RU2794894C9 - Bicyclic derivatives - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a veterinarily or pharmaceutically acceptable salt thereof or their use for the manufacture either as a drug for the treatment and/or control of D. immitis, H. contortus, T. colubriformis, A. viteae, or L. sigmodontis. In the general formula (I), n is 0 or 1; X1 is N; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is CR6; X1 is N; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is CR6; X1 is N; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is CR6; X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is CR6; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is CR5; and X6 is CR6; X1 is CR1; X2 is N; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is CR6; G is a group Y1 is selected from the group consisting of CR8R9, O, and S; Y2 is selected from the group consisting of CR8R9, O, and S; where at least one of the Y1 or Y2 groups is CR8R9; Z1 is selected from the group consisting of N and CR11; Z2 is CR11; Z3 is absent or selected from the group consisting of N and CR11;

Z4 is selected from the group consisting of O, S and CR11; and Z3 is absent only if Z4 is O or S; R1, R2, R3 are hydrogen; R4 is selected from the group consisting of halo, cyano, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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)(C1-C4 alkoxy), 6-membered aryl; and a monocyclic heterocycle selected from the group consisting of 4–7 membered heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, a 5-membered heteroaryl containing one nitrogen atom, through which the 5-membered the heteroaryl ring is attached to the rest of the molecule; 6-membered heteroaryl containing 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 halo, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy; and where each of 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 halo, hydroxyl,

-NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, cyano and C1-C4 alkoxy; R5, R6, R7, R8, R9 are hydrogen; R11 is at each occurrence independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; and Q is selected from the group consisting of 6- or 10-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3- C6cycloalkyl,

-NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), where 6- or 10-membered aryl is optional fused to a 4-7 membered heterocycloalkyl containing 1 or 2 N heteroatoms, and wherein the carbon atoms of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl , C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and any N in heterocycloalkyl, if valency permits, is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; 5-10 membered heteroaryl containing 1 or 2 N heteroatoms, and wherein the carbon atoms of the 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and any N in heteroaryl, if valency permits, is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; 4-7 membered heterocycloalkyl containing 1 or 2 N heteroatoms, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbon atoms of the 4-7 membered heterocycloalkyl or optionally benzo-fused 4-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and any N in heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; 6- or 10-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl ), -N(C1-C4 alkyl)2; 6- or 10-membered arylthiooxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl ), -N(C1-C4alkyl)2.

EFFECT: development of compounds for treatment and/or control of endoparasites D. immitis, H. contortus, T. colubriformis, A. viteae, or L. sigmodontis.

8 cl, 1 tbl, 12 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to medicinal chemistry, pharmacology and veterinary medicine, as well as human medicine. More specifically, 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 OF THE INVENTION

The heartworm ( Dirofilaria immitis ) is a parasitic roundworm that is transmitted from host to host by mosquito bites. The life cycle begins when a female mosquito drinks blood from an infected host. The mosquito ingests immature heartworms, which then molt to the infective larval stage and are carried in parts of the mosquito's mouthparts. The mosquito then feeds on a susceptible host such as a dog or cat, leaving behind infective larvae. The larvae then molt to the next larval stage in the new host and then move around the body, eventually reaching the blood vessels. When the larvae are carried through the tissues, they molt to juvenile adults. Juvenile adults eventually move into the blood vessels of the lungs, where they develop into sexually mature adults. Adult heartworms then multiply and release immature heartworms, completing the cycle. Heartworm infection can lead to serious illness in the host.

Adult heartworm infections can be treated with arsenic-based compounds; treatment is time consuming, difficult and often only partially successful. Accordingly, treatment is aimed at controlling the heartworm infection. The control of heartworm is currently carried out exclusively through year-round periodic administration of drugs. Typical treatments include macrocyclic lactones such as ivermectin, moxidectin and milbemycin oxime. Unfortunately, the development of resistance of Dirofilaria immitis to macrocyclic lactones has been observed. Accordingly, there is a need for new compounds that can effectively control heartworm infections, either through prophylaxis or direct elimination of heartworms. Some endoparasite treatments are described in WO 2017/178416, WO 2018/087036, WO 2018/197401, WO 2019/025341 and WO 2019/002132.

SHORT DESCRIPTION

The present invention provides compounds of formula (I) which effectively treat and/or control endoparasites (eg heartworm) in warm-blooded animals.

