IP Library › Granted Patent US 12,264,134

Granted Patent B2

US 12,264,134 · App. 17/295,497 · Granted Apr 1, 2025

Substituted piperazine amide compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Inventors: Dane Clausen (Rahway, NJ); Ping Chen (Edison, NJ); Xavier Fradera (Brookline, MA); Liangqin Guo (Monroe Township, NJ); Yongxin Han (Needham, MA); Shuwen He (Fanwood, NJ); Xianhai Huang (Warren, NJ); Joseph Kozlowski (Princeton, NJ); Guoqing Li (Belle Mead, NJ); Theodore A. Martinot (Southborough, MA); Alexander Pasternak (Jamaica Plain, MA); Andreas Verras (New York, NY); Li Xiao (Cranbury, NJ); Feng Ye (Scotch Plains, NJ); Wensheng Yu (Edison, NJ); Rui Zhang (Plainsboro, NJ)

Assignee: Merck Sharp & Dohme LLC

C07D231/56 A61K31/496 A61K31/5377 A61K31/541 C07D231/54 C07D401/12 C07D401/14 C07D403/12 C07D405/12 C07D413/12 C07D413/14 C07D471/10 C07D487/04 C07D487/10 C07D491/052 C07D491/107 C07D498/04 C07D498/08 C07D498/10

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,264,134
App. No.: 17/295,497
Granted: Apr 1, 2025
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (621)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

m is 1, 2, or 3;

A is selected from: (1) —O— and (2) —CR g R g —, wherein:

each occurrence of R g is independently selected from:

(a) hydrogen,

(b) halogen,

(d) C 1-6 alkyl, optionally substituted with 1-4 halogens;

or alternatively, one R g is hydrogen and the other R g together with one Rd and the two carbons to which R d and R g are attached form a C 3-4 cycloalkyl;

or alternatively, two R g groups together with the carbon to which they are attached form a C 3-4 cycloalkyl, optionally substituted with 1-4 halogens;

or alternatively, m is 1, one R8 is hydrogen and the other R g together with one Re and the two carbons to which R e and R g are attached form a C 3-4 cycloalkyl;

or alternatively, m is 2, one R g is hydrogen and the other R g together with one R e on the carbon adjacent to A and the two carbons to which R e and R g are attached form a C 3-4 cycloalkyl;

R a is selected from: (1) hydrogen and (2) C 1-6 alkyl;

each occurrence of R b is independently selected from: (1) hydrogen, (2) halogen, and (3) C 1-6 alkyl, optionally substituted with 1-4 halogens;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a spiro-C 3-4 cycloalkyl;

each occurrence of R o is independently selected from:

(1) hydrogen,

(2) halogen,

(3) —OH, and

(4) C 1-6 alkyl, optionally substituted with 1-4 halogens;

or alternatively, m is 1, A is —CR g R g —, and one R e together with one R8 and the two carbons to

which R e and R g are attached form a C 3-4 cycloalkyl;

each occurrence of R d is independently selected from: (1) hydrogen and (2) C 1-6 alkyl, optionally substituted with 1-4 halogens;

or alternatively, when A is —CR g R g —, one R d is hydrogen and the other R d together with one R g and the two carbons to which R d and R g are attached form a C 3-4 cycloalkyl;

R 1 and R 2 together with the nitrogen to which they are attached form a 4-10 membered mono-cyclic, fused bicyclic, spiro bicyclic, or bridged bicyclic heterocyclyl containing the one nitrogen to which they are attached and zero to two additional hetero atoms independently selected from N, S and O; wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—C 1-6 alkyl,

(iv) —NH 2 ,

(v) —N(C 1-6 alkyl)(C 1-6 alkyl),

(vi) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen and C 1-6 alkyl, and

(vii) heterocyclyl,

(d) —O—C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from (i) —OH and (ii) halogen,

(e) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) C 1-6 alkyl, optionally substituted with —OH,

(iii) —C(O)—C 1-6 alkyl, optionally substituted with —OH or —O—C 1-6 alkyl,

(iv) —C(O)—NH 2 ,

(v) —C(O)—NH—NH 2 ,

(vi) —C(O)—NH—C 1-6 alkyl,

(vii) —C(O)—C 3-6 cycloalkyl,

(viii) —SO 2 —C 1-6 alkyl,

(ix) —SO 2 —NH 2 , and

(x) —C(O)—O—C 1-6 alkyl,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-6 alkyl, optionally substituted with —OH, —O—C 1-6 alkyl, —O—C(O)—C 1-6 alkyl, or —NH 2 ,

