US 12,264,134 B2
Substituted piperazine amide compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
Dane Clausen, Rahway, NJ (US); Ping Chen, Edison, NJ (US); Xavier Fradera, Brookline, MA (US); Liangqin Guo, Monroe Township, NJ (US); Yongxin Han, Needham, MA (US); Shuwen He, Fanwood, NJ (US); Xianhai Huang, Warren, NJ (US); Joseph Kozlowski, Princeton, NJ (US); Guoqing Li, Belle Mead, NJ (US); Theodore A. Martinot, Southborough, MA (US); Alexander Pasternak, Jamaica Plain, MA (US); Andreas Verras, New York, NY (US); Li Xiao, Cranbury, NJ (US); Feng Ye, Scotch Plains, NJ (US); Wensheng Yu, Edison, NJ (US); and Rui Zhang, Plainsboro, NJ (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/295,497
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Nov. 25, 2019, PCT No. PCT/US2019/062902
§ 371(c)(1), (2) Date May 20, 2021,
PCT Pub. No. WO2020/112581, PCT Pub. Date Jun. 4, 2020.
Claims priority of provisional application 62/772,357, filed on Nov. 28, 2018.
Prior Publication US 2023/0008022 A1, Jan. 12, 2023
Int. Cl. C07D 231/56 (2006.01); A61K 31/496 (2006.01); A61K 31/5377 (2006.01); A61K 31/541 (2006.01); C07D 231/54 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 405/12 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 471/10 (2006.01); C07D 487/04 (2006.01); C07D 487/10 (2006.01); C07D 491/052 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01); C07D 498/08 (2006.01); C07D 498/10 (2006.01)
CPC C07D 231/56 (2013.01) [A61K 31/496 (2013.01); A61K 31/5377 (2013.01); A61K 31/541 (2013.01); C07D 231/54 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 405/12 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 471/10 (2013.01); C07D 487/04 (2013.01); C07D 487/10 (2013.01); C07D 491/052 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01); C07D 498/08 (2013.01); C07D 498/10 (2013.01)] 21 Claims
 
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein:
m is 1, 2, or 3;
A is selected from: (1) —O— and (2) —CRgRg—, wherein:
each occurrence of Rg is independently selected from:
(a) hydrogen,
(b) halogen,
(c) —OH, and
(d) C1-6 alkyl, optionally substituted with 1-4 halogens;
or alternatively, one Rg is hydrogen and the other Rg together with one Rd and the two carbons to which Rd and Rg are attached form a C3-4 cycloalkyl;
or alternatively, two Rg groups together with the carbon to which they are attached form a C3-4 cycloalkyl, optionally substituted with 1-4 halogens;
or alternatively, m is 1, one R8 is hydrogen and the other Rg together with one Re and the two carbons to which Re and Rg are attached form a C3-4 cycloalkyl;
or alternatively, m is 2, one Rg is hydrogen and the other Rg together with one Re on the carbon adjacent to A and the two carbons to which Re and Rg are attached form a C3-4 cycloalkyl;
Ra is selected from: (1) hydrogen and (2) C1-6 alkyl;
each occurrence of Rb is independently selected from: (1) hydrogen, (2) halogen, and (3) C1-6 alkyl, optionally substituted with 1-4 halogens;
or alternatively, two Rb groups on the same carbon together with the carbon to which they are attached form a spiro-C3-4 cycloalkyl;
each occurrence of Ro is independently selected from:
(1) hydrogen,
(2) halogen,
(3) —OH, and
(4) C1-6 alkyl, optionally substituted with 1-4 halogens;
or alternatively, m is 1, A is —CRgRg—, and one Re together with one R8 and the two carbons to
which Re and Rg are attached form a C3-4 cycloalkyl;
each occurrence of Rd is independently selected from: (1) hydrogen and (2) C1-6 alkyl, optionally substituted with 1-4 halogens;
or alternatively, when A is —CRgRg—, one Rd is hydrogen and the other Rd together with one Rg and the two carbons to which Rd and Rg are attached form a C3-4 cycloalkyl;
R1 and R2 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,
(c) C1-6 alkyl, optionally substituted with 1-4 substituents independently selected from:
(i) halogen,
(ii) —OH,
(iii) —O—C1-6 alkyl,
(iv) —NH2,
(v) —N(C1-6alkyl)(C1-6alkyl),
(vi) —C(O)—NReRe, wherein each occurrence of Re is independently selected from hydrogen and C1-6 alkyl, and
(vii) heterocyclyl,
(d) —O—C1-6 alkyl, optionally substituted with 1-4 substituents independently selected from (i) —OH and (ii) halogen,
(e) —NRfRf, wherein each occurrence of Rf is independently selected from:
(i) hydrogen,
(ii) C1-6 alkyl, optionally substituted with —OH,
(iii) —C(O)—C1-6 alkyl, optionally substituted with —OH or —O—C1-6 alkyl,
(iv) —C(O)—NH2,
(v) —C(O)—NH—NH2,
(vi) —C(O)—NH—C1-6 alkyl,
(vii) —C(O)—C3-6 cycloalkyl,
(viii) —SO2—C1-6 alkyl,
(ix) —SO2—NH2, and
(x) —C(O)—O—C1-6 alkyl,
(f) —C(O)—Rh, wherein Rh is selected from:
(i) C1-6 alkyl, optionally substituted with —OH, —O—C1-6 alkyl, —O—C(O)—C1-6 alkyl, or —NH2,
(ii) —O—C1-6 alkyl, optionally substituted with 1-4 halogens,
(iii) —NH2,
(iv) —NH (C1-6 alkyl), and
(v) —N(C1-6alkyl)(C1-6alkyl),
(g) heterocyclyl, optionally substituted with 1-3 substituents independently selected from (i) —OH, (ii) oxo, and (iii) C1-6 alkyl,
(h) oxo,
(i) C3-6 cycloalkyl,
(j) —CN,
(k) ═NH,
(l) aryl, optionally substituted with 1-3 substituents independently selected from halogen and C1-6 alkyl, and
(m) —SO2—Ri, wherein Ri is selected from:
(i) C1-6 alkyl, and
(ii) —N(C1-6alkyl)(C1-6alkyl);
R3 is selected from (1) a C6-10 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) C1-6 alkyl, optionally substituted with 1-4 halogens,
(c) —O—C1-6 alkyl, optionally substituted with 1-4 halogens,
(d) —CN, and
(e) C3-6 cycloalkyl, optionally substituted with C1-6 alkyl.