US 12,281,114 B2
NK3 modulators and uses thereof
Shuwen He, Fanwood, NJ (US); Scott B. Joseph, New York, NY (US); Christopher Moyes, Westfield, NJ (US); Tesfaye Biftu, Freehold, NJ (US); and Santhosh F. Neelamkavil, Edison, NJ (US)
Assigned to KALLYOPE, INC., New York, NY (US)
Filed by Kallyope, Inc., New York, NY (US)
Filed on Aug. 12, 2024, as Appl. No. 18/800,581.
Application 18/800,581 is a continuation of application No. PCT/US2024/024989, filed on Apr. 17, 2024.
Claims priority of provisional application 63/545,395, filed on Oct. 24, 2023.
Claims priority of provisional application 63/541,107, filed on Sep. 28, 2023.
Claims priority of provisional application 63/460,109, filed on Apr. 18, 2023.
Prior Publication US 2024/0409541 A1, Dec. 12, 2024
Int. Cl. C07D 471/04 (2006.01); A61K 31/437 (2006.01); A61K 31/4375 (2006.01); A61K 31/438 (2006.01); A61K 31/444 (2006.01); A61K 31/4545 (2006.01); A61K 31/496 (2006.01); A61K 31/4985 (2006.01); A61K 31/506 (2006.01); A61K 31/5377 (2006.01); A61K 45/06 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61K 31/437 (2013.01); A61K 31/4375 (2013.01); A61K 31/438 (2013.01); A61K 31/444 (2013.01); A61K 31/4545 (2013.01); A61K 31/496 (2013.01); A61K 31/4985 (2013.01); A61K 31/506 (2013.01); A61K 31/5377 (2013.01); A61K 45/06 (2013.01); C07D 519/00 (2013.01)] 20 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Z is a bivalent group selected from —S—, —N═C(R5)—, —C(R5)=N—, or —C(R5)═C(R5)—;
R1 is pyrazole, wherein said pyrazole is optionally substituted with 1-3 groups independently selected from R6;
R2 is C1-C10 alkyl, C1-C10 heteroalkyl, —C(═O)OR7, —C(═O)N(R8)(R7), —N(R8)(R7), —C(═NR9)N(R8)(R7), —N(R7)C(═NR9)N(R8)(R7), C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 3-to-15 membered heterocycloalkyl, wherein the aryl, and heteroaryl is optionally substituted with 1-4 groups independently selected from R10, and the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with 1-4 groups independently selected from oxo and R10;
R3 is halogen, cyano, —C(═O)OH, —C(═O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, —O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl;
each R4 is independently hydrogen, halogen, C1-C6 alkyl, —O—C1-C6 alkyl, C1-C6 haloalkyl, or —O—(C1-C6 haloalkyl);
L is a bond, C1-C2 alkylene, or C3-C6 cycloalkylene, wherein said alkylene, or cycloalkylene is optionally substituted with 1 or 2 —OH groups;
each R5 is independently hydrogen, cyano, halogen, C1-C6 alkyl, —O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or —O(C1-C6 haloalkyl);
each R6 is independently selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C3-C6 cycloalkyl, —CH2—(C3-6 cycloalkyl), —O—(C3-6 cycloalkyl), C1-C6 haloalkyl, and —O(C1-C6 haloalkyl);
wherein if an R6 is attached to a nitrogen atom, then it is selected from the group consisting of C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, —CH2—(C3-6 cycloalkyl), and C1-C6 haloalkyl;
each R7 is independently hydrogen or C1-C6 alkyl, wherein said alkyl is optionally substituted with 1-2 hydroxy groups;
R8 is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C12 cycloalkyl, 3- to 15-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; wherein the aryl, and heteroaryl is optionally substituted with 1-6 groups independently selected from R11, and the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1-6 groups independently selected from oxo and R11;
or one R7 and one R8 bound to the same nitrogen atom come together to form a 3- to 15-membered heterocycloalkyl that is optionally substituted with 1-6 groups independently selected from oxo and R11;
R9 is hydrogen, —C(O)OR12, —C(O)N(R12)2, —S(O)2R12, —S(O)2N(R12)2, or C1-C6 alkyl;
each R10 is independently selected from hydroxy, amino, cyano, fluoro, —C(═O)OR12, —C(═O)N(R12)2, C1-C4 alkyl, C1-C4 haloalkyl, —O(C1-C6 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C3-C6 cycloalkyl, wherein said alkyl, haloalkyl or cycloalkyl is optionally substituted with 1-2 groups selected from hydroxy, amino, cyano, fluoro, —C(═O)OR12, and —C(═O)N(R12)2;
each R11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, —S(═O)2(R13), —N(R12)S(═O)2(R13), —S(═O)(R13), —N(R12)S(═O)(R13), —C(═O)R13, —N(R12)C(═O)R13, C1-C6 alkyl, —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, wherein the aryl, and heteroaryl is optionally substituted with 1-4 groups independently selected from R14, and the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with 1-4 groups independently selected from oxo and R14;
or two R11 bound to the same carbon or nitrogen atom come together to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the cycloalkyl, and heterocycloalkyl is optionally substituted with 1-4 groups independently selected from oxo and R14;
each R12 is independently hydrogen or C1-C6 alkyl;
each R13 is independently hydroxy, amino, C1-C6 alkyl, —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; and
each R14 is independently cyano, amino, hydroxy, —C(═O)OR12, —C(═O)N(R12)2, C1-C6 alkyl, —O(C1-C6 alkyl), —NR12(C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein each alkyl is optionally substituted with 1-2 hydroxy groups.