US 11,912,708 B2
Macrocyclic heterocycles and uses thereof
Baogen Wu, San Diego, CA (US); Pingda Ren, San Diego, CA (US); Zhiyong Chen, San Diego, CA (US); and Yi Liu, San Diego, CA (US)
Assigned to KUMQUAT BIOSCIENCES INC., San Diego, CA (US)
Filed by Kumquat Biosciences Inc., San Diego, CA (US)
Filed on Jun. 2, 2023, as Appl. No. 18/328,109.
Application 18/328,109 is a continuation of application No. PCT/US2023/065963, filed on Apr. 19, 2023.
Claims priority of provisional application 63/486,922, filed on Feb. 24, 2023.
Claims priority of provisional application 63/404,482, filed on Sep. 7, 2022.
Claims priority of provisional application 63/332,794, filed on Apr. 20, 2022.
Prior Publication US 2023/0339952 A1, Oct. 26, 2023
Int. Cl. C07D 471/22 (2006.01); A61K 45/06 (2006.01); C07D 495/22 (2006.01); C07D 498/22 (2006.01)
CPC C07D 471/22 (2013.01) [A61K 45/06 (2013.01); C07D 495/22 (2013.01); C07D 498/22 (2013.01)] 30 Claims
 
1. A compound of the formula:

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

OG Complex Work Unit Chemistry
is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11;

OG Complex Work Unit Chemistry
is absent or selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R11a;
L1 is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene;
L2 is selected from C5-25 alkylene, C5-25 alkenylene, C5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2 is covalently bound to one of W3, W4, W5, W6, or W7;
W3 is selected from N(R3b), N, C(R3), and C(O);
W4 is selected from N(R4b), N, C(R4), and C(O);
W5 is selected from N(R5b), N, and C(R5);
W6 is selected from C(R6) and C(O);
W7 is C(R7);
R1 is C1-3 alkyl optionally substituted with one or more R11c;
R8 is selected from hydrogen, halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R14)C(O)N(R12)(R13), —N(R14)C(O)OR15, —N(R14)S(O)2R15, —C(O)R15, —S(O)R15, —OC(O)R15, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R14)C(O)R15, —S(O)2R15, —S(O)2N(R12)(R13), —S(═O)(═NH)N(R12)(R13), —CH2C(O)N(R12)(R13), —CH2N(R14)C(O)R15, —CH2S(O)2R15, and —CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;
R3, R4, R5, R6, and R7 are each independently selected from a bond to L2, hydrogen, halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R14)C(O)N(R12)(R13), —N(R14)C(O)OR15, —N(R14)S(O)2R15, —C(O)R15, —S(O)R15, —OC(O)R15, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R14)C(O)R15, —S(O)2R15, —S(O)2N(R12)(R13), —S(═O)(═NH)N(R12)(R13), —CH2C(O)N(R12)(R13), —CH2N(R14)C(O)R15, —CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;
R3b, R4b, and R5b are each independently selected from a bond to L2, hydrogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, —OR12, —SR12, —C(O)OR12, —OC(O)N(R12)(R13), —C(O)R15, —S(O)R15, —OC(O)R15, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —S(O)2R15, —S(O)2N(R12)(R13), —S(═O)(═NH)N(R12)(R13), —CH2C(O)N(R12)(R13), —CH2N(R14)C(O)R15, —CH2S(O)2R15, and —CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;
R11 and R11a are each independently selected at each occurrence from halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R14)C(O)N(R12)(R13), —N(R14)C(O)OR15, —N(R14)S(O)2R15, —C(O)R15, —S(O)R15, —OC(O)R15, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R14)C(O)R15, —S(O)2R15, —S(O)2N(R12)(R13), —S(═O)(═NH)N(R12)(R13), —CH2C(O)N(R12)(R13), —CH2N(R14)C(O)R15, —CH2S(O)2R15, —CH2S(O)2N(R12)(R13), —CH2N(R12)S(O)2(R13), and —P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;
R11b is independently selected at each occurrence from halogen, oxo, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R14)C(O)N(R12)(R13), —N(R14)C(O)OR15, —N(R14)S(O)2R15, —C(O)R15, —S(O)R15, —OC(O)R15, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R14)C(O)R15, —S(O)2R15, —S(O)2N(R12)(R13), —S(═O)(═NH)N(R12)(R13), —CH2C(O)N(R12)(R13), —CH2N(R14)C(O)R15, —CH2S(O)2R15, —CH2S(O)2N(R12)(R13), —CH2N(R12)S(O)2(R13), and —P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;
R11c is independently selected at each occurrence from halogen, —OR12, and —N(R12)(R13);
R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;
R13 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12 and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;
R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
R15 is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;
R17 and R17a are each independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17 and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle;
R20 is independently selected at each occurrence from halogen, oxo, ═NH, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, —CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, —CH2-(3- to 10-membered heterocycle), —OR21, —SR21, —N(R22)(R23), —C(O)OR22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —OC(O)N(R22)(R23), —N(R24)C(O)N(R22)(R23), —N(R24)C(O)OR25, —N(R24)C(O)R25, —N(R24)S(O)2R25, —C(O)R25, —S(O)2R25, —S(O)2N(R22)(R23), —OCH2C(O)OR22, and —OC(O)R25, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, —CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and —CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, ═NH, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, —OR21, —SR21, —N(R22)(R23), —C(O)OR22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —OC(O)N(R22)(R23), —N(R24)C(O)N(R22)(R23), —N(R24)C(O)OR25, —N(R24)C(O)R25, —N(R24)S(O)2R25, —C(O)R25, —S(O)2R25, —S(O)2N(R22)(R23), and —OC(O)R25;
R21 is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl;
R22 is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl;
R23 is independently selected at each occurrence from H and C1-6 alkyl;
R24 is independently selected at each occurrence from H and C1-6 alkyl;
R25 is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and
custom character indicates a single or double bond such that all valences are satisfied.