US 12,466,829 B2
Spirocyclic piperidine melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof
Sangdon Han, San Diego, CA (US); Sun Hee Kim, San Diego, CA (US); and Yunfei Zhu, San Diego, CA (US)
Assigned to CRINETICS PHARMACEUTICALS, INC., San Diego, CA (US)
Appl. No. 17/785,791
Filed by Crinetics Pharmaceuticals, Inc., San Diego, CA (US)
PCT Filed Dec. 10, 2020, PCT No. PCT/US2020/064252
§ 371(c)(1), (2) Date Jun. 15, 2022,
PCT Pub. No. WO2021/133563, PCT Pub. Date Jul. 1, 2021.
Claims priority of provisional application 62/953,001, filed on Dec. 23, 2019.
Prior Publication US 2023/0126662 A1, Apr. 27, 2023
Int. Cl. C07D 471/10 (2006.01); A61K 31/438 (2006.01); C07D 471/20 (2006.01)
CPC C07D 471/10 (2013.01) [C07D 471/20 (2013.01)] 19 Claims
 
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein:
RA is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc;
Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, halogen, —OR4, —CN, —N(R4)2, —C(═O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Ra, Rb, and Rc is substituted with one or more R6 groups;
wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, —C(═O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;
RB is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf;
Rd, Re, and Rf are independently selected from the group consisting of hydrogen, halogen, —OR4, —CN, —N(R4)2, —C(═O)R7, —C(═O)N(R4)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Rd, Re, and Rf is substituted with one or more R6 groups;
wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, —C(═O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;
X1 is CR11 or N;
X3 is CR13 or N;
X4 is CR14 or N;
R11, R13, and R14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, —CN, —OR4, —SR4, —CO2R4, —C(═O)N(R4)2, or —N(R4)2;
W is absent, —C(R3)2—, —C(R3)2—C(R3)2—, —C(═O)—, #—C(═O)—O—, #—C(═O)—C(R3)2—, or #—C(═O) NR2—; wherein # indicates the attachment point to the N atom of the ring;
Y is absent, —(C═O)—, *—O(C═O)—, *—NR2—(C═O)—, —(SO2)—, or *—NR2—(SO2)—; wherein * indicates the attachment point to R1;
R1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted —(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted —(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R4)2, —OR5, —CN, —CO2R5, —C(═O)N(R4)2, —SR5, —S(═O)R7, —S(═O)2R7, —NR4C(═O)R5, —NR4SO2R7, —SO2R7, or —SO2N(R4)2;
each R2 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;
each R3 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;
each R4 is independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
or two R4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle;
each R5 is independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4alkoxy, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C1-C4fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO2R5, —CH2CO2R5, —C(═O)N(R4)2, —C(═O)N(R4) OR5, —CH2C(═O)N(R4)2, —N(R4)2, —CH2N(R4)2, —C(R5)2N(R4)2, —NR4C(═O)R5, —CH2NR4C(═O)R3, —NR4C(═O)N(R5)2, —NR4C(═O)N(R4)2, C(R5)═N(R4)—OR3, —SR3, —S(═O)R7, —SO2R7, or —SO2N(R4)2; and
each R7 is independently selected from the group consisting substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.