US 11,787,812 B2
Substituted pyrazolo[4,3-d]pyrimidines and imidazo[5,1 -f][1,2,4]triazines as androgen receptor and phosphodiesterase dual inhibitors
Yoonsuk Lee, Hwaseong-si (KR); Kyung Sun Kim, Hwaseong-si (KR); Jeong-Ah Kim, Hwaseong-si (KR); Anna Moon, Hwaseong-si (KR); Dongkeun Song, Hwaseong-si (KR); Juyoung Jung, Hwaseong-si (KR); Jun-Su Ban, Hwaseong-si (KR); and Soo-Jin Lee, Hwaseong-si (KR)
Assigned to ILDONG PHARMACEUTICAL CO., LTD., Seoul (KR)
Filed by ILDONG PHARMACEUTICAL CO., LTD., Seoul (KR)
Filed on Dec. 10, 2021, as Appl. No. 17/548,279.
Claims priority of provisional application 63/124,615, filed on Dec. 11, 2020.
Prior Publication US 2022/0194948 A1, Jun. 23, 2022
Int. Cl. A61K 31/519 (2006.01); A61K 31/53 (2006.01); C07D 239/70 (2006.01); C07D 253/08 (2006.01); C07D 487/04 (2006.01); G01N 33/50 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 519/00 (2013.01); G01N 33/5041 (2013.01)] 44 Claims
 
