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CA-3122105-C - BICYCLIC DERIVATIVES

CA3122105CCA 3122105 CCA3122105 CCA 3122105CCA-3122105-C

Abstract

The present invention provides compounds of formula (I): which are useful in the control of endoparasites, for example heartworms, in warm-blooded animals.

Inventors

  • Pierre Ducray
  • Francois Pautrat
  • Denise RAGEOT
  • Chouaib Tahtaoui

Assignees

  • ELANCO TIERGESUNDHEIT AG

Dates

Publication Date
20260505
Application Date
20191213
Priority Date
20181218

Claims (16)

  1. CLAIMS: 1. A compound of formula (I): Y1 X2' ' ii I I 2,i . ..,,Z2 X1, ::;.,Xs 'Z3 x6 Q (I) wherein 5 n is 0 or l; X1 is selected from the group consisting ofN and CR1; X2 is selected from the group consisting ofN and CR2; X3 is selected from the group consisting of N and CR3; X4 is selected from the group consisting ofN and CR4; 10 Xs is selected from the group consisting ofN and CRs; ~ is selected from the group consisting of N and CR6; wherein at least two ofX1, X2, X3, X4, Xs, and X6 are N; G is the group 15 Y1 is selected from the group consisting of CRsR9, 0, S, and NR10; Y2 is selected from the group consisting of CRsR9, 0, Sand NR10; wherein at least one of the groups Y 1 or Y 2 is CRsR9; 21 is selected from the group consisting ofN, 0, S and CRn; 22 is selected from the group consisting of nil, N and CRn; 20 23 is selected from the group consisting of nil, N and CRn; 24 is selected from the group consisting of N, 0, S and CRn; Date Rei;ue/Date Received 2024-04-04 88570529 wherein no more than 2 of Z1, Z2, Z3, and Z4 are N and wherein only one of Z1 and Z4 is 0 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)z(C1-C4 alkyl, cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, 5 -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and -B(OR12)(OR13), wherein R12 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, RB is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R12 and R13 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; 10 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, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)z, and -B(OR12)(OR13), wherein R12 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R13 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or 15 R12 and R13 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; 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, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and -B(OR12)(ORB), wherein R12 is, each time taken, 20 selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, RB is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and CJ-C6 cycloalkyl, or R12 and RB 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; R4 is selected from the group consisting of halogen, cyano, -CHO, hydroxyl, C1-C4 alkyl, 25 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), -NH(4- to 7-membered heterocycloalkyl), -N(C1-C4 alkyl) (4- to 7-memberedheterocycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -N(C1-C4 alkyl) 30 (C1-C4alkoxy), -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)z, -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, and -B(OR12)(OR13) wherein R12 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, RB is, Date Rei;ue/Date Received 2024-04-04 88570529 each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R12 and RB 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 IO-membered aryl; and a monocyclic heterocycle selected from the group consisting of 5 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 ring in R4 is 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, 10 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 15 halogen, hydroxyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, cyano, carboxyl, carbamoyl, C1-C4 alkoxycarbonyl, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, and C1-C4 alkoxy; Rs 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, and -B(OR12)(QR13) wherein R12 is, each time taken, selected from the group consisting of 20 hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, RB is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R12 and RB 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, 25 -S(O)(C1-C4 alkyl, -S(O)2(C1-C4 alkyl, cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, and -B(OR12)(QR13) wherein R12 is, each time taken, selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, RB is, each time taken, selected from the group