(ii) —O—C 1-6 alkyl, optionally substituted with 1-4 halogens,

(iii) —NH 2 ,

(iv) —NH (C 1-6 alkyl), and

(v) —N(C 1-6 alkyl)(C 1-6 alkyl),

(g) heterocyclyl, optionally substituted with 1-3 substituents independently selected from (i) —OH, (ii) oxo, and (iii) C 1-6 alkyl,

(h) oxo,

(i) C 3-6 cycloalkyl,

(j) —CN,

(k) ═NH,

(l) aryl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-6 alkyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) C 1-6 alkyl, and

(ii) —N(C 1-6 alkyl)(C 1-6 alkyl);

R 3 is selected from (1) a C 6-10 carbocyclyl and (2) a heterocyclyl, wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) C 1-6 alkyl, optionally substituted with 1-4 halogens,

(d) —CN, and

(e) C 3-6 cycloalkyl, optionally substituted with C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a is selected from (1) hydrogen and (2) methyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

R a is hydrogen;

each occurrence of R b is independently selected from: (1) hydrogen and (2) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R a is hydrogen;

each occurrence of R o is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, m is 1, A is —CR g R g —, and one R e together with one R g and the two carbons to which the one R e and the one R g are attached form a cyclopropyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of R d is independently selected from: (1) hydrogen and (2) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, when A is —CR g R g —, one R d is hydrogen and the other R d together with one R g and the two carbons to which the R d and the R g are attached form a cyclopropyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —O—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —CR g R g —, and wherein:

each occurrence of R g is independently selected from: (a) hydrogen, (b) halogen, (c) —OH, and (d) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, one R g is hydrogen and the other R g together with one R d and the two carbons to which the R d and R g are attached form a cyclopropyl;

or alternatively, two R g groups together with the carbon to which they are attached form a cyclopropyl, optionally substituted with 1-3 halogens;

or alternatively, m is 1, one R g is hydrogen and the other R g together with one R e and the two carbons to which the R e and the R g are attached form a cyclopropyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 together with the nitrogen to which they are attached form a 4-10 membered mono-cyclic, fused bicyclic, spiro bicyclic, or bridged bicyclic containing the one nitrogen to which they are attached and zero to two additional hetero atoms independently selected from N, S and O; wherein the heterocyclyl is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—C 1-4 alkyl,

(iv) —NH 2 ,

(v) —N(C 1-4 alkyl)(C 1-4 alkyl),

(vi) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen and C 1-4 alkyl, and

(vii) heterocyclyl,

(d) —O—C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from (i) —OH and (ii) halogen,

(e) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) C 1-4 alkyl, optionally substituted with —OH,

(iii) —C(O)—C 1-4 alkyl, optionally substituted with —OH or —O—C 1-4 alkyl,

(iv) —C(O)—NH 2 ,

(v) —C(O)—NH—NH 2 ,

(vi) —C(O)—NH—C 1-4 alkyl,

(vii) —C(O)—C 3-6 cycloalkyl,

(viii) —SO 2 —C 1-4 alkyl, and

(ix) —SO 2 —NH 2 ,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—C 1-4 alkyl,

(ii) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,

(iii) —NH 2 ,

(iv) —NH (C 1-4 alkyl), and

(v) —N(C 1-4 alkyl)(C 1-4 alkyl),

(g) heterocyclyl, optionally substituted with 1-3 substituents independently selected from (i) —OH, (ii) oxo, and (iii) C 1-4 alkyl,

(h) oxo,

(i) C 3-6 cycloalkyl,

(j) —CN,

(k) ═NH,

(l) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-6 alkyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) C 1-4 alkyl, and

(ii) —N(C 1-4 alkyl)(C 1-4 alkyl).

