US 12,473,304 B2
Heterocyclic PAD4 inhibitors
Kumaravel Selvakumar, Bangalore (IN); Venkatram Reddy Paidi, Kamareddy (IN); Srinivasan Thangathirupathy, Hosur (IN); Vijaya Kumar Cm, Hosur (IN); Tirupathi Rao Alajangi, Vizianagaram (IN); Mallikarjun Reddy Sura, Kadapa (IN); Krishna Mahadevu, Mandya (IN); Ramesh Kumar Sistla, Bangalore (IN); Piyush Agarwal, Jodhpur (IN); Arul Mozhi Subbiah Karuppiah, Bangalore (IN); Jalathi S. Nair, Bangalore (IN); Ooha Morampudi, Khammam (IN); Manoranjan Panda, Bangalore (IN); Joseph A. Tino, Lawrenceville, NJ (US); Robert J. Cherney, Newtown, PA (US); John V. Duncia, Newtown, PA (US); Daniel S. Gardner, Furlong, PA (US); T. G. Murali Dhar, Newtown, PA (US); Audrey Graham Ross, Cambridge, MA (US); Paul E. Gormisky, Belmont, MA (US); Xiao Zhu, Winchester, MA (US); Boris M. Seletsky, Andover, MA (US); Alyssa H. Antropow, Boston, MA (US); Deqiang Niu, Lexington, MA (US); Zhengdong Zhu, Westborough, MA (US); Guobin Miao, Lexington, MA (US); and Julio Hernan Cuervo, Arlington, MA (US)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/799,028
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Feb. 11, 2021, PCT No. PCT/US2021/017554
§ 371(c)(1), (2) Date Aug. 11, 2022,
PCT Pub. No. WO2021/163254, PCT Pub. Date Aug. 19, 2021.
Claims priority of application No. 202041006146 (IN), filed on Feb. 12, 2020.
Prior Publication US 2023/0167131 A1, Jun. 1, 2023
Int. Cl. C07D 519/00 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01)
CPC C07D 519/00 (2013.01) [C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01)] 29 Claims
 
1. A compound of Formula (Ia):

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

OG Complex Work Unit Chemistry
is selected from

OG Complex Work Unit Chemistry
is selected from

OG Complex Work Unit Chemistry
X1 is independently selected from CR2, and N;
X2 is independently selected from CR4, and N;
X3 is independently selected from O, and S;
X4 is independently selected from CR2, and N; provided X1 and X4 are not both N;
X5 is independently selected from O and S;
X6 is independently selected from CR4, and N; provided 1) X2 and X6 are not both N; 2) when X2 and X6 are both CR4, one of R4 is H;
R1 is independently selected from —NH—C1-5 alkyl optionally substituted with one or more substituents selected from F, Cl, and NH2, 4-10 membered heterocyclyl, and —NH-4-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents selected from F, Cl, CN, C1-3 alkyl, ═N—ORb, —(CH2)rORb, —(CH2)rNRaRa, —NRaC(═NH)C1-3 alkyl, —NRaC(═O)ORb, carbocyclyl, and heterocyclyl;
R2 is independently selected from H, F, Cl, C1-4 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and —OC1-4 alkyl;
R3 is independently selected from H, F, Cl, CN, —C(═O)ORb, and C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, NH2, and N3;
R4 is independently selected from H, F, Cl, Br, —C(═O)Rb, C1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C3-6 cycloalkyl, —NH—C1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C3-6 cycloalkyl, —(CH2)r-aryl substituted with one or more R5, —O—C1-6 alkyl substituted with one or more R5, —(CH2)r—C3-12 cycloalkyl substituted with one or more R5, and —(CH2)r-4-10 membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, NR6, O, and S and substituted with one or more R5;
R5 is independently selected from H, F, Cl, Br, CN, ═O, C1-4 alkyl optionally substituted with one or more Re, C2-4 alkenyl optionally substituted with one or more Re, C2-4 alkynyl optionally substituted with one or more Re, —CRdRd)rORb, —(CRdRd)rS(O)pRc, —(CRdRd)rS(O)pNRaRa, —(CRdRd)rNRaS(O)pRc, —(CRdRd)rNRaRa, —(CRdRd)rNRaC(═O)Rb, —(CRdRd)rNRaC(═O)ORb, —(CRdRd)rNRaC(═O)NRaRa, —(CRdRd)rC(═O)Rb, —(CRdRd)rC(═O)ORb, —(CRdRd)rC(═O)NRaRa, —(CRdRd)rOC(═O)Rb, —(CRdRd)rOC(═O)ORb, (CRdRd)rO(CH2)rC(═O)NRaRa, C3-6 cycloalkyl optionally substituted with one or more Re, aryl optionally substituted with one or more Re, and heterocyclyl optionally substituted with one or more Re;
R6 is independently selected from H, C1-6 alkyl optionally substituted with one or more Re, —S(O)pRc, —S(O)pNRaRa, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, C3-6 cycloalkyl optionally substituted with one or more Re, aryl optionally substituted with one or more Re, and heterocyclyl optionally substituted with one or more Re;
R7 is independently selected from H, F, and Cl;
R8 is independently selected from H, and C1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C3-6 cycloalkyl;
Ra is independently selected from H, C1-6 alkyl optionally substituted with one or more Re, C2-6 alkenyl optionally substituted with one or more Re, C2-6 alkynyl optionally substituted with one or more Re, —(CH2)rC3-10 carbocyclyl optionally substituted with one or more Re, and —(CH2)r-heterocyclyl optionally substituted with one or more Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with one or more Re;
Rb is independently selected from H, C1-6 alkyl optionally substituted with one or more Re, C2-6 alkenyl optionally substituted with one or more Re, C2-6 alkynyl optionally substituted with one or more Re, —(CH2)r—C3-10 carbocyclyl optionally substituted with one or more Re, and —(CH2)r-heterocyclyl optionally substituted with one or more Re;
Rc is independently selected from C1-6 alkyl optionally substituted with one or more Re, C2-6 alkenyl optionally substituted with one or more Re, C2-6 alkynyl optionally substituted with one or more Re, —(CH2)r—C3-10 carbocyclyl optionally substituted with one or more Re, and —(CH2)r-heterocyclyl optionally substituted with one or more Re;
Rd is independently selected from H, and C1-6 alkyl optionally substituted with one or more Re;
Re is independently selected from F, Cl, Br, CN, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, ═O, OH, —OC1-6 alkyl, —CO2H, C1-6 alkyl optionally substituted with one or more Rf, C2-6 alkenyl, C2-6 alkynyl, —(CH2)r—C3-6 cycloalkyl optionally substituted with one or more Rf, —(CH2)r-aryl optionally substituted with one or more Rf, and —(CH2)r-heterocyclyl optionally substituted with one or more Rf;
Rf is independently selected from F, Cl, Br, CN, OH, OC1-5 alkyl, C1-5 alkyl optionally substituted with OH, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, and phenyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.