	US 12,018,011 B2
	Macrocyclic compounds and compositions, and methods of preparing and using the same
Xuefeng Zhu, San Diego, CA (US); Pingda Ren, San Diego, CA (US); Zhu Bai, Shanghai (CN); Wanting Xiong, Shanghai (CN); Dan Xu, Shanghai (CN); and Yahu Arthur Liu, San Diego, CA (US)
Assigned to Kura Oncology, Inc., San Diego, CA (US)
Filed by Kura Oncology, Inc., San Diego, CA (US)
Filed on Jun. 5, 2023, as Appl. No. 18/329,479.
Application 18/329,479 is a continuation of application No. PCT/US2022/080565, filed on Nov. 29, 2022.
Claims priority of provisional application 63/385,117, filed on Nov. 28, 2022.
Claims priority of provisional application 63/285,412, filed on Dec. 2, 2021.
Claims priority of application No. 202111442658.4 (CN), filed on Nov. 30, 2021; and application No. 202211471486.8 (CN), filed on Nov. 23, 2022.
Prior Publication US 2023/0322711 A1, Oct. 12, 2023
Int. Cl. A61P 35/00 (2006.01); C07D 401/10 (2006.01); C07D 491/044 (2006.01)

CPC C07D 401/10 (2013.01) [A61P 35/00 (2018.01); C07D 491/044 (2013.01)]

222 Claims

1. A compound of Formula (II):

wherein:

A³is CR³or N;

A⁴is CR⁸or N;

A⁵and A⁶are each independently CR⁸or N, or A⁵and A⁶taken together are O, NR⁹, or S;

W¹, W², W³, and W⁴are each independently N or CR⁴, or W¹and W²taken together are O, NR⁴, or S, or W²and W³taken together are O, NR^4A, or S;

Y is a bond or a linker having a length of up to 6 atoms;

Z¹, Z², Z³, and Z⁴are each independently N or CR⁵, or Z²and Z³taken together are O, NR^5A, or S, or Z³and Z⁴taken together are O, NR^5A, or S;

R^1ais R⁹, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR¹⁰R¹¹, —S(O)_pR⁹, or −S(O)₂NR¹⁰R¹¹;

R³, R⁵, and R⁸, at each occurrence, are each independently R⁹, —OR⁹, halo, CN, NO₂, —C(O)R⁹, —C(O)OR⁹, —OC(O)R⁹, —OC(O)OR⁹, —C(O)NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, —NR¹⁰C(O)NR¹⁰R¹¹, —NR¹⁰S(O)₂R⁹, —S(O)_pR⁹, —S(O)₂NR¹⁰R¹¹, or —NR¹⁰S(O)₂NR¹⁰R¹¹;

R⁴, at each occurrence, is independently hydrogen, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkoxy, C_1-6heteroalkoxy, C_3-6cycloalkoxy, 3-6 membered heterocycloalkoxy, —NR¹⁴R¹⁵, C_6-12aryl, or 5-12 membered heteroaryl, wherein each C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkoxy, C_1-6heteroalkoxy, C_3-6cycloalkoxy, 3-6 membered heterocycloalkoxy, C_6-12aryl, or 5-12 membered heteroaryl of the R⁴is optionally substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, and (O);

R^4Aand R^5Aare each independently hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl, wherein each C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl of the R^4Aand the R^Ais optionally substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, and (O);

R⁶is CN, R⁹, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —OC(O)R⁹, —OC(O)OR⁹, —C(O)NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹⁰OR⁹, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, —NR¹⁰C(O)NR¹⁰R¹¹, —NR¹⁰S(O)₂R⁹, —NR¹⁰C(NR¹⁰)NR¹⁰R¹¹, —S(O)_pR⁹, —S(O)₂NR¹⁰R¹¹, or —NR¹⁰S(O)₂NR¹⁰R¹¹;

R⁷is a 5-12 membered heteroaryl, optionally substituted with one, two, three, or four substituents independently selected from halo, CN, NO₂, R⁹, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —OC(O)R⁹, —OC(O)OR⁹, —C(O)NR¹⁰R¹¹, —NROR¹¹, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, —NR¹⁰C(O)NR¹⁰R¹¹, —NR¹⁰S(O)₂R⁹, —S(O)_pR⁹, —S(O)₂NR¹⁰R¹¹, and —NR¹⁰S(O)₂NR¹⁰R¹¹;

R⁹, at each occurrence, is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl of the R⁹is optionally substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, CN, NO₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, (O), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)OR¹², —C(O)NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹⁰C(O)R¹², —NR¹⁰C(O)OR¹², —NR¹⁰C(O)NR¹⁰R¹¹, —NR¹⁰S(O)₂R¹², —S(O)_pR¹², —S(O)₂NR¹⁰R¹¹, and —NR¹⁰S(O)₂NR¹⁰R¹¹;

R¹⁰and R¹¹, at each occurrence, are each independently hydrogen, hydroxy, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_6-12aryl, or 5-12 membered heteroaryl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_6-12aryl, or 5-12 membered heteroaryl of the R¹⁰and the R¹¹is optionally substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, CN, NO₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, (O), —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(O)R¹³, —NR¹⁴C(O)OR¹³, —NR¹⁴C(O)NR¹⁴R¹⁵, —NR¹⁴S(O)₂R¹³, —S(O)_pR¹³—S(O)₂NR¹⁴R¹⁵, and —NR¹⁴S(O)₂NR¹⁴R¹⁵;

R¹², at each occurrence, is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_6-12aryl, or 5-12 membered heteroaryl of the R¹²is optionally substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, CN, NO₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, (O), —C(O)R¹³, —C(O)R¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹⁰C(O)R¹³, —NR¹⁰C(O)OR¹³, —NR¹⁰C(O)NR¹⁰R¹¹, —NR¹⁰S(O)₂R¹³, —S(O)_pR¹³, —S(O)₂NR¹⁰R¹¹, and —NR¹⁰S(O)₂NR¹⁰R¹¹;

R¹³, at each occurrence, is independently hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_1-4heteroalkyl, C_3-6cycloalkyl, or 3-6 membered heterocycloalkyl;

R¹⁴and R¹⁵, at each occurrence, are each independently hydrogen, hydroxy, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_1-4heteroalkyl, C_3-6cycloalkyl, 3-6 membered heterocycloalkyl, or C_1-6alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; and

each p is independently an integer of 0, 1, or 2;

or a pharmaceutically acceptable form thereof.