US 12,448,391 B2
Bicyclic derivatives for treating endoparasites
Pierre Ducray, Village-Neuf (FR); Francois Pautrat, Mulhouse (FR); Denise Rageot, Saint-Louis (FR); and Chouaib Tahtaoui, Rixheim (FR)
Assigned to Elanco Tiergesundheit AG, Basel (CH)
Appl. No. 17/616,436
Filed by Elanco Tiergesundheit AG, Basel (CH)
PCT Filed Jun. 5, 2020, PCT No. PCT/US2020/036322
§ 371(c)(1), (2) Date Dec. 3, 2021,
PCT Pub. No. WO2020/247747, PCT Pub. Date Dec. 10, 2020.
Claims priority of provisional application 62/947,852, filed on Dec. 13, 2019.
Claims priority of provisional application 62/858,465, filed on Jun. 7, 2019.
Prior Publication US 2022/0242857 A1, Aug. 4, 2022
Int. Cl. C07D 491/107 (2006.01); A61P 33/10 (2006.01); C07D 265/36 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01)
CPC C07D 491/107 (2013.01) [A61P 33/10 (2018.01); C07D 265/36 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01)] 28 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
wherein
n is 0 or 1;
X1 is selected from the group consisting of N and CR1;
X2 is selected from the group consisting of N and CR2;
X5 is selected from the group consisting of N and CR3;
X4 is selected from the group consisting of N and CR4;
X5 is selected from the group consisting of N and CR5;
X5 is selected from the group consisting of N and CR6;
G is selected from the group consisting of

OG Complex Work Unit Chemistry
M is selected from the group consisting of N—R13, O, and S;
Y1 is selected from the group consisting of CR8R9, O, S, and NR10;
Y2 is selected from the group consisting of CR8R9, O, S, and NR10;
wherein at least one of the groups Y1 or Y2 is CR8R9;
Z1 is selected from the group consisting of N, O, S, and CR11;
Z2 is selected from the group consisting of nil, N, and CR11;
Z3 is selected from the group consisting of nil, N and CR11;
Z4 is selected from the group consisting of N, O, S, and CR11;
wherein no more than 2 of Z1, Z2, Z3, and Z4 are N and wherein only one of Z1 and Z4 is O or S, Z2 is nil only when Z1 is O or S, and Z3 is nil only when Z4 is O or S;
R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, —SH, —SC1-C4 alkyl, —S(O)(C1-C4 alkyl), —S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenalkyl, C1-C4-alkoxy, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, —SH, —SC1-C4 alkyl, —S(O)(C1-C4 alkyl), —S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, —SH, —SC1-C4 alkyl, —S(O)(C1-C4 alkyl), —S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
R4 is selected from the group consisting of halogen, cyano, —CHO, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy substituted-C1-C4 alkyl, benzyl optionally substituted with 1 to 5 halogen atoms, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —N(C1-C4 alkyl)(4- to 7-membered heterocycloalkyl), —NH (4- to 7-membered heterocycloalkyl), —N(C1-C4 alkyl)(C1-C4 alkoxy), —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —C(O)N(C1-C4 alkyl)(4- to 7-membered heterocycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; 6- or 10 membered aryl; a monocyclic heterocycle selected from the group consisting of 4- to 7-membered heterocycloalkyl, 5-membered heteroaryl having at least one nitrogen atom via which the 5-membered heteroaryl ring is connected to the rest of the molecule, and 6-membered heteroaryl having at least one nitrogen atom; each of the aryl, heterocycloalkyl, and heteroaryl rings in R4 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy,
—NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl; wherein the C3-C6 cycloalkyl and the heterocycloalkyl rings in R4 are optionally substituted with a spiro group, wherein said spiro group is a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, S and O, wherein said spiro group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl; and wherein each C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy in R4 may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, cyano, carboxy, carbamoyl, C1-C4 alkoxycarbonyl, —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, and C1-C4 alkoxy;
R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, —SH, —SC1-C4 alkyl, —S(O)(C1-C4 alkyl), —S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, —SH, —SC1-C4 alkyl, —S(O)(C1-C4 alkyl), —S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, —B(OR15)(OR16) wherein R15 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R16 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R15 and R16 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally substituted with 1 to 4 C1-C4 alkyl; —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
R7 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl optionally substituted with 1 to 5 halogen atoms, —C(H)O, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 halogenoalkyl, and C1-C4-alkoxy;
R8 is, each time selected, independently selected from the group consisting of hydrogen, fluoro, and C1-C4 alkyl;
R9 is, each time selected, independently selected from the group consisting of hydrogen, fluoro, and C1-C4 alkyl;
R10 is selected from the group consisting of hydrogen and C1-C4 alkyl;
R11 is, each time selected, independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, C3-C6 cycloalkyl, —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
Q is selected from the group consisting of
(i) 6- or 10 membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl, wherein the 6- or 10 membered aryl is optionally fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, and N and wherein the carbons of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the group halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2 and any N in the heterocycloalkyl is, valency permitting, substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
(ii) 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N and wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, benzyloxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl, and any N in the heteroaryl, valency permitting, is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
(iii) 4- to 7-membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2 and any N in the heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
(iv) 6- or 10 membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl;
(v) 6- or 10 membered arylthio-oxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl; and
(vi) 5- to 10-membered heteroaryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6-cycloalkyl), —NHSO2(C1-C4 alkyl), —SC1-C4 alkyl, —S(O)C1-C4 alkyl, —SO2C1-C4 alkyl, —S(O)C1-C4-halogenoalkyl and —SO2C1-C4 halogenoalkyl;
R13 is selected from the group consisting of hydroxy, C1-C4 alkoxy, and —NH2; and
R14 is, each time selected, independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C1-C4 halogenalkoxy, —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2;
or a salt thereof.