consisting ofhydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, orR12 andR13 together with the oxygen atoms to which they are attached form a 5- to 7-membered ring which is optionally 30 substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2; Date Rei;ue/Date Received 2024-04-04 88570529 R1 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; Rs is, each time selected, independently selected from the group consisting of hydrogen, fluoro, 5 and C 1-C4 alkyl; R9 is, each time selected, independently selected from the group consisting of hydrogen, fluoro, and C 1-C4 alkyl; R10 is selected from the group consisting of hydrogen and C1-C4 alkyl; Rn is, each time selected, independently selected from the group consisting of hydrogen, 10 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; and Q is selected from the group consisting of 6- or IO-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 15 -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 IO-membered aryl is optionally fused with a 4- to 7-membered heterocycloalkyl having I or 2 heteroatoms selected from the group 0, S, and N and wherein the carbons of the heterocycloalkyl are optionally 20 substituted with I, 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), and -N(C1-C4 alkyl)2 and any Nin the heterocycloalkyl is, valency permitting, substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; 25 5- to IO-membered heteroary 1 having I or 2 heteroatoms selected from the group consisting of 0, S, and N and wherein the carbons of the 5- to IO-membered heteroaryl are 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), and-N(C1-C4 alkyl)2 and any Nin the heteroaryl, valency 30 permitting, is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; Date Rei;ue/Date Received 2024-04-04 88570529 a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of 0, 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 heterocycloalk:yl are optionally substituted with 1, 2, 3, or 4 substituents independently selected 5 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 Nin the heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; 6- or IO-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently 10 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; 6- or IO-membered arylthio-oxy optionally substituted with 1, 2 or 3 substituents independently 15 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)z, -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 20 5- to IO-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)z, -NH(C3-C6 cycloalk:yl), -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; 25 excluding the compounds: N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; 30 N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-l,7-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-l,7-naphthyridine-3- carboxamide; 4-chloro-N-[ ( 4S)-chroman-4-y l]-8-(2,3-dichloropheny 1 )-1,6-naphthyridine-3-carboxamide; 8-bromo-N-[( 4S)-chroman-4-y l]-4-oxo-1,4-dihydro- l ,6-naphthyridine-3-carboxamide; 5 N-[ ( 4S)-chroman-4-y l]-8-(3 ,5-dichloropheny 1 )-4-oxo-1,4-dihydro- l,6-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-3- carboxamide; 4-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-l,6-naphthyridine-3-carboxamide; 10 4-chloro-N-[( 4S)-chroman-4-y l]-8-(2,3-dichloropheny 1 )-1,6-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,6-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,6-naphthyridine-3- carboxamide; 15 N-[ ( 4S)-chroman-4-y l]-8-(2,3-dichlorophenyl )-4-(morpholin-4-y 1)-1,6-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-l,6-naphthyridine-3- carboxamide; 4-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-l,5-naphthyridine-3-carboxamide; 20 4-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-l,5-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,5-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-l,5-naphthyridine-3- carboxamide; 25 N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,5-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-l,5-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 8-chloro-4-(3,5-dichlorophenyl )-N-[( 4S)-chroman-4-y l]pyrido[3,2-d]pyrimidine-7-carboxamide; 4-(3,5-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(dimethylamino)-pyrido[3,2-d]pyrimidine-7- carboxamide; 4-(3,5-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(morpholin-4-yl)-pyrido[3,2-d]pyrimidine-7- 5 carboxamide; 8-bromo-4-chloro-4-N-[(4S)-chroman-4-yl]cinnoline-3-carboxamide; 