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from (i) hydrogen, (ii) —CH 3 , and (ii) —CH 2 CH 3 , and

(vii) piperidinyl,

(d) —O—C 1-4 alkyl, optionally substituted with —OH,

(e) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cycloalkyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(g) heterocyclyl, optionally substituted with —OH,

(h) oxo,

(i) C 3-6 cycloalkyl,

(j) —CN,

(k) ═NH,

(l) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-4 alkyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) C 1-4 alkyl, and

(ii) —N(C 1-4 alkyl)(C 1-4 alkyl).

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 together with the nitrogen to which they are attached form a 4-10 membered mono-cyclic, fused bicyclic, spiro bicyclic, or bridged bicyclic heterocyclyl; wherein the heterocyclyl is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NH 2 , and

(vii) piperidinyl,

(d) —O—C 1-4 alkyl, optionally substituted with —OH,

(e) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cyclopropyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(g) heterocyclyl selected from azetidinyl, imidazolidinyl, oxazolidinyl, oxetanyl, pyrazolyl, pyrrolidinyl, tetrazolyl, triazolyl, optionally substituted with —OH,

(h) oxo,

(i) cyclopropyl,

(j) —CN,

(k) ═NH,

(l) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and methyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 ,

(ii) —CH 2 CH 3 , and

(iii) —N(CH 3 )(CH 3 ).

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1,3,5-trienyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, 1,2,3,4-tetrahydronaphthalenyl, and tetralinyl, and

(2) a heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, chromanyl, indazolyl, and pyridinyl,

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) C 1-4 alkyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) C 3-6 cycloalkyl, optionally substituted with C 1-4 alkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, and phenyl, and

(2) a heterocyclyl selected from indazolyl and pyridinyl,

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) —CH 3 , optionally substituted with 1-3 halogens,

(d) —O—CH 3 , optionally substituted with 1-3 halogens,

(e) —O—CH 2 CH 3 , optionally substituted with 1-3 halogens,

(f) —CN, and

(g) C 3-6 cycloalkyl, optionally substituted with —CH 3 or —CH 2 CH 3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is selected from (1) —O— and (2) —CR g R g —, wherein:

each occurrence of R g is independently selected from: (a) hydrogen, (b) halogen, (c) —OH, and (d) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, one R g is hydrogen and the other R g together with one R d and the two carbons to which the R d and R g are attached form a cyclopropyl;

or alternatively, two R g groups together with the carbon to which they are attached form a cyclopropyl, optionally substituted with 1-3 halogens;

or alternatively, m is 1, one R g is hydrogen and the other R g together with one R e and the two carbons to which R e and R g are attached form a cyclopropyl;

R a is selected from hydrogen and methyl;

each occurrence of R b is independently selected from: (1) hydrogen, (2) halogen, and (3) C 1-4 alkyl;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl;

each occurrence of R o is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, m is 1, A is —CR g R g —, and R c together with one R g and the two carbons to which R c and R g are attached form a cyclopropyl;

each occurrence of R d is independently selected from: (1) hydrogen and (2) C 1-4 alkyl, optionally substituted with 1-3 halogens;

or alternatively, when A is —CR g R g —, one R d is hydrogen and the other R d together with one R g and the two carbons to which R d and R g are attached form a cyclopropyl;

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from (i) hydrogen, (ii) —CH 3 , and (ii) —CH 2 CH 3 , and

(vii) piperidinyl,

(d) —O—C 1-4 alkyl, optionally substituted with —OH,

(e) —NR f R f , wherein each occurrence of R″ is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cycloalkyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(g) heterocyclyl, optionally substituted with —OH,

(h) oxo,

(i) C 3-6 cycloalkyl,

(j) —CN,

(k) ═NH,

(l) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-4 alkyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) C 1-4 alkyl, and

(ii) —N(C 1-4 alkyl)(C 1-4 alkyl); and

R 3 is selected from (1) C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, and tetralinyl and (2) heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, indazolyl, and pyridinyl, wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) C 1-4 alkyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) C 3-6 cycloalkyl, optionally substituted with C 1-4 alkyl.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:

(a) halogen,

(b) —OH,

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NH 2 , and

(vii) piperidinyl,

(d) —O—C 1-4 alkyl, optionally substituted with —OH,

(e) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cyclopropyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(f) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(g) heterocyclyl selected from azetidinyl, imidazolidinyl, oxazolidinyl, oxetanyl, pyrazolyl, pyrrolidinyl, tetrazolyl, and triazolyl, optionally substituted with —OH,

