US 11,667,636 B2
Modulators of Mas-related G-protein receptor X2 and related products and methods
Marion Lanier, San Diego, CA (US); Marcos Sainz, San Diego, CA (US); Marcus Boehm, San Diego, CA (US); Liming Huang, San Diego, CA (US); Esther Martinborough, San Diego, CA (US); Brandon Selfridge, San Diego, CA (US); and Adam Yeager, San Diego, CA (US)
Assigned to ESCIENT PHARMACEUTICALS, INC., San Diego, CA (US)
Filed by Escient Pharmaceuticals, Inc., San Diego, CA (US)
Filed on Dec. 22, 2021, as Appl. No. 17/559,084.
Claims priority of provisional application 63/130,525, filed on Dec. 24, 2020.
Prior Publication US 2022/0340559 A1, Oct. 27, 2022
Int. Cl. C07D 471/04 (2006.01); C07D 277/64 (2006.01); C07D 333/56 (2006.01); C07D 333/54 (2006.01); C07D 519/00 (2006.01); C07D 231/56 (2006.01); C07D 235/06 (2006.01); C07D 263/56 (2006.01); C07D 409/12 (2006.01); C07D 333/58 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 231/56 (2013.01); C07D 235/06 (2013.01); C07D 263/56 (2013.01); C07D 277/64 (2013.01); C07D 333/54 (2013.01); C07D 333/56 (2013.01); C07D 333/58 (2013.01); C07D 409/12 (2013.01); C07D 519/00 (2013.01)] 32 Claims
 
1. A compound having structure (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:
R1 is cycloalkyl, aryl, heterocyclyl, —(CH2)nQ, —CHQR, or —CQ(R)2, wherein R1 is optionally substituted with one or more Rq1;
Q is C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, —CH2C(O)OR, —C(O)OR, —C(O)NHR, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2;
Rq1 and Rq2 are independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —O(CH2)nR, haloalkoxy, —C(O)OR, —C(O)R, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, S(O)2R, —C(H)Q′R, or —(CH2)nQ′ where Q′ is selected from C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, OR′, —C(O)OR′, —OC(O)R′, haloalkyl, —CN, —N(R′)2, —N(R′)C(O)R′, and —N(R′)S(O)2R′;
A is N or CRa;
B is N or CRb;
C is N or CRc;
D is CRd;
E is N or CRe;
G is N or CRg;
W is CRw;
Y is N, S or CRy;
Z is N, CRz, S or O;
each R is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, alkylamino, —(CH2)nR′, halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to which they are attached form a carbocyle or heterocycle;
R′ is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;
Ra is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rb is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rc is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rd is either absent, or when present, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Re is either absent, or when present, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rg is either absent, or when present, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rw is either absent, or when present, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Ry is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
Rz is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
n is independently 0, 1, 2, 3, 4 and 5;
R6 is C1-4 alkyl, phenyl, —C(O)R, —(CH2)nOR, —CN, F, Cl, Br, CF3, CF2H or CFH2, with the proviso that R is not H;
each R8 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
R2, R3, R4, R5 and R7 are the same or different and either absent or, when present, independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, —CN, —N(R)2, —N(R)C(O)R, —N(R)S(O)2R, or S(O)2R;
wherein:
adjacent atoms on either the “a” ring or “b” ring may be joined together by single bonds to form a 9 atom carbocyclic or heterocyclic ring structure; or
atoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure; or
atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure;
with the provisos that:
when Z is S or N, then A and C cannot both be N; and
when Z is N, then C and G cannot both be N.