US 12,258,365 B2
Organophosphorus-substituted compounds as c-MET inhibitors and therapeutic uses thereof
Don Zhang, Princeton, NJ (US); Jirong Peng, Mequon, WI (US); Michael Nicholas Greco, Lansdale, PA (US); Michael John Costanzo, Warminster, PA (US); and Michael Alan Green, Easton, PA (US)
Assigned to BETA PHARMA, INC., Wilmington, DE (US)
Appl. No. 17/312,669
Filed by BETA PHARMA, INC., Wilmington, DE (US)
PCT Filed Dec. 14, 2019, PCT No. PCT/US2019/066414
§ 371(c)(1), (2) Date Jun. 10, 2021,
PCT Pub. No. WO2020/124060, PCT Pub. Date Jun. 18, 2020.
Claims priority of provisional application 62/779,960, filed on Dec. 14, 2018.
Prior Publication US 2022/0064194 A1, Mar. 3, 2022
Int. Cl. C07F 9/6561 (2006.01); A61K 31/675 (2006.01); A61P 35/00 (2006.01)
CPC C07F 9/6561 (2013.01) [A61K 31/675 (2013.01); A61P 35/00 (2018.01)] 30 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
A is absent, arylene or heteroarylene, each optionally substituted by one to four substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 acyl, cyano, nitro, and NRcRd;
L is absent, O, S, NR1, C(O), or C(RL)2, wherein RL at each occurrence is independently hydrogen, halogen, or C1-C4 alkyl;
Q is absent or C(RQ)2, wherein RQ at each occurrence is independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy;
X and Y are each C or N;
Z is CRZ or N, wherein RZ is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy;
when X is C and Y is N, then W is O, NR1, S, or CR5R6;
when X is N, then W is CR5R6, provided that at least one of X and Y is N,
R1 is H or C1-C6 alkyl;
R2 and R3 are each independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR4, —NR7R8, or —OCH2(C═O)OR9, wherein said alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl is each optionally substituted by one to five substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR9, —SR9, —C(O)OR9, —C(O)R10, —NRaRb, and —C(O)NRcRd; or alternatively R2 and R3 together with the phosphorus atom to which they are attached form a 4- to 8-membered ring optionally substituted with one to five substituents independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR9, —SR9, —C(O)OR9, —C(O)R10, —NRaRb, —C(O)NRcRd, and oxo;
R4 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or arylalkyl, each except hydrogen optionally substituted;
R5 and R6 are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy; or R5 and R6 together form oxo (═O) or with the carbon atom to which they are attached form a 3- to 6-membered ring optionally substituted by one to five substituents independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy;
R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; or alternatively, R7 and R8 together with the nitrogen atom to which they are attached, form a 4- to 6-membered ring, wherein said 4- to 6-membered ring optionally may contain one to five substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and —OR9;
B is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, CN, P(═O)(R9)2, P(═O)(OR9)2, —C(O)R10, —CO2R9, —OR9, —SR9, —NRaRb, —CONRaRb, —NR12C(O)R10, —NR12SO2R11, —NR12SO2NRaRb, —SO2R11, and —SO2NRaRb;
R9 at each occurrence is independently hydrogen, C1-C6 alkyl, or C6-C10 aryl;
R10 at each occurrence is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, each except hydrogen optionally substituted;
R11 at each occurrence is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, each optionally substituted;
R12 each occurrence is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;
wherein, unless specifically defined, cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one to five substituents independently selected from the group consisting of halogen, cyano, nitro, —OR13, —SR13, C1-C6 alkyl, C6-C10 aryl, —NRaRb, and —C(O)OR14;
wherein, unless specifically defined, any said aryl and heteroaryl may optionally be substituted with one to five substituents independently selected from halogen, cyano, nitro, —OR13, —SR13, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, —C(O)OR14, —NRaRb, and —C(O)NcRd;
R13 at each occurrence is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
R14 at each occurrence is independently hydrogen or C1-C6 alkyl;
Ra and Rb are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and benzyl; and
Rc and Rd are independently hydrogen or C1-C6 alkyl.