In one embodiment, the present invention provides compounds of formula (I),

Where

n is 0 or 1;

X ₁ is selected from the group consisting of N and CR ₁ ;

X ₂ is selected from the group consisting of N and CR ₂ ;

X ₃ is selected from the group consisting of N and CR ₃ ;

X ₄ is selected from the group consisting of N and CR ₄ ;

X ₅ is selected from the group consisting of N and CR ₅ ;

X ₆ is selected from the group consisting of N and CR ₆ ;

where at least one of X ₁ , X ₂ , X ₃ and X ₅ is N, or where none of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ ; and X ₆ is not N;

G is a group

;

Y ₁ is selected from the group consisting of CR ₈ R ₉ , O, S and NR ₁₀ ;

Y ₂ is selected from the group consisting of CR ₈ R ₉ , O, S and NR ₁₀ ;

where at least one of the groups Y ₁ or Y ₂ represents CR ₈ R ₉ ;

Z ₁ is selected from the group consisting of N, O, S and CR ₁₁ ;

Z ₂ is absent or selected from the group consisting of N and CR ₁₁ ;

Z ₃ is absent or selected from the group consisting of N and CR ₁₁ ;

Z ₄ is selected from the group consisting of N, O, S and CR ₁₁ ;

where at most 2 of Z ₁ , Z ₂ , Z ₃ and Z ₄ are N, and where only one of Z ₁ and Z ₄ is O or S, Z ₂ is absent only if Z ₁ is O or S, and Z ₃ is absent only if Z ₄ is O or S;

R ₁ is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC ₁ -C ₄ alkyl, -S(O)(C ₁ -C ₄ alkyl, -S(O) ₂ (C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl C ₁ -C ₄ alkoxy, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case is selected from the group consisting of hydrogen C ₁ -C ₄ alkyl and ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ;

R ₂ is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC ₁ -C ₄ alkyl, -S(O)(C ₁ -C ₄ alkyl, -S(O) ₂ (C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl C ₁ -C ₄ alkoxy, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case is selected from the group consisting of hydrogen C ₁ -C ₄ alkyl and ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ;

R ₃ is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC ₁ -C ₄ alkyl, -S(O)(C ₁ -C ₄ alkyl, -S(O) ₂ (C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl C ₁ -C ₄ alkoxy, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case is selected from the group consisting of hydrogen C ₁ -C ₄ alkyl and ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ;

R ₄ is selected from the group consisting of halogen, cyano, -CHO, hydroxyl, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy-substituted C ₁ -C ₄ alkyl, benzyl optionally substituted with 1-5 halogen atoms, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), - N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -NH(4-7 membered heterocycloalkyl ), -N(C ₁ -C ₄ alkyl)(4-7-membered heterocycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkoxy), -C (O) NH (C ₁ -C ₄ alkyl), -C (O) N (C ₁ -C ₄ alkyl) ₂ , -NHSO ₂ (C ₁ -C ₄ alkyl ), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with the oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls; 6- or 10-membered aryl; and a monocyclic heterocycle selected from the group consisting of 4-7 membered heterocycloalkyl, 5-membered heteroaryl containing at least one nitrogen atom, through which the 5-membered heteroaryl ring is attached to the rest of the molecule; 6-membered heteroaryl containing at least one nitrogen atom; each of the aryl, heterocycloalkyl and heteroaryl rings in R ₄ is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl , C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ ,

-NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl,

-S(O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl; and where each C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₄ alkoxy in R ₄ may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl,

-NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , cyano, carboxyl, carbamoyl, C ₁ -C ₄ alkoxycarbonyl, -C (O) NH (C ₁ - C ₄ alkyl), -C(O)N(C ₁ -C ₄ alkyl) ₂ and C ₁ -C ₄ alkoxy;

R ₅ is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC ₁ -C ₄ alkyl, -S(O)(C ₁ -C ₄ alkyl, -S(O) ₂ (C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl C ₁ -C ₄ alkoxy, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case is selected from the group consisting of hydrogen C ₁ -C ₄ alkyl and ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ;

R ₆ is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC ₁ -C ₄ alkyl, -S(O)(C ₁ -C ₄ alkyl, -S(O) ₂ (C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl C ₁ -C ₄ alkoxy, -B(OR ₁₂ )(OR ₁₃ ), where R ₁₂ in each individual case is selected from the group consisting of hydrogen C ₁ -C ₄ alkyl and ₃ -C ₆ cycloalkyl, R ₁₃ in each case selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, or R ₁₂ and R ₁₃ together with oxygen atoms to which they are attached form a 5-7 membered ring which is optionally substituted with 1-4 C ₁ -C ₄ alkyls, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ;

R ₇ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl optionally substituted with 1-5 halogen atoms, -C(H)O, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ alkoxy;

R ₈ at each occurrence is independently selected from the group consisting of hydrogen, fluorine and C ₁ -C ₄ alkyl;

R ₉ at each occurrence is independently selected from the group consisting of hydrogen, fluorine and C ₁ -C ₄ alkyl;