8-bromo-4-N-[(4S)-chroman-4-yl]-4-(dimethylamino)cinnoline-3-carboxamide; 8-bromo-4-N-[(4S)-chroman-4-yl]-4-methoxycinnoline-3-carboxamide; 8-(3,5-dichlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-(dimethylamino)cinnoline-3-carboxamide; 10 8-(3-chlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-(dimethylamino)cinnoline-3-carboxamide; 8-(2,3-dichlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-(dimethylamino)cinnoline-3-carboxamide; 8-(3,4-difluorophenyl)-4-N-[(4S)-chroman-4-yl]-4-(dimethylamino)cinnoline-3-carboxamide; 8-(3,5-dichlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-methoxycinnoline-3-carboxamide; 8-(3-chlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-methoxycinnoline-3-carboxamide; 15 8-(2,3-dichlorophenyl)-4-N-[(4S)-chroman-4-yl]-4-methoxycinnoline-3-carboxamide; 8-(3,4-fluorophenyl)-4-N-[(4S)-chroman-4-yl]-4-methoxycinnoline-3-carboxamide; 8-chloro-4-(2,3-dichlorophenyl)-N-[ ( 4S)-chroman-4-y l]pyrido[3,2-d]pyridazine-7-carboxamide; 4-(2,3-dichloropheny 1)-N-[ ( 4S)-chroman-4-y l]-8-( dimethy lamino )-pyrido[3 ,2-d]pyridazine-7- carboxamide; 20 4-(2,3-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(morpholin-4-yl)-pyrido[3,2-d]pyridazine-7- carboxamide; 4-(3,5-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(dimethylamino)-pyrido[3,2-d]pyridazine-7- carboxamide; 4-(3,5-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(morpholin-4-yl)-pyrido[3,2-d]pyridazine-7- 25 carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-l,7-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 N-[ ( 4S )-chroman-4-y l]-8-(2,3 ,5-trichloropheny 1)-4-(morpholin-4-yl)-l, 7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-fluoro-4-(morpholin-4-yl)-l,7-naphthyridine-3- carboxamide; 5 N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-fluoro-4-(morpholin-4-yl)-l,7-naphthyridine- 3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-methoxy-4-(morpholin-4-yl)-1,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-fluoro-4-(dimethylamino)-l,7-naphthyridine-3- l O carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(dimethylamino)-l,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-fluoro-4-(dimethylamino)-l,7-naphthyridine- 3-carboxamide; 15 N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-methoxy-4-(dimethylamino)-l,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-l,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-5-methoxy-4-(dimethylamino)-l,6- 20 naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-7-methoxy-4-(morpholin-4-yl)-l,6- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-7-methoxy-4-(dimethylamino)-l,6- naphthyridine-3-carboxamide; 25 N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-7-methoxy-4-(dimethylamino)-l,6- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-7-methoxy-4-(morpholin-4-yl)-l,6- naphthyridine-3-carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-l,6- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-l,6- naphthyridine-3-carboxamide; 5 N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(dimethylamino)-l,6- naphthyridine-3-carboxamide; 7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(dimethylamino)-l,5-naphthyridine- 3-carboxamide; 7 -chloro-N-[ ( 4S )-chroman-4-y l]-8-( 2,3 ,5-trifluoropheny 1)-4-(morpholin-4-y 1)-1,5-naphthyridine- 10 3-carboxamide; 7-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,5-naphthyridine-3- carboxamide; 7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,5-naphthyridine-3- carboxamide; 15 7-chloro-N-[ ( 4S)-chroman-4-y l]-8-(2,3-dichloropheny 1)-4-(morpholin-4-yl)-l ,5-naphthyridine-3- carboxamide; 7-methoxy-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,5- naphthyridine-3-carboxamide; 7-fluoro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,5-naphthyridine-3- 20 carboxamide; 7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,5- naphthyridine-3-carboxamide; 7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-l,5- naphthyridine-3-carboxamide; 25 7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(dimethylamino)-l,5- naphthyridine-3-carboxamide; 7-methoxy-N-[ ( 4S)-chroman-4-y l]-8-(2,3 ,5-trifluoropheny 1)-4-(morpholin-4-y 1)-1,5- naphthyridine-3-carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 7-fluoro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3- carboxamide; 7-fluoro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3- carboxamide; 5 7-fluoro-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(dimethylamino)-1,5-naphthyridine- 3-carboxamide; and 7-fluoro-N-[( 4S)-chroman-4-y l]-8-(2,3,5-trifluoropheny l)-4-(morpholin-4-y l)-1,5-naphthyridine- 3-carboxamide; or a salt thereof.