1. A compound of formula (I):

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

OG Complex Work Unit Chemistry
R1 is H, (C1-C6) alkyl, (C2-C4) alkenyl, O(C1-C6) alkyl, or (C3-C6) cycloalkyl;
wherein the (C1-C6) alkyl, (C2-C4) alkenyl, or O(C1-C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, ═OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
wherein the (C3-C6) cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
R2 is H, (C1-C6) alkyl, (C2-C4) alkenyl, O(C1-C6) alkyl, or (C3-C6) cycloalkyl;
wherein the (C1-C6) alkyl, (C2-C4) alkenyl, or O(C1-C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
wherein the (C3-C6) cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
L is -A-B—;
A is a covalent bond, —NHC(O)R5—, —NR6C(Z1)NR7—, —NR11S(O)2—, 3- to 6-membered heterocyclylene, (C6-C12) arylene, —(C3-C12) heteroarylene-(C1-C5) alkylene-, or (C3-C12) heteroarylene;
wherein the 3- to 6-membered heterocyclylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
wherein each haloalkyl substituent of the 3- to 6-membered heterocyclylene is optionally and independently substituted with one or more OH substituents;
wherein the (C3-C12) heteroarylene portion of —(C3-C12) heteroarylene-(C1-C5) alkylene- is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, OH, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
wherein the (C6-C12) arylene or (C3-C12) heteroarylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, OH, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa; and
wherein A is bonded to the aromatic ring bearing X1;
B is a covalent bond, —NHC(O)R5—, —NR6C(Z1)NR7—, —NR11—, —NR11S(O)2—, —O—, —S—, —S(O)2—, or 3- to 6-membered heterocyclylene;
wherein the 3- to 6-membered heterocyclylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa; and
wherein B is bonded to the aromatic ring bearing X2 and X3;
each R5 is independently (C1-C5) alkylene, (C1-C5) haloalkylene, or —O;
wherein each (C1-C5) alkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each R6 is independently H or (C1-C3) alkyl;
wherein each (C1-C3) alkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each R7 is independently H or (C1-C3) alkyl;
wherein each (C1-C3) alkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or
any R6 and R7, taken together with the nitrogen atoms to which they are attached, independently forms a 3- to 6-membered heterocyclylene;
wherein each 3- to 6-membered heterocyclylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa; or
wherein each 3- to 6-membered heterocyclylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of ═O, ═S, R8, and R9;
each R8 is independently H or (C1-C3) alkyl;
wherein the (C1-C3) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C(O)Ra, C(O)N(Ra)2, C(O)ORa, N(Ra)2, NRaC(O)Ra, NRaC(O)ORa, NRaS(O)tRa, ORa, OC(O)Ra, OC(O)N(Ra)2, OC(O)ORa, ORcC(O)N(Ra)2, S(O)tRa, S(O)tN(Ra)2, and S(O)tORa;
each R9 is independently H or (C1-C3) alkyl;
wherein the (C1-C3) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C(O)Ra, C(O)N(Ra)2, C(O)ORa, N(Ra)2, NRaC(O)Ra, NRaC(O)ORa, NRaS(O)tRa, ORa, OC(O)Ra, OC(O)N(Ra)2, OC(O)ORa, ORcC(O)N(Ra)2, S(O)tRa, S(O)tN(Ra)2, and S(O)tORa; or
each R8 and R9, taken together with the carbon atom to which they are attached, independently forms a spirocyclic 3- to 6-membered carbocyclyl or a spirocyclic 3- to 6-membered heterocyclyl;
wherein each spirocyclic 3- to 6-membered carbocyclyl or spirocyclic 3- to 6-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORcC(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
each R11 is independently H or (C1-C3) alkyl;
wherein each (C1-C3) alkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each Z1 is independently O or S;
X1 is C R14 or N;
X2 is C R13 or N;
X3 is C R13 or N;
each R13 is independently H, (C1-C6) alkyl, or O(C1-C6) alkyl;
wherein each (C1-C6) alkyl and O(C1-C6) alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each R14 is independently H, halogen, CN, NO2, (C1-C5) alkyl, (C2-C4) alkenyl, NH2, OH, O(C1-C5) alkyl, or (C3-C6) cycloalkyl;
wherein each (C1-C5) alkyl, (C2-C4) alkenyl, and O(C1-C5) alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
wherein each (C3-C6) cycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, ═S, RbC(O)Ra, RbC(O)N(Ra)2, RbC(O)ORa, RbN(Ra)2, RbNRaC(O)Ra, RbNRaC(O)ORa, RbNRaS(O)tRa, RbORa, RbOC(O)Ra, RbOC(O)N(Ra)2, RbOC(O)ORa, RbORc(O)N(Ra)2, RbS(O)tRa, RbS(O)tN(Ra)2, and RbS(O)tORa;
each Ra is independently H, alkyl, alkyl(cycloalkyl), alkyl(heterocycloalkyl), aralkyl, alkyl(heteroaryl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein each alkyl, alkyl portion of alkyl(cycloalkyl), alkyl portion of alkyl(heterocycloalkyl), alkyl portion of aralkyl, and alkyl portion of alkyl(heteroaryl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S;
wherein each cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S; and
wherein each aryl and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and OH;
each Rb is independently alkylene, alkylene(cycloalkyl), alkylene(heterocycloalkyl), aralkylene, alkylene(heteroaryl), cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
wherein each alkylene, alkylene portion of alkylene(cycloalkyl), alkylene portion of alkylene(heterocycloalkyl), alkylene portion of aralkylene, and alkylene portion of alkylene(heteroaryl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S;
wherein each cycloalkylene and heterocycloalkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S; and
wherein each arylene and heteroarylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and OH;
each Rc is independently alkylene, alkylene(cycloalkyl), alkylene(heterocycloalkyl), aralkylene, alkylene(heteroaryl), cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
wherein each alkylene, alkylene portion of alkylene(cycloalkyl), alkylene portion of alkylene(heterocycloalkyl), alkylene portion of aralkylene, and alkylene portion of alkylene(heteroaryl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S;
wherein each cycloalkylene and heterocycloalkylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, ═NH, ═NNH2, ═NOH, OH, ═O, and ═S; and
wherein each arylene and heteroarylene is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and OH;
m is 0, 1, or 2;
n is 1, 2, 3, or 4; and
each t is independently 1 or 2;
with the provisos that:
(1) if A is a covalent bond, then B is not a covalent bond; and
(2) if B is a covalent bond, then A is not a covalent bond.
 
41. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.