R ₁₀ is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;

R ₁₁ is at each occurrence independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ ; And

Q is selected from the group consisting of 6- or 10-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl,

-NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl,

-S(O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl, where a 6- or 10-membered aryl is optionally fused to a 4-7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from the group, consisting of O, S and N, and where the carbon atoms of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heterocycloalkyl, if valence permits, substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; A 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O, S and N, and where the carbon atoms of the 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of from halogen, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl ) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heteroaryl, if valence permits, is optionally substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from the group consisting of O, S, N, where heterocycloalkyl is optionally benzo-fused, where carbon atoms of 4-7-membered heterocycloalkyl or optionally benzo-fused 4-7 -membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of from hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; 6- or 10-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -NH (C ₃ -C ₆ cycloalkyl), -N ( C ₁ -C ₄ alkyl) (C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S (O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl; 6- or 10-membered arylthiooxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -NH (C ₃ -C ₆ cycloalkyl), -N ( C ₁ -C ₄ alkyl) (C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S (O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl; and 5-10 membered heteroaryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl) (C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl , -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ haloalkyl and

-SO ₂ C ₁ -C ₄ haloalkyl;

with the exception of N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide compounds;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

4-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-1,6-naphthyridine-3-carboxamide;

8-bromo-N-[(4S)-chroman-4-yl]-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxamide;

4-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-1,6-naphthyridine-3-carboxamide;

4-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

4-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-1,5-naphthyridine-3-carboxamide;

4-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-1,5-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

8-chloro-4-(3,5-dichlorophenyl)-N-[(4S)-chroman-4-yl]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-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;

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;

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-yl]pyrido[3,2-d]pyridazine-7-carboxamide;

4-(2,3-dichlorophenyl)-N-[(4S)-chroman-4-yl]-8-(dimethylamino)-pyrido[3,2-d]pyridazine-7-carboxamide;

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-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3,5-trichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-fluoro-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-fluoro-4-(morpholin-4-yl)-1,7-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)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-fluoro-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-5-methoxy-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-5-methoxy-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-7-methoxy-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-7-methoxy-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-7-methoxy-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-7-methoxy-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(morpholin-4-yl)-1,6-naphthyridine-3-carboxamide;

N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-5-methoxy-4-(dimethylamino)-1,6-naphthyridine-3-carboxamide;

7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

7-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-chloro-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

7-methoxy-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-fluoro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;

7-methoxy-N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide;

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;

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-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-1,5-naphthyridine-3-carboxamide

or its salt.

In one embodiment, the present invention also provides compositions comprising a compound of formula (I) or a salt thereof and a suitable excipient, the composition optionally further comprising at least one additional active compound.

In one embodiment, the present invention also provides a method of treating parasites comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

In one embodiment, the present invention also provides a method of controlling parasites comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

In one embodiment, the present invention also provides a method of treating or controlling parasites, comprising contacting the subject's environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound. .

Thus, the present invention provides for the use of the compounds of the present invention as a medicinal product, including for the manufacture of a medicinal product. In one embodiment, the present invention provides for the manufacture of a medicament containing a compound of formula (I), or a salt thereof, for the treatment of parasites. In one embodiment, the present invention provides for the manufacture of a medicament containing a compound of formula (I) or a salt thereof, for the control of parasites.

The present invention also provides methods for preparing the compounds of the present invention and their intermediates.

DETAILED DESCRIPTION

The term "C ₁ -C ₄ alkyl" refers to a straight or branched chain alkyl having one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, and the like.

The term "C ₁ -C ₄ haloalkyl" refers to a straight or branched alkyl chain containing from one to four carbon atoms and 1-5 halogen atoms, and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2 ,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like.

The term "C ₂ -C ₄ alkenyl" refers to a straight or branched alkenyl chain containing two to four carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, etc. P.

The term "C ₂ -C ₄ alkynyl" refers to a straight or branched alkynyl chain containing two to four carbon atoms and one carbon-carbon triple bond, and includes acetylene, propargyl, and the like.

The term "C ₁ -C ₄ alkoxy" refers to C ₁ -C ₄ alkyl attached via an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

The term "C ₃ -C ₆ cycloalkyl" refers to an alkyl ring containing three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The terms "halogen" and "halo" refer to a chlorine, fluorine, bromine or iodine atom.

The term "C ₆ or C ₁₀ membered aryl" refers to phenyl or naphthyl.

The term "C ₆ or C ₁₀ membered aryloxy" refers to phenyl or naphthyl attached via an oxygen atom and includes phenoxy and naphthyloxy.

