b and R c are independently selected from the group consisting of H, C 1-8 alkyl, —S(O) 2 —C 1-6 alkyl, —C(O)OR a , and —X 1 —C(O)OR a ; and

each R d and R e are independently selected from the group consisting of H, C 1-8 alkyl, and —S(O) 2 —C 1-6 alkyl.

2. The compound of claim 1 , wherein each R 9 is independently selected from the group consisting of C 1-8 alkyl, —O—C 1-8 alkyl, —X 1 —O—C 1-8 alkyl, —O—X 1 —O—C 1-8 alkyl, —X 1 —O—X 1 —O—C 1-8 alkyl, —C(O)OR a , halogen, cyano, —NR b R c , Y, —X 1 —C 3-8 cycloalkyl, and —X 2 —Z, wherein X 2 is selected from the group consisting of C 1-6 alkylene, —C 1-6 alkylene-O—, —C 1-4 alkylene-O—C 1-4 alkylene-, —C(O)—, and S(O) 2 —, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each of said R 9 substituents is optionally substituted with 1-3 R 11 .

3. The compound of claim 1 , having Formula (Ia):