  2. 2. A compound according to claim 1 wherein X1 is N; X2 is CR2; X3 is CR3; .xi is C~; 10 Xs is CRs; and X6 is N; or a salt thereof.
  3. 3. A compound according to claim 1 wherein X1 is CR1; X2 is CR2; X3 is CR3; .xi is C~; Xs is N; and X6 is N; or a salt thereof.
  4. 4. A compound according to any one of claims 1 to 3 wherein Q is a 6- or IO-membered aryl optionally substituted with 1, 2 or 3 substituents independently 15 selected from the group consisting of halogen, cyano, nitro, hydroxy, 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-CG-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; or a salt thereof. 20
  5. 5. A compound according to any one of claims 1 to 3 wherein Q is 6-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, 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-CG-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, 25 -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, wherein the 6-membered aryl is fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of 0, S, and N and wherein the carbons of the heterocycloalkyl are 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, 30 C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2 and any Nin Date Rei;ue/Date Received 2024-04-04 88570529 the heterocyclalkyl is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; or a salt thereof.
  6. 6. A compound according to any one of claims 1 to 3 wherein 5 Q is a 5- to IO-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of 0, S, and N and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, 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 Nin the heteroaryl is optionally substituted with 10 a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; or a salt thereof.
  7. 7. A compound according to any one of claims 1 to 3 wherein Q is a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of 0, S, and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the 15 carbons of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 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), and-N(C1-C4 alkyl)2 and any Nin the heterocyclalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, 20 C1-C4 alkyl, and C3-C6 cycloalkyl; or a salt thereof.
  8. 8. The compound according to any one of claims 1 to 7 wherein n is l; or a salt thereof.
  9. 9. The compound according to any one of claims 1 to 8wherein 25 Y1 is CRsR9 and Y2 is O; or a salt thereof.
  10. 10. The compound according to any one of claims 1 to 9 wherein R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, -N(C1-C4 alkyl)2, and 4- to 7-membered heterocycloalkyl; or a salt thereof. Date Rei;ue/Date Received 2024-04-04 88570529
  11. 11. A compound according to claim 1 wherein the compound is selected from the group consisting of: N-[( 4S)-chroman-4-yl]-4-( dimethylamino )-8-[(lR)-tetralin- l-yl]- l, 7-naphthyridine-3- carboxamide; 5 N-[( 4S)-chroman-4-yl]-4-( dimethylamino )-8-[(l S)-tetralin-1-y l]-1, 7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[(lR or S)-tetralin-l-yl]-1,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(l,2-dihydronaphthalen-l-yl)-4-(dimethylamino)-l,7-naphthyridine-3- 10 carboxamide; trans-8-(2,3,3a,4,5,6, 7,7a-octahydroindol-l-yl)-N-[(4S)-chroman-4-yl]-4-(dimethylamino )-1,7- naphthyridine-3-carboxamide; cis-8-(2,3,3a,4,5,6, 7, 7a-octahydroindol-l-yl)-N-[( 4S)-chroman-4-yl]-4-( dimethylamino )-1, 7- naphthyridine-3-carboxamide; 15 8-(5-chloroindolin-l-yl)-N-[( 4S)-chroman-4-yl]-4-( dimethy lamino )-1, 7-naphthyridine-3- carboxamide; N-(5-chloroindol- l-yl)-N-[( 4S)-chroman-4-yl]-4-( dimethy lamino )-1, 7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-4-morpholino-8-phenylsulfanyl-1,7-naphthyridine-3-carboxamide; 20 8-(benzenesulfony 1)-N-[ ( 4S)-chroman-4-y l]-4-morpholino- l, 7-naphthyridine-3-carboxamide; 4-amino-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-l,7-naphthyridine-3-carboxamide; N-[ ( 4S )-chroman-4-y l]-8-(3 ,5-dichloropheny 1 )-4-isopropoxy-l, 7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(4-methylpiperazin-l-yl)-l,7-naphthyridine-3- carboxamide; 25 N-[ ( 4S)-chroman-4-yl]-8-(2,6-di:fluorophenyl)-4-(4-methy lpiperazin-l -yl)-1, 7-naphthyridine-3- carboxamide; N-[ ( 4S)-chroman-4-y l]-8-(3 ,5-dichlorophenyl)-4-pyrrolidin-l -yl- l, 7-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(4S)-7-fluorochroman-4-yl]-l,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(lH-indol-4-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-phenyl-l,7-naphthyridine-3-carboxamide; 5 N-[ ( 4S)-chroman-4-y l]-4-cyclopropy l-8-(3,5-dichloropheny l)-1, 7-naphthyridine-3-carboxamide; 8-(3,5-dichloropheny l)-4-( dimethylamino )-N-[ (1S)-indan-l-yl]-1, 7-naphthyridine-3- carboxamide; N-[(4S)-6-cyanochroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; 10 N-((4S)-7-chlorochroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; N-((4R)-7-chlorochroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2,6-difluoro-3-methoxy-phenyl)-4-(dimethylamino)-l,7- 15 naphthyridine-3-carboxamide; 8-((4S)-3,5-dichlorophenyl)-4-(dimethylamino)-N-(7-methoxychroman-4-yl)-l,7-naphthyridine- 3-carboxamide; 8-((4R)-3,5-dichlorophenyl)-4-(dimethylamino)-N-(7-methoxychroman-4-yl)-l,7-naphthyridine- 3-carboxamide; 20 8-(3,5-dichloropheny l)-4-( dimethylamino )-N-( (8S)-5,6, 7,8-tetrahydroquinolin-5-yl)-l, 7- naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-((8R)-5,6,7,8-tetrahydroquinolin-5-yl)-l,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichloro-2-pyridyl)-4-(dimethylamino)-l,7-naphthyridine-3- 25 carboxamide; 4-chloro-N-[ ( 4S)-chroman-4-y 1]-8-(3,5-dichloropheny l)-1, 7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-[methoxy(methyl)amino]-l,7-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 8-(3,5-dichloropheny l)-4-( dimethylamino )-N-[(1S )-tetralin-1-yl]-l, 7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-methoxy-l,7-naphthyridine-3-carboxamide; 8-(3,5-dichloropheny l)-4-( dimethylamino )-N-[ (lR)-indan-1-yl]-l, 7-naphthyridine-3- 5 carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino )-N-[(lR)-tetralin- l-yl]-1,7-naphthyridine-3- carboxamide; 8-(3,5-dichlorophenyl)-N-((8S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-4-(dimethylamino)l, 7 -naphthyridine-3-carboxamide; 10 8-(3,5-dichlorophenyl)-N-((8R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-4-(dimethylamino)- l, 7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(4-oxoimidazolidin-l-yl)-l,7-naphthyridine-3- carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[rac-(3R,4S)-3-methylchroman-4-yl]-l,7- 15 naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-cyano-8-(3,5-dichlorophenyl)-l,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-isopropyl-l,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[3-(dimethylamino)-2,6-difluoro-phenyl]-l,7- naphthyridine-3-carboxamide; 20 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(4S)-7-methylchroman-4-yl]-l,7-naphthyridine-3- carboxamide; 8-(3,5-dichlorophenyl)-N-[(7S)-6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl]-4-(dimethylamino)- l, 7 -naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-[(7R)-6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl]-4-(dimethylamino)- 25 1, 7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-difluorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(2-fluorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; Date Rei;ue/Date Received 2024-04-04 88570529 N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(2,3,5-trifluorophenyl)-l,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(3,4,5-trifluorophenyl)-l,7-naphthyridine-3- carboxamide; 5 8-[3,5-bis(trifluoromethyl)pheny l]-N-[(4S)-chroman-4-yl]-4-(dimethylamino )-1, 7- naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl]-4-(dimethylamino)l, 7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,4-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- 10 carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-l,7-naphthyridine-3- carboxamide; and N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-2,7-naphthyridine-3- carboxamide. 15
  12. 12. A composition comprising a compound of any one of claims 1 to 11, or a salt thereof, and at least one acceptable carrier.
  13. 13. The use of a compound of any one of claims 1 to 11, or a salt thereof, as a medicament.
  14. 14. The use of a compound of any one of claims 1 to 11, or a salt thereof, for treating endoparasites. 20
  15. 15. The use of a compound of any one of claims 1 to 11, or a salt thereof, for treating heartworm.
  16. 16. The use of a compound of any one of claims 1 to 11, or a salt thereof, for controlling heartworm. Date Rei;ue/Date Received 2024-04-04