The term "C ₆ or C ₁₀ membered arylthiooxy" refers to phenyl or naphthyl attached via a sulfur atom and includes fentiooxy and naphthylthiooxy. Additionally, it should be understood that the term "C ₆ - or C ₁₀ -membered arylthiooxy" also covers compounds in which sulfur represents -SO ₂ - and -S(O)-.

The term "4-7 membered heterocycloalkyl" refers to a 4-7 membered monocyclic saturated or partially (but not completely) unsaturated ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the ring optionally includes carbonyl to form a lactam or lactone. It is understood that if sulfur is included, sulfur may be either -S-, -SO- or -SO ₂ -. For example, without limitation, the term includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like.

The term "5-membered heteroaryl" refers to a five-membered monocyclic fully unsaturated ring containing one to four carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For example, without limitation, the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like. It is understood that a 5-membered heteroaryl can be attached as a substituent via a ring carbon atom or a ring nitrogen atom if such an attachment method is available, for example, in the case of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and the like.

The term "6-membered heteroaryl" refers to a six-membered monocyclic fully unsaturated ring containing one to five carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For example, without limitation, the term includes pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, and the like. It is understood that a 6-membered heteroaryl can be attached as a substituent via a ring carbon atom or a ring nitrogen atom, if such an attachment method is available.

The term "5 to 10 membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O, S and N" refers to a five to ten membered monocyclic or polycyclic fully unsaturated ring or ring system containing from one to nine carbon atoms and one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For example, without limitation, the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benz isothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, quinazolyl, thienopyridyl, quinolyl, isoquinolyl, benzothiazolyl, and the like. It is understood that a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O, S and N may be substituted via a ring carbon atom or a ring nitrogen atom if such an attachment method is available.

The term "5-10 membered heteroaryloxy" refers to a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O, S, and N attached via an oxygen atom, and includes imidazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidyloxy, quinolyloxy, and the like.

The term "oxo" refers to an oxygen atom double bonded to the carbon to which it is attached to form a ketone or aldehyde carbonyl. For example, the pyridone radical is considered to be an oxo-substituted 6-membered heteroaryl.

The term "carboxyl" refers to the group below:

.

The term "carbamoyl" refers to the group below:

.

The term "C ₁ -C ₄ alkoxycarbonyl" refers to the group below:

where R represents C ₁ -C ₄ alkyl.

The term "absent" as used herein in relation to a group, substituent, fragment, or the like, indicates that such a group, substituent, or fragment is not present. If a group, substituent, or moiety is normally linked to two or more other groups, substituents, or moieties, then others are linked together instead of linked to a group, substituent, or moiety that is not present. For example, if the compound is characterized by the structure A-B-C; where B is absent, then A is directly connected to C and the connection is A-C. As another example, if the compound is characterized by the structure A-B-C; where C is absent, then the connection is A-B.

The term "salt" refers to salts of veterinarily or pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). An example is the hydrochloride salt.

The term "substituted", including when used in "optionally substituted", refers to one or more hydrogen radicals of a group that are replaced by radicals (substituent(s)) other than hydrogen. It is understood that the substituents may be either the same or different at each substituted position. The combinations of groups and substituents contemplated in the present invention are those that are stable or chemically feasible.

The term "stable" refers to compounds that do not change substantially when subjected to conditions that ensure their production. In a non-limiting example, a stable compound or chemically feasible compound is a compound that is substantially unchanged when stored at 40° C. or less in the absence of moisture or other conditions conducive to a chemical reaction for about a week.

It is understood that when the terms defined herein refer to the number of carbon atoms, that number refers to the specified group and does not include any carbon atoms that may be present in any optional substituent(s), or any carbon atoms that may be present as part of a fused ring, including a benzo-fused ring.

One skilled in the art will appreciate that some of the compounds of the present invention exist as isomers. All stereoisomers of the compounds of the present invention, including geometric isomers, enantiomers and diastereomers in any ratio, are considered to be within the scope of the present invention.

One skilled in the art will also appreciate that some of the compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the present invention are considered to be within the scope of the present invention.

The compounds of the present invention also include all isotopic variants in which at least one atom of the bulk of the atoms is replaced by an atom having the same atomic number but a different atomic mass from the bulk of the atoms. The use of isotopic variants (for example, deuterium,²H) can provide greater metabolic stability. Additionally, some isotopic variants of the compounds of the present invention may include a radioactive isotope (for example, tritium,³H, or¹⁴C), which may be applicable in drug and/or tissue distribution studies. Substitution with positron active isotopes such as^elevenc,¹⁸F,¹⁵O and¹³N, may be applicable in studies using positron emission tomography (PET).