(h) oxo,

(i) cyclopropyl,

(j) —CN,

(k) ═NH,

(l) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and methyl, and

(m) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 ,

(ii) —CH 2 CH 3 , and

(iii) —N(CH 3 )(CH 3 ); and

R 3 is selected from:

(1) C 6-10 carbocyclyl selected from 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, and phenyl, and

(2) heterocyclyl selected from indazolyl and pyridinyl,

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) —CH 3 , optionally substituted with 1-3 halogens,

(d) —O—CH 3 ,

(e) —O—CH 2 CH 3 ,

(f) —CN, and

(g) C 3-4 cycloalkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ia):

wherein:

m is 1, 2, or 3;

A is selected from (1) —O— and (2) —CR g R g —, each occurrence of R g is independently selected from: (a) hydrogen, (b) halogen, (c) —OH, and (d) C 1-4 alkyl, optionally substituted with 1-3 halogens;

V is —(CR m R m )n-, wherein n is 0, 1, or 2; and each occurrence of R m is independently selected from:

(a) hydrogen,

(b) halogen,

(d) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH,

(e) —NH (C 1-4 alkyl),

(f) —N(C 1-4 alkyl)(C 1-4 alkyl),

(g) —NH—C(O)—C 1-4 alkyl,

(h) —NH—C(O)—NH 2 , and

(i) 5-6 membered monocyclic heterocyclyl;

W is selected from (1) —O—, (2) —S—, (3) —C(O)—, (4) —S(O)—, (5) —NR n —, and (6) —CR n R n —, wherein each occurrence of R″ is independently selected from:

(a) hydrogen,

(b) halogen,

(d) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from:

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen, —CH 3 , and —CH 2 CH 3 , and

(viii) piperidinyl,

(e) —O—C 1-4 alkyl, optionally substituted with —OH,

(f) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cyclopropyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(g) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(h) heterocyclyl, optionally substituted with —OH,

(i) oxo,

(j) C 3-6 cycloalkyl,

(k) —CN,

(l) ═NH,

(m) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-4 alkyl, and

(n) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 ,

(ii) —CH 2 CH 3 , and

(iii) —N(CH 3 )(CH 3 );

each occurrence of R b is independently selected from: (1) hydrogen, (2) halogen, and (3) C 1-4 alkyl;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl;

each occurrence of R o is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) C 1-4 alkyl, optionally substituted with 1-3 halogens;

each occurrence of R d is independently selected from: (1) hydrogen and (2) C 1-4 alkyl, optionally substituted with 1-3 halogens;

each occurrence of R k is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) C 1-4 alkyl, optionally substituted with 1-3 halogens; and

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, and tetralinyl, and

(2) a heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, indazolyl, and pyridinyl;

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) C 1-4 alkyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) C 3-6 cycloalkyl.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof:

wherein:

A is selected from (1) —O— and (2) —CR g R g —, each occurrence of R g is independently selected from: (a) hydrogen, (b) halogen, (c) —OH, and (d) methyl, optionally substituted with 1-3 halogens;

V is —(CR m R m )n-, wherein n is 0, 1, or 2; and each occurrence of R m is independently selected from:

(a) hydrogen,

(b) halogen,

(d) methyl or ethyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH,

(e) —NH (CH 3 ),

(f) —N(CH 3 )(CH 3 ),

(g) —NH—C(O) —CH 3 ,

(h) —NH—C(O)—NH 2 , and

(i) 5-6 membered monocyclic heterocyclyl;

W is selected from (1) —O—, (2) —S—, (3) —C(O)—, (4) —S(O)—, (5) —NR n —, and (6) —CR n R n —, wherein each occurrence of R″ is independently selected from:

(a) hydrogen,

(b) halogen,

(d) methyl, optionally substituted with 1-3 substituents independently selected from:

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —NH 2 ,

(v) —N(CH 3 )(CH 3 ),

(vi) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen and —CH 3 , and

(vii) piperidinyl,

(e) —O—C 1-4 alkyl, optionally substituted with —OH,

(f) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(iv) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(v) —C(O)—NH 2 ,

