US 12,134,620 B2
Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer
Liansheng Li, San Diego, CA (US); Jun Feng, San Diego, CA (US); Tao Wu, Carlsbad, CA (US); Yuan Liu, San Diego, CA (US); Yi Wang, San Diego, CA (US); Alana K. Borum, Encinitas, CA (US); Pingda Ren, San Diego, CA (US); and Yi Liu, San Diego, CA (US)
Assigned to ARAXES PHARMA LLC, San Diego, CA (US)
Appl. No. 17/264,744
Filed by ARAXES PHARMA LLC, San Diego, CA (US)
PCT Filed Aug. 1, 2019, PCT No. PCT/US2019/044729
§ 371(c)(1), (2) Date Jan. 29, 2021,
PCT Pub. No. WO2020/028706, PCT Pub. Date Feb. 6, 2020.
Claims priority of provisional application 62/713,298, filed on Aug. 1, 2018.
Claims priority of provisional application 62/713,371, filed on Aug. 1, 2018.
Prior Publication US 2021/0317127 A1, Oct. 14, 2021
Int. Cl. C07D 487/10 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/10 (2013.01) [C07D 519/00 (2013.01); C07B 2200/09 (2013.01)] 29 Claims
 
1. A compound having the following structure (I):

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

OG Complex Work Unit Chemistry
indicates an aromatic ring;
A1, A2, A3 and A4 are, at each occurrence, independently CR4aR4b or NR5;
X, Y and Z are each, independently, N, CR3a or NR3b provided that at least one of at least one of X, Y and Z is N or NR3b;
W is CR2 or N;
G1 and G2 are each independently CR′ or N, provided that G1 is CR′ when at least one of A1 and A2 is NR5, and provided that G2 is CR′ when at least one of A3 and A4 is NR5;
L1 is a bond or —NR5—;
L2 is a bond or C1-C6 alkylene;
L3 is a bond, alkenylene, cycloalkylene, alkynylene, CR4aR4b, —S—, —O—, C(═O), —S(O)2—, —S(O)—, —C(═O)NR5—, —S(O)2NR5—, —NR5C(═O)NR5—, —NR5S(O)2NR5— or —NR5—;
R′ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, C1-C6 haloalkyl or C3-C8 cycloalkylalkyl;
R1 is aryl, cycloalkyl, heterocyclyl or heteroaryl;
R2 is H, cyano, hydroxyl, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, aminylalkyl, alkylaminyl, aminylcarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
R3a is H, cyano, amino, oxo, alkyl, cycloalkyl, haloalkyl, alkynyl, alkenyl, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylalkylaminyl, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy or heteroarylcarbonylaminyl;
R3b is H, cyano, alkyl, cycloalkyl, haloalkyl, alkynyl, alkenyl, aminylcarbonyl, aminylsulfonyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclylthioether, aminylalkyl, aminylalkynyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C1-C6 cyanoalkyl, C1-C6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, or R4a and R4b, when attached to the same carbon, join to form oxo or a carbocyclic or heterocyclic ring, or R4a and R4b, when attached to different carbons, join to form a carbocyclic or heterocyclic ring;
R5 is, at each occurrence, independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, C1-C6 haloalkyl or C3-C8 cycloalkylalkyl;
m is 2;
n is 1 or 2; and
E has the following structure:

OG Complex Work Unit Chemistry
wherein:
custom character represents a double or triple bond;
Q is —C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
R8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocyclylalkyl;
R8′ is H, —OH, —CN or C1-C6 alkyl;
when custom character is a double bond then R9 and R10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl;
when custom character is a triple bond then R9 is absent and R10 is H, C1-C6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl,
wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic and heteroaryl rings is optionally substituted with one or more substituents unless otherwise specified.