US 12,459,938 B2
ORAI channel inhibitors
Lijun Sun, Harvard, MA (US)
Assigned to Beth Israel Deaconess Medical Center, Inc., Boston, MA (US)
Appl. No. 17/435,863
Filed by Beth Israel Deaconess Medical Center, Inc., Boston, MA (US)
PCT Filed Mar. 3, 2020, PCT No. PCT/US2020/020812
§ 371(c)(1), (2) Date Sep. 2, 2021,
PCT Pub. No. WO2020/180876, PCT Pub. Date Sep. 10, 2020.
Claims priority of provisional application 62/813,402, filed on Mar. 4, 2019.
Prior Publication US 2022/0153735 A1, May 19, 2022
Int. Cl. C07D 471/04 (2006.01); C07D 209/24 (2006.01); C07D 231/14 (2006.01); C07D 231/54 (2006.01); C07D 401/12 (2006.01); C07D 487/04 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 209/24 (2013.01); C07D 231/14 (2013.01); C07D 231/54 (2013.01); C07D 401/12 (2013.01); C07D 487/04 (2013.01)] 19 Claims
 
1. A compound of

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:

OG Complex Work Unit Chemistry
represents that the ring is saturated, partially unsaturated, or aromatic;

OG Complex Work Unit Chemistry
represents that the ring is aromatic;
X1 is selected from N and CR1;
X2 is selected from N and CR2;
X3 is selected from N, NRN3, O, S, CR3, and C(R3)2;
X4 is selected from N, NRN4, O, S, CR4, and C(R4)2;
X5 is selected from N, NRN5, O, S, CR5, and C(R5)2;
X6 is selected from N, NRN6, O, S, CR6, and C(R6)2;
Y1, Y2, and Y3 are each independently selected from C and N; provided that at least one of Y1, Y2, and Y3 is N;
Cy1 is selected from C3-6 cycloalkyl; 4-7 membered heterocycloalkyl comprising at least 2 heteroatoms selected from O, S, and N; and 3-4 membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N; wherein said C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, and 3-4 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1,
R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
RN3, RN4, RN5, and RN6 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2S(O)2Rb2, S(O)2Rb2, and S(O)2NRc2Rd2;
R9 and R10 are each independently selected from H, C1-3 alkyl, and halo, provided that at least one of R9 and R10 is C1-3 alkyl or halo;
R11 is selected from H and C1-3 alkyl;
RA and RB are each independently selected from H and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-3 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, halo, CN, NO2, OH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
Ra1, Ra2, Rc1, Rc2, Rd1, and Rd2 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, S(O)2Rb3, S(O)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy3, halo, CN, NO2, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3;
Rb1 and Rb2 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-4 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy3, halo, CN, NO2, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;
each Cy2 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy2;
each Cy3 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy3,
Ra3, Rc3, and Rd3 are each independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4S(O)2Rb4, S(O)2Rb4, and S(O)2NRc4Rd4;
Rb3 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, halo, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
RCy1, RCy2, and RCy3 are each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4S(O)2Rb4 NRc4S(O)2NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4,
Ra4, Rc4, and Rd4 are each independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
each Rb4 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-12 membered heterocycloalkyl)-C1-4 alkylene is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO-C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-12 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
provided that the compound of Formula (I) is not:

OG Complex Work Unit Chemistry