(vi) —C(O)—NH—NH 2 ,

(vii) —C(O)—NH—CH 3 ,

(viii) —C(O)-cyclopropyl,

(ix) —SO 2 —CH 3 , and

(x) —SO 2 —NH 2 ,

(g) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ), and

(v) —N(CH 3 )(CH 3 ),

(h) heterocyclyl, optionally substituted with —OH,

(i) oxo,

(j) cyclopropyl,

(k) —CN,

(l) ═NH,

(m) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and methyl, and

(n) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 , and

(ii) —N(CH 3 )(CH 3 );

each occurrence of R b is independently selected from: (1) hydrogen, (2) halogen, (3) methyl, and (4) ethyl;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl;

each occurrence of R e is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) methyl, optionally substituted with 1-3 halogens;

each occurrence of R d is independently selected from: (1) hydrogen and (2) methyl, optionally substituted with 1-3 halogens;

each occurrence of R k is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) methyl, optionally substituted with 1-3 halogens; and

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, and tetralinyl, and

(2) a heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, indazolyl, and pyridinyl;

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) methyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) cyclopropyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ib):

wherein:

V is —(CR m R m )n-, wherein n is 0, 1, or 2; and each occurrence of R m is independently selected from:

(a) hydrogen,

(b) halogen,

(d) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH,

(e) —NH (C 1-4 alkyl),

(f) —N(C 1-4 alkyl)(C 1-4 alkyl),

(g) —NH—C(O)—C 1-4 alkyl,

(h) —NH—C(O)—NH 2 , and

(i) 5-6 membered monocyclic heterocyclyl;

W is selected from (1) —O—, (2) —S—, (3) —NR n —, and (4) —CR n R n —, wherein each occurrence of R n is independently selected from:

(a) hydrogen,

(b) halogen,

(d) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from:

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —O—CH 2 CH 3 ,

(v) —NH 2 ,

(vi) —N(CH 3 )(CH 3 ),

(vii) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen, —CH 3 , and —CH 2 CH 3 , and

(viii) piperidinyl,

(e) —O—C 1-4 alkyl, optionally substituted with —OH,

(f) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —CH 2 CH 3 , optionally substituted with —OH,

(iv) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(v) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(vi) —C(O)—NH 2 ,

(vii) —C(O)—NH—NH 2 ,

(viii) —C(O)—NH—CH 3 ,

(ix) —C(O)—NH—CH 2 CH 3 ,

(x) —C(O)-cyclopropyl,

(xi) —SO 2 —CH 3 , and

(xii) —SO 2 —NH 2 ,

(g) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ),

(v) —NH (CH 2 CH 3 ), and

(vi) —N(CH 3 )(CH 3 ),

(h) heterocyclyl, optionally substituted with —OH,

(i) oxo,

(j) C 3-6 cycloalkyl,

(k) —CN,

(l) ═NH,

(m) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and C 1-4 alkyl, and

(n) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 ,

(ii) —CH 2 CH 3 , and

(iii) —N(CH 3 )(CH 3 );

each occurrence of R b is independently selected from: (1) hydrogen, (2) halogen, (3) methyl, and (4) ethyl;

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl;

each occurrence of R k is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) C 1-4 alkyl, optionally substituted with 1-3 halogens; and

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, and tetralinyl, and

(2) a heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, indazolyl, and pyridinyl;

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) C 1-4 alkyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) C 3-6 cycloalkyl.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof:

wherein:

V is —(CR m R m )n-, wherein n is 0, 1, or 2; and each occurrence of R m is independently selected from:

(a) hydrogen,

(b) halogen,

(d) methyl or ethyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH,

(e) —NH (CH 3 ),

(f) —N(CH 3 )(CH 3 ),

(g) —NH—C(O) —CH 3 ,

(h) —NH—C(O)—NH 2 , and

(i) 5-6 membered monocyclic heterocyclyl;

W is selected from (1) —O—, (2) —S—, (3) —NR n —, and (4) —CR n R n —, wherein each occurrence of R″ is independently selected from:

(a) hydrogen,

(b) halogen,

(d) methyl, optionally substituted with 1-3 substituents independently selected from:

(i) halogen,

(ii) —OH,

(iii) —O—CH 3 ,

(iv) —NH 2 ,

(v) —N(CH 3 )(CH 3 ),

(vi) —C(O)—NR e R e , wherein each occurrence of R e is independently selected from hydrogen and —CH 3 , and