The terms "compounds of the present invention" and "compound of the present invention" as well as "compounds of the present invention" and the like include an embodiment of formula (I) and other more specific embodiments encompassed by formula (I) described herein. document, and illustrative compounds described in this document, as well as the salt of each of these embodiments.

It will be understood that compounds in which one of Z ₁ and Z ₄ is O or S, Z ₂ is absent if Z ₁ is O or S, and Z ₃ is absent if Z ₄ is O or S, form compounds in which the thienyl or furyl ring is fused to a ring containing Y ₁ and Y ₂ .

A compound of formula (I) with defined G is characterized by the formula

.

Additional embodiments of the compounds of the present invention are provided below.

(a) One embodiment relates to a compound of formula (I).

(d) One embodiment relates to compounds of formula (I) wherein X ₁ is N; X ₂ is CR ₂ ;

X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is N; or its salt.

(e) One embodiment relates to compounds of formula (I) wherein X ₁ is CR ₁ ; X ₂ is CR ₂ ;

X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is N; and X ₆ is CR ₆ ; or its salt.

(f) One embodiment relates to compounds of formula (I) where X ₁ is CR ₁ ; X ₂ is CR ₂ ;

X ₃ is CR ₃ ; X ₄ is N; X ₅ is N; and X ₆ is N; or its salt.

(g) One embodiment relates to embodiments (a), (d), (e), and (f), where Q is a 6- or 10-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from a group consisting of halogen, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH (C ₁ - C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ haloalkyl And

-SO ₂ C ₁ -C ₄ haloalkyl; or its salt.

(h) One embodiment relates to embodiments (a), (d), (e), and (f), where Q is a 6-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of from halogen, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl ), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl, where a 6-membered aryl is fused with a 4-7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from the group consisting of O, S and N, and where the carbon atoms of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, - _NH2 ,

-NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in the heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; or its salt.

(i) One embodiment relates to embodiments (a), (d), (e) and (f), where Q is a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of O , S and N, and where the carbon atoms of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro,

-OH, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; or its salt.

(j) One embodiment relates to embodiments (a), (d), (e) and (f), where Q is a 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from the group consisting of O , S, N, where the heterocycloalkyl is optionally benzo-fused, wherein the carbon atoms 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 halo, cyano, nitro, hydroxyl, oxo , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl) and -N (C ₁ - C ₄ alkyl) ₂ , and any N in heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; or its salt.

(k) One embodiment relates to embodiments (a), (b), (c), (d), (e) and (f), where Q is a 6- or 10-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -NH (C ₃ -C ₆ cycloalkyl), -N (C ₁ -C ₄ alkyl) (C ₃ - C ₆ cycloalkyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S (O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S ( O)C ₁ -C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl; or its salt.

(l) One embodiment relates to embodiments (a), (d), (e), and (f), where Q is and 5-10 membered heteroaryloxy optionally substituted with 1, 2, or 3 substituents independently selected from a group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl),

-NHSO ₂ (C ₁ -C ₄ alkyl), -SC ₁ -C ₄ alkyl, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -S(O)C ₁ - C ₄ haloalkyl and -SO ₂ C ₁ -C ₄ haloalkyl; or its salt.

(m) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k) and (l), where n is 1; or its salt.

(n) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k), (l) and (m) where Y ₁ is CR ₈ R ₉ and Y ₂ is O; or its salt.

(o) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) and (n), where Z ₁ is CR ₁₁ , Z ₂ is CR ₁₁ , Z ₃ is CR ₁₁ and Z ₄ is CR ₁₁ ; or its salt.

(p) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) and (n), where Z ₁ is CR ₁₁ , Z ₂ is CR ₁₁ , Z ₃ is absent and Z ₄ is S; or its salt.

(q) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o) and (p), where R ₄ is selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -N(C ₁ -C ₄ alkyl) ₂ and 4-7 membered heterocycloalkyl; or its salt.

(r) One embodiment refers to embodiments (a), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o) and (p), where R ₄ represents -N(C ₁ -C ₄ alkyl) ₂ ; or its salt.

(s) Another embodiment relates to a salt of each of the exemplary compounds.

Compounds of the present invention can be obtained through various procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined.

The products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. Procedures may require the protection of certain groups, such as hydroxyl, thiol, amino or carboxy groups, to minimize unwanted reactions. The choice, application, and deprotection of protecting groups is widely known and appreciated as standard practice, for example, T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Chemistry (John Wiley and Sons, 1991).

