US 12,018,021 B2
Thiophene derivatives for the treatment of disorders caused by IgE
Pfrafulkumar Tulshibhai Chovatia, Oxfordshire (GB); Rickki Lee Connelly, Oxfordshire (GB); Richard Jeremy Franklin, Berkshire (GB); Gregory William Haslett, Berkshire (GB); Alistair James Henry, Berkshire (GB); James Madden, Oxfordshire (GB); Judi Charlotte Neuss, Berkshire (GB); Timothy John Norman, Berkshire (GB); Oliver Philps, Oxfordshire (GB); William Ross Pitt, Berkshire (GB); Konstantinos Rampalakos, Oxfordshire (GB); Matthew Duncan Selby, Berkshire (GB); Selvaratnam Suganthan, Oxfordshire (GB); Giancarlo Trani, Oxfordshire (GB); and Zhaoning Zhu, Berkshire (GB)
Assigned to UCB BIOPHARMA SRL, Brussels (BE)
Appl. No. 16/973,701
Filed by UCB Biopharma SRL, Brussels (BE)
PCT Filed Jun. 20, 2019, PCT No. PCT/EP2019/066414
§ 371(c)(1), (2) Date Dec. 9, 2020,
PCT Pub. No. WO2019/243550, PCT Pub. Date Dec. 26, 2019.
Claims priority of application No. 18179126 (EP), filed on Jun. 21, 2018.
Prior Publication US 2022/0332709 A1, Oct. 20, 2022
Int. Cl. C07D 409/14 (2006.01); C07D 333/50 (2006.01); C07D 333/78 (2006.01); C07D 409/04 (2006.01); C07D 409/06 (2006.01); C07D 409/12 (2006.01); C07D 413/04 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 487/04 (2006.01); C07D 495/04 (2006.01); C07D 495/10 (2006.01); C07D 498/10 (2006.01)
CPC C07D 409/14 (2013.01) [C07D 333/50 (2013.01); C07D 333/78 (2013.01); C07D 409/04 (2013.01); C07D 409/06 (2013.01); C07D 409/12 (2013.01); C07D 413/04 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 487/04 (2013.01); C07D 495/04 (2013.01); C07D 495/10 (2013.01); C07D 498/10 (2013.01)] 15 Claims
 
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein
X represents CH or C—R4, wherein R3 and R4 together with the carbon to which they are attached optionally form a 4-6 membered cycloalkyl or heterocyclic ring,
wherein each 4-6 membered cycloalkyl or heterocyclic ring is optionally substituted by one or more substituents selected from halogen, ═O, OH, SMe, C1-C2 alkoxy, O—C1-C2 haloalkyl, C1-C2alkyl, C1-C2 heteroalkyl, C1-C2haloalkyl, NH2, NHMe, NMe2, aryl and heteroaryl, with aryl and heteroaryl optionally substituted by one or more substituents selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy and C1-C2 haloalkyl;
W, Y and Z are CH
and each is optionally substituted by 1 or 2 groups which are independently selected from H, halogen, SF5, ═O, ═NOH, —OH, —CN, —C(O)Me, —C(O)OH, —C(O)NH2, NH—C(O)O—C1-C4 alkyl, —NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, heterocycle, and C1-C4 heteroalkyl,
each of which is optionally substituted by one or more substituents selected from halogen, ═O, OH, SMe, C1-C2 alkoxy, O—C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, and NMe2;
R1 is

OG Complex Work Unit Chemistry
R2 represents —N(R12)C(O)R13;
R3 is selected from —OH, —NRdRc, —NH-R14—NH—Ra, —NMe-R14—NH—Ra, —NH-R14—NMe-Ra, —CO—NRdRc, —NH—COO—Rc, —NH—CO—Rc, —COOH, —COO—C1-C8 alkyl, —CO—C1-C8 alkyl, —C1-C8 alkylene-COO—C1-C8 alkyl, —C1-C8 alkylene-NRa—COO—C1-C8 alkyl, —C1-C8 alkylene-NRdRc, —C1-C8 alkylene-NH-R14—NH—Ra, heteroaryl, —CN, —CH═N—OH, —CF3, alkylamino, amino, —NH—SO—C1-C8 alkyl, —NH—SO2—C1-C8 alkyl, heteroalkyl-amino, aryl, heterocycle, C3-C6 cycloalkyl, —NHS(O)(═NH)Me, —SO2—C1-C8 alkyl, —NH—C(CH3)═N-CN, —NH—CH═N—CN, and —NH—S(═O)(═N)—C1-C2 alkyl,
each of which is optionally substituted by one or more substituents selected from halogen, —OH, ═O, —COOH, —COH, —CN, SMe, —NRdRc, —ORc, C1-C2 alkoxy, O—C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, C1-C2 alkylene-O—C1-C2 alkyl, C1-C2alkylene-C3-C4 cycloalkyl, heterocycle, C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 cycloalkyl-amino, heterocyclo-amino, aryl-amino, heteroaryl-amino, —CONRdRc, —NHCO—Ra, —NHCOO—C1-C4 alkyl, —CO—C1-C2 alkyl, and —COO—Ra, or wherein each of —CONRdRc and —NRdRc optionally forms a seven-membered ring fused to a six-membered aryl group;