(vii) piperidinyl,

(e) —O—C 1-4 alkyl, optionally substituted with —OH,

(f) —NR f R f , wherein each occurrence of R f is independently selected from:

(i) hydrogen,

(ii) —CH 3 , optionally substituted with —OH,

(iii) —C(O) —CH 3 , optionally substituted with —OH or —O—CH 3 ,

(iv) —C(O) —CH 2 CH 3 , optionally substituted with —OH,

(v) —C(O)—NH 2 ,

(vi) —C(O)—NH—NH 2 ,

(vii) —C(O)—NH—CH 3 ,

(viii) —C(O)-cyclopropyl,

(ix) —SO 2 —CH 3 , and

(x) —SO 2 —NH 2 ,

(g) —C(O)—R h , wherein R h is selected from:

(i) C 1-4 alkyl, optionally substituted with —OH, —NH 2 , or —O—CH 3 ,

(ii) —O—C 1-4 alkyl,

(iii) —NH 2 ,

(iv) —NH (CH 3 ), and

(v) —N(CH 3 )(CH 3 ),

(h) heterocyclyl, optionally substituted with —OH,

(i) oxo,

(j) cyclopropyl,

(k) —CN,

(l) ═NH,

(m) phenyl, optionally substituted with 1-3 substituents independently selected from halogen and methyl, and

(n) —SO 2 —R i , wherein R i is selected from:

(i) —CH 3 , and

(ii) —N(CH 3 )(CH 3 );

or alternatively, two R b groups on the same carbon together with the carbon to which they are attached form a cyclopropyl;

each occurrence of R k is independently selected from: (1) hydrogen, (2) halogen, (3) —OH, and (4) methyl, optionally substituted with 1-3 halogens; and

R 3 is selected from:

(1) a C 6-10 carbocyclyl selected from bicyclo[4.2.0]octa-1(6),2,4-trienyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, naphthyl, phenyl, and tetralinyl, and

(2) a heterocyclyl selected from 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyran-6-yl, indazolyl, and pyridinyl;

wherein each of the carbocyclyl and heterocyclyl is optionally substituted with 1-4 substituents independently selected from:

(a) halogen,

(b) methyl, optionally substituted with 1-3 halogens,

(d) —CN, and

(e) cyclopropyl.

19. The compound of claim 1 selected from the group consisting of: compounds of examples 1-489, or a pharmaceutically acceptable salt thereof.

20. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. A method for treating an IDO-associated disease or disorder in a mammalian subject selected from cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, and an autoimmune disease, which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 20, 2021

From: CLAUSEN, DANE; CHEN, PING; FRADERA, XAVIER; GUO, LIANGQIN; HAN, YONGXIN; HE, SHUWEN; HUANG, XIANHAI; KOZLOWSKI, JOSEPH; LI, GUOQING; MARTINOT, THEODORE A.; PASTERNAK, ALEXANDER; VERRAS, ANDREAS; XIAO, LI; YE, FENG; YU, WENSHENG; ZHANG, RUI

To: MERCK SHARP & DOHME CORP.

Reel/Frame 056298/0443 →

Continuity (2)

Provisional Application 62772357 · Nov 28, 2018

Related Publication 20230008022A1 · Jan 12, 2023

References Cited (9)

US 7589199B2 · Pennell et al. · 2009 [cited by applicant]

US 8778950B2 · Jones et al. · 2014 [cited by applicant]

US 20210395240A1 · Clausen · 2021 [cited by examiner]

WO 2015130854A1 · 2015 [cited by applicant]

WO 2017192813A1 · 2017 [cited by applicant]

WO 2018136437A2 · 2018 [cited by applicant]

Divanovic et. al., (2012), Opposing Biological Functions of Tryptophan Catabolizing Enzymes During Intracellular Infection, JID, 205 , 152-161 (Year: 2012). [cited by examiner]

Takikawa, (2007), Clinical aspects of indoleamine 2,3-dioxygenase (IDO)-initiated tryptophan metabolism: IDO is a target of drug discovery for various diseases, International Congress Series, 1304, 290-297 (Year: 2007). [cited by examiner]

Ongnok et al. ((2020), Doxorubicin and cisplatin induced cognitive impairment The possible mechanisms and interventions, Experimental Neurology, 324, 1-22 (Year: 2020). [cited by examiner]