Used in this document: AcOH stands for acetic acid; aq. is aqueous, br is broad, CH ₃ CN is acetonitrile, CH ₂ Cl ₂ is methylene chloride, d is a doublet,

dd stands for doublet of doublets, DIPEA stands for N-diisopropylethylamine, DMA stands for N,N-dimethylacetamide, DMF stands for N,N-dimethylformamide, DMSO stands for dimethyl sulfoxide, ee: stands for enantiomeric excess, eq. denotes equivalent, ES denotes electrospray ionization, EtOAc denotes ethyl acetate, EtOH denotes ethanol, HATU denotes 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium-3 hexafluorophosphate -oxide, HPLC stands for high performance liquid chromatography, iPrOH stands for isopropanol, J stands for coupling constant, KOAc stands for potassium acetate, K ₂ CO ₃ stands for potassium carbonate, LCMS stands for liquid chromatography-mass spectrometry, mass/charge: stands for the ratio of mass and charge, M is molarity, m is multiplet, MeOH is methanol, min is minutes, NaHCO ₃ is sodium bicarbonate, Na ₂ CO ₃ is sodium carbonate, NEt ₃ is triethylamine, NMR is nuclear magnetic resonance, NMP is N-methylpyrrolidone, q is quartet , rt denotes room temperature, R _t denotes retention time, s denotes singlet, sat. is saturated, T is temperature, t is triplet, dt is doublet of triplets, td is triplet of doublets, THF is tetrahydrofuran, weight is weight, and δ is chemical shift.

Scheme A

Scheme A shows the amidation reaction of a compound of formula (1) and a compound of formula (2) to give a compound of formula (I). The depicted compound of formula (1) is one in which the A ₁ group is a hydroxyl group or the activating groups discussed below and Q, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are as required in the final compound of formula (I), or is the group from which Q, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are derived as required in the final compound of formula (I). For example, the compound of formula (1) may be one in which the depicted group "Q" is a halogen, which is further changed, and in the subsequent step it is not shown, to obtain a compound in which Q is as defined in the formula ( I). The preparation of such compounds of formula (1) is well known in the art. The compound of formula (2) is one in which R ₇ , n, Y ₁ , Y ₂ , Z ₁ , Z ₂ , Z ₃ and Z ₄ are as required in the final product of formula (I), or represent a group, from which R ₇ , Y ₁ , Y ₂ , Z ₁ , Z ₂ , Z ₃ and Z ₄ are obtained as required in the final product of formula (I). The preparation of such compounds of formula (2) is well known in the art.

Scheme A above depicts the amidation of a compound of formula (1) using a compound of formula (2) to give a compound of formula (I). Typical A ₁ groups are a hydroxyl or leaving group such as chlorine, bromine, or imidazolyl, an activating moiety, a mixture of anhydrides of another carboxylic acid such as formic acid, acetic acid, or another part of a symmetrical anhydride formed from two compounds of formula ( 1). For example, standard conditions for amide formation can be used, such as using condensation aids, including those used in peptide condensation reactions, such as hexafluorophosphate methanamine 2-(1H-7-azabenzotriazol-1-yl)-1,1,3 ,3-tetramethyluronium (HATU), dicyclohexylcarbodiimide (DCC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. If necessary or required, an additive such as 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, and the like can be used. to facilitate the reaction. Such reactions are usually carried out using a base such as N-methylmorpholine or NEt ₃ in a wide variety of suitable solvents such as CH ₂ Cl ₂ , DMF, NMP, DMA, THF, etc. Such amide formation reactions are well understood and appreciated. in this field of technology.

A person skilled in the art will understand that the compound of formula (I) can be modified in various ways to obtain other compounds of formula (I). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (including heteroaryl groups), amidation species, sulfonation species, and the like.

Also, in an optional step not shown, the compounds of formula (I) may be converted to salts by methods well known and appreciated in the art.

Scheme B

Scheme B depicts the preparation of compounds of formula (1) in which X ₁ is N, X ₄ is CR ₄ , X ₅ is CR ₅ , where R ₅ is hydrogen; and X ₆ is N.

In step a of scheme B, a compound of formula (3) is contacted with a compound of formula (4) to give a compound of formula (5). The compound of formula (3) is a compound in which X ₂ and X ₃ are as required in the final compound of formula I, or form X ₂ and X ₃ as required in the final compound of formula I. The compound of formula (4) may vary from the depicted compound, eg the depicted dimethylamino group, and may be other disubstituted amines, such as diethylamino or pyrolidin-1-yl, and the ester may be other than the depicted ethyl, such as methyl or benzyl, and other variations.

Such reactions are generally carried out in a solvent such as CH ₂ Cl ₂ , CH ₃ CN, THF or DMF and the like, and the reaction can be carried out using a suitable base such as K ₂ CO ₃ , NaH, NEt ₃ or DIPEA etc. The reaction is usually carried out using 1-3 equivalents of the compound of formula (4). The reaction is generally carried out at temperatures ranging from 0° C. to 120° C. and takes from about 0.5 hour to 1 day.