Description

BICYCLIC DERIVATIVES FIELD The present invention relates to medicinal chemistry, pharmacology, and veterinary and 5 human medicine. More particularly, the present invention relates to compounds of formula (I) and their use in the control of endoparasites, for example heartworms, in warm-blooded animals. BACKGROUND 10 Heartworm (Dirofilaria immitis) is a parasitic roundworm that is spread from host to host through the bites of mosquitoes. The lifecycle starts when a female mosquito takes a blood meal from an infected host. The mosquito ingests immature heartworms which then molt to the infective larvae stage and travel to the mosquitoes' mouth parts. The mosquito then feeds on a susceptible host, such as a dog or cat, depositing the infective larvae. The 15 larvae then molt to the next larval stage in the new host and then migrate through the body, eventually ending up in the blood vessels. As the larvae migrate through the tissues they molt into juvenile adults. The juvenile adults eventually move into the blood vessels of the lungs where they mature into sexually active adults. The adult heartworms then breed and release immature heartworms completing the cycle. Heartworm infection may 20 result in serious disease for the host. Adult heartworm infections may be treated with arsenic-based compounds; the treatment is time consuming, cumbersome, and often only partly successful. Accordingly, treatment is focused on the control ofheartworm infection. Heartworm control is currently 25 performed exclusively by year round periodical administration of drugs. Typical treatments include macrocyclic lactones such as ivermectin, moxidectin, and milbemycin oxime. Unfortunately, developing resistance of Dirojilaria immitis to macrocyclic lactones has been observed. Accordingly, there is a need for new compounds which effectively control heartworm infections either by way of prophylaxis or by directly 30 killing heartworms. Certain treatments of endoparasites are described in WO 2017/178416, WO 2018/087036, WO 2018/197401, WO 2019/025341, and WO 2019/002132. WO 2020/131629 PCT/0S2019/066298 SUMMARY The present invention provides compounds of formula (I) which effectively treat and/or control endoparasites (e.g., heartworm) in warm-blooded animals. In one embodiment, the present invention provides compounds of formula (I): Y1 X2" , •I XI I y_ 24,7~22 1, -;_,."b «-;:i Xa Q (I) wherein 10 nis0orl; X1 is selected from the group consisting ofN and CR1; X2 is selected from the group consisting of N and CR2; X3 is selected from the group consisting ofN and CR3; X4 is selected from the group consisting ofN and CR4; 15 Xs is selected from the group consisting ofN and CRs; :&, is selected from the group consisting ofN and CR<;; wherein at least one ofX1, X2, X3, and Xs is Nor wherein none ofX1, X2, X3, X4, Xs, and X6 are N; G is the group Y 1 is selected from the group consisting of CRsR9, 0, S, and NR10; Y 2 is selected from the group consisting of CRsR9, 0, S, and NR10; wherein at least one of the groups Y 1 or Y 2 is CR.gR9; WO 2020/131629 Z1 is selected from the group consisting of N, 0, 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 CRu; Z4 is selected from the group consisting of N, 0, S, and CRu; PCT/US2019/066298 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 halogenoalkyl, C1-C4-alkoxy, -B(OR12)(ORn) wherein R12 is, each time taken, selected from the group 10 consisting or hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R13 is, each time taken, selected from the group consisting or hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R12 and R13 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; 15 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(OR12)(ORn) wherein R12 is, each time taken, selected from the group consisting or hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R13 is, each time taken, selected from the group consisting or hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R12 20 and Rn 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, 25 C1-C4-alkoxy, -B(OR12)(ORn) wherein R12 is, ea