US 10,538,497 B2 · Compounds as indoleamine 2,3-dioxygenase inhibitors

Abstract

Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
m is 0, 1, 2, 3, 4, 5 or 6;
X is O or S;
ring A is a 5-membered heterocyclyl selected from 1,2,5-oxadiazolyl and 1,2,5-thiadiazolyl;
each of which is optionally substituted with:
(i) halogen,
(ii) C1-6 alkyl, optionally substituted with one to four halogens,
(iii) C3-6 cycloalkyl,
(iv) C2-6 alkenyl,
(v) C2-6 alkynyl,
(vi) aryl,
(vii) heteroaryl,
(viii) CN,
(ix) NO2,
(x) OR4,
(xi) SR4,
(xii) C(O)R4,
(xiii) NR4R4,
(xiv) S(O)R4, and
(xv) S(O)2R4;
R is selected from:
(a) hydrogen,
(b) ORa,
(c) C3-6cycloalkyl, optionally substituted with one to four substituents independently selected from:
(i) C1-6alkyl,
(ii) CN, and
(iii) —(C═O)—O—C1-6alkyl,
(d) aryl, optionally substituted with one to four substituents independently selected from:
(i) halogen,
(ii) C1-6alkyl, optionally substituted with one to three halogens,
(iii) oxo, and
(iv) —S(O)2—NH—R4,
(e) a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from:
(i) halogen,
(ii) C1-6alkyl, optionally substituted with one to three halogens,
(iii) oxo,
(iv) —S(O)2—NH—R4,
(v) —(C═O)—C1-6alkyl, and
(vi) —(C═O)NH—R4,
(f) CN,
(g) —(C═O)—Ra,
(h) —(C═O)NH—Ra,
(i) —P(O)(ORa)2,
(j) —P(O)(NHRa)(ORa),
(k) —P(O)(NR4Ra)2,
(l) C2-4alkynyl,
(m) —NRxRy, wherein each of Rx and Ry is independently selected from:
(i) hydrogen,
(ii) C1-6alkyl, optionally substituted with a 4-, 5- or 6-membered heterocyclyl,
(iii) C3-6cycloalkenyl, optionally substituted with one to four substituents independently selected from NH—Ra, oxo, and 4-, 5- or 6-membered heterocyclyl,
(iv) C2-4alkenyl, optionally substituted with one to four substituents independently selected from NR4 and NO2,
(v) —(C═O)—Ra,
(vi) —(C═O)—C3-6cycloalkyl,
(vii) —(C═O)—NR4Ra,
(viii) aryl,
(ix) heteroaryl,
(x) —(C═NH)(NH2)—CN,
(xi) —S(O)2—Ra, and
(xii) —S(O)2—NH—Ra;
R1 is aryl, optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, optionally substituted with one to four halogens,
(c) CN,
(d) C2-6 alkenyl,
(e) C2-6 alkynyl,
(f) C3-6cycloalkyl,
(g) OR4,
(h) SR4,
(i) C(O)R4,
(j) C(O)NR4R4,
(k) S(O)R4,
(l) S(O)2R4, and
(m) S(O)2NR4R4;
each occurrence of R2 and R3 is independently selected from:
(a) R4,
(b) OH,
(c) NH—R4,
(d) NH—(C═O)—R4,
(e) halogen,
(f) C3-6cycloalkyl, and
(g) C1-6alkoxy;
or R2 and R3 together form an oxo group;
or R2 and R3 together with the carbon to which they are attached form a C3-6cycloalkyl group;
each occurrence of R4 is independently selected from hydrogen and C1-6 alkyl;
and
each occurrence of Ra is independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, optionally substituted with one or three substituents independently selected from halogen, OR4, —O—(C═O)—O—C1-6alkyl, —(C═O)—O—C1-6alkyl, aryl, and 4-, 5- or 6-membered heterocyclyl,
(c) C3-6cycloalkyl, optionally substituted with one or three substituents independently selected from halogen, C1-6alkyl and OR4,
(d) —O—C1-6alkyl,
(e) —(C═O)—O—C1-6alkyl,
(f) aryl, optionally substituted with C1-6alkyl, and
(g) 4, 5- or 6-membered heterocyclyl, optionally substituted with —C1-6alkyl or —C1-6alkyl-OR4.

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Compounds as indoleamine 2,3-dioxygenase inhibitors

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Compounds as indoleamine 2,3-dioxygenase inhibitors

Life of this patent

Abstract

Claims19