wherein each aryl, heteroaryl, heterocycle and cycloalkyl is optionally substituted by one or more substituents selected from halogen oxo, cyano, OH, —NOOH, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6-cycloalkyl-C1-C3-alkoxy, —O—CO—C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2haloalkyl, C2-C4 heterocycle, acetyl, acetyl-phenyl, —CONRdRc, COO—C1-C8 alkyl, —S(O)NH-C1-C2-alkyl, —S(O)n—C1-C2-alkyl, and heteroaryl, wherein each heteroaryl is optionally substituted with one or more halogen group or C1-C2-alkyl,
with n equal 0, 1 or 2;
R4 is selected from halogen, OH, CN, NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C1-C3 heteroalkyl, heterocycle, each of which is optionally substituted by one or more substituents selected from halogen, ═O, OH, SMe, C1-C2 alkoxy, O—C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl NH2, NHMe, and NMe2;
R12 is selected from H and C1-C3 alkyl,
each of which is optionally substituted by 1 to 7 halogen;
R13 is selected from C1-C7 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, —C1-C2 alkylene-C3-C6 cycloalkyl, C3-C5 heterocycle,
wherein cycloalkyl includes spirocyclic carbocyclic rings;
each of which R13 groups is optionally substituted by one or more substituents selected from halogen, ═O, OH, SMe, C1-C2 alkoxy, O—C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, and NMe2;
R14 is C═O, C═S, C═N-OH, C═NRb, C═CH-NO2, SO2, and C3-C6 cycloalkenyl which may be substituted with 1 or 2 ═O;
Ra is selected from H, C1-C8 alkyl, heteroalkyl, C1-C8 alkoxy, heterocycle, C3-C8 cycloalkyl, heteroaryl and aryl,
each of which is optionally substituted by one or more substituents selected from halogen, ═O, OH, SMe, C1-C2 alkoxy, —O—C1-C2haloalkyl, C1-C2 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C2heteroalkyl, C1-C2 haloalkyl, aryl, heteroaryl, NH2, NHMe, and NMe2;
Rb is selected from CN, aryl, heteroaryl, —NO2, —O—C1-C2 alkyl, and —CO—O—C1-C2 alkyl, wherein each aryl and heteroaryl is optionally substituted by one or more C1-C2 alkyl;
Rc is selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, and C1-C4 alkylene-C3-C6 cycloalkyl;
each of which is optionally substituted by one or more substituents selected from C(O)(Rg), C(O)N(Rf)(Rg), halogen, SF5, OH, ═O, —COH, —COOH, —CO—O—Ra, CN, SMe, SO2Me, SO2Rg, C1-C4 alkoxy, O—C1-C4haloalkyl, C1-C4 alkyl, C1-C2 heteroalkyl, C1-C4haloalkyl, N(Rf)(Rg), N(Rf)SO2(Rg), SO2NH2, SO2NHMe, SO2NMe2, S(O)(NRf)Rg, C3-C6 cycloalkyl, heterocycle, C1-C4 alkylene-C3-C6 cycloalkyl, aryl and heteroaryl,
wherein each aryl, heteroaryl, heterocycle and cycloalkyl is optionally substituted by one or more substituents selected from halogen, ═O, ═NH, ═NMe, OH, C1-C2 alkyl, C1-C2 alkoxy, —COOH, —COO—C1-C2 alkyl, SO2Ra, CORa, SORa, S(O)(NH)Ra, and CONHRa;
Rd represents H or C1-C4 alkyl;
or Rc and Rd together with a nitrogen atom to which they are linked form a 5-7 membered heterocyclic group containing at least one nitrogen ring atom;
Rf is selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, and C1-C4 alkylene-C3-C6 cycloalkyl,
each of which is optionally substituted by one or more substituents selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2haloalkyl, C1-C2 alkoxy, O—C1-C2 haloalkyl, —COOH, —COO—C1-C2 alkyl, SO2Ra, CORa, SORa, S(O)(NH)Ra, and CONHRa;
Rg is selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, and C1-C4 alkylene-C3-C6 cycloalkyl,
each of which is optionally substituted by one or more substituents selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2haloalkyl, C1-C2 alkoxy, O—C1-C2 haloalkyl, —COOH, —COO—C1-C2 alkyl, SO2Ra, CORa, SORa, and S(O)(NH)Ra, CONHRa.