In step b of scheme B, a compound of formula (5) is contacted with a compound of formula (6) to give a compound of formula (7). The compound of formula (6) is a compound in which G ₁ represents 1-3 substituents independently selected from the group consisting of halogen, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy. Such reactions are usually carried out in a solvent such as

Et ₂ O, EtOH, CH ₃ CN, THF or DMF, etc. The reaction is usually carried out using 1-3 equivalents of the compound of formula (6). The reaction is generally carried out at temperatures ranging from RT to 50° C. and takes from about 0.5 hour to 1 day.

In step c of scheme B, a compound of formula (7) was cyclized to give a compound of formula (8). Such reactions are generally carried out in a solvent such as CH ₃ CN, THF or DMF and the like, and the reaction can be carried out using a suitable base such as K ₂ CO ₃ , NEt ₃ or DIPEA and the like. The reaction is typically carried out at temperatures ranging from RT to 100° C. and takes from about 1 hour to 1 day.

In step d of scheme B, a compound of formula (8) was converted to a compound of formula (9). For example, a compound of formula (8) can undergo various substitution reactions, as well as amination, alkylation, alkoxylation, aryloxylation, arylthiooxylation, heteroaryloxylation, and arylation, including heteroarylation, to give a compound of formula (9). One particularly useful method uses boronic acid or a group Q boronic ester. The reactions are generally known as the Suzuki reaction and are well known in the art. Although the Suzuki reaction is indicated herein in Scheme B, it is known that other coupling reactions forming a carbon-carbon bond can be used with compounds of formula (8) to obtain compounds of formula (9).

In step e of scheme B, the protecting group of the compound of formula (9) is removed to give the compound of formula (10). Such deprotection reactions are widely known in the art.

In step f of Scheme BR ₄ the hydroxyl of a compound of formula (10) is converted to a halogen, typically chlorine, to give the depicted compound of formula (11). Such reactions are widely known and use halogenation reagents such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, phosphorus oxybromide, phosphorus pentachloride and phosphorus pentabromide. Such reactions are generally carried out in a solvent such as DMF and the like. The reaction is generally carried out at temperatures ranging from rt to rt. up to 50°C, and takes from about 0.5 hour to 1 day.

In step g of Scheme B, a compound of formula (11) in which R ₄ is halogen, typically depicted as chlorine, is modified to give a compound of formula (12) having different R ₄ groups. Such reactions include amination, alkoxylation, thioalkoxylation, carboxylation, alkylation, alkenylation, alkynylation and arylation, and the like. Such reactions are well known in the art.

In a step not shown in Scheme B, an ester of a compound of formula (12) is hydrolyzed to give a compound of formula (1) in which A ₁ is hydroxyl and X ₁ is N, X ₄ is CR ₄ , X ₅ is is CR ₅ where R ₅ is hydrogen; and X ₆ is N.

Scheme B, continued.

The order of some of the steps is not critical, as depicted in Scheme B, continuing above. In step h of scheme B, the protecting group of the compound of formula (8) is removed as described for step e above to give the compound of formula (13).

In step i of scheme BR ₄ the hydroxyl of a compound of formula (13) is converted to a halogen, typically the depicted chlorine, to give the depicted compound of formula (14) using a similar methodology as discussed in step f above.

In step j of scheme B, a compound of formula (14) in which R ₄ is halogen, typically depicted as chlorine, is modified to give a compound of formula (15) having different R ₄ as discussed in step g above.

In step k of scheme B, compounds of formula (15) were converted to a compound of formula (l) using the methodology from step d above.

In a step not shown in Scheme B, continued, an ester of a compound of formula (12) is hydrolyzed to give a compound of formula (1) in which A ₁ is hydroxyl and X ₁ is N, X ₄ is CR ₄ , X ₅ is CR ₅ where R ₅ is hydrogen; and X ₆ is N.

Scheme C

Scheme C depicts the preparation of compounds of formula (I) in which X₁ represents N,X₂ is a CR₂, where R₂ is hydrogen, X₃ is a CR₃, where R₃ is hydrogen, X₄ is a CR₄, Where R₄ is amino or substituted amino, and X₅ represents N.

In step a of scheme C, a compound of formula (16) was converted to a compound of formula (17). Such transformations are easily achieved using organometallic reagents or the action of malonate diesters, followed by hydrolysis and decarboxylation.

In step b of scheme C, a compound of formula (18) is obtained using a compound of formula (17). This reaction is carried out using an alkali metal cyanide salt such as sodium cyanide or potassium cyanide and the like, and is generally carried out in a solvent such as 1,4-dioxane, MeOH, toluene, CH ₃ CN, THF , DMF, etc. The reaction is usually carried out using 1-2 equivalents of an alkali metal cyanide compound. The reaction is generally carried out at temperatures ranging from RT to 150° C. and takes from about 2 hours to 1 day.

In step c of scheme C, the compound of formula (18) was subjected to homologue formation and cyclized to give the compound of formula (19). The formation of homologs can be carried out using N , N -dimethylformamide dimethyl acetal or its equivalents to obtain a compound such as 4-[( E )-2-(dimethylamino)vinyl]-5-nitro-pyridine-3-carbonitrile (not shown). Such reactions are generally carried out in a solvent such as CH ₂ Cl ₂ , CH ₃ CN, MeOH, THF, DMF, and the like. The reaction is usually carried out using 1-4 equivalents of N , N -dimethylformamide dimethyl acetal. The reaction is usually carried out at temperatures ranging from r.t. up to 60°C, and takes from about 1 hour to 1 day. The aminovinyl compound can then be cyclized under acidic conditions. Such cyclizations are generally carried out in a solvent such as acetic acid and the like, and the reaction can be carried out using a suitable acid such as hydrobromic acid, sulfuric acid and the like. The reaction is usually carried out at temperatures ranging from r.t. up to 150°C, and takes from about 0.5 hour to 6 hours.

In step d of scheme C, a compound of formula (19) was halogenated using the methodology from step f of scheme B to give a compound of formula (20).

In step e of scheme C, a compound of formula (20) was converted to a compound of formula (21) using the methodology from step d of scheme B.

In step f of scheme C, the compound of formula (21) was reduced to give the compound of formula (22). Such reduction of nitro groups to amines is widely known in the art. For example, hydrogenation over catalysts or the action of reducing agents such as iron.

In step g of scheme C, a compound of formula (22) was halogenated to give a compound of formula (23). Such halogenation reactions are widely known using reagents such as N-bromosuccinimide, bromine, and the like.

In step h of scheme C, a compound of formula (23) is converted to a compound of formula (I) in which R ₄ is amino. Such aminohomology or aminocabonylation carboxylation reactions are widely known in the art. Such reactions are carried out using carbon dioxide and carbon monoxide, amino formula (2) and various catalysts such as palladium, molybdenum and iron catalysts. The reactions are generally carried out in a solvent such as 1,4-dioxane, CH ₃ CN, THF, DMF, etc. The reaction is generally carried out at temperatures ranging from r.t. up to 150°C, and takes from about 2 hours to 1 day.

It is known that the compound of formula (23) and the compound of formula (I), in which R ₄ represents amino, can be converted into other compounds containing amino. For example, the amino group of a compound of formula (23) or a compound of formula (I) in which R ₄ is amino may be alkylated or cyclized to give heterocycloalkyl, or may be sulfonated.

As indicated above in a step not shown, the compound of formula (I) may be converted to its salt.

Scheme D

Scheme D depicts the preparation of compounds of formula (I) in which X₄ is a CR₄, Where R₄ is amino and X₅ represents N.

In step a of scheme D, a compound of formula (24) was converted to a compound of formula (25) using the methodology from step d of scheme B.

In step b of scheme D, a compound of formula (25) was converted to a compound of formula (26) using the methodology from step g of scheme C above.

In step c of scheme D, a compound of formula (26) was aminocarboxylated to give a compound of formula (27). Such reactions, well known in the art, are carried out using catalysts such as palladium catalysts and t-butyl carbamate and the like. The reaction is generally carried out using a solvent such as 1,4-dioxane, THF, CH ₂ Cl ₂ , CH ₃ CN, MeOH, DMF, toluene, and the like. The reaction is carried out using a base such as Cs ₂ CO ₃ , NEt ₃ , K ₂ CO ₃ , KOAc, NaHCO ₃ and the like. The reaction is carried out at temperatures ranging from 40°C to 120°C, and, as a rule, it takes from about 1 hour to 2 days.

Step d of Scheme D depicts deprotection of a compound of formula (27) to give a compound of formula (28). Such acid deprotections are well known in the art.

In step e of Scheme C, a compound of formula (28) was brominated using the methodology from step g of Scheme C to give a compound of formula (29).

In step (f) of scheme D, a compound of formula (29) was converted to a compound of formula (I) wherein R ₄ is amino using the methodology from step h of scheme C.

It is known that a compound of formula (29) and a compound of formula (I) in which R ₄ is amino can be converted to other compounds of formula (I) containing amino.

As indicated above in an optional step which is not shown, the compound of formula (I) may be converted to its salt.

The following examples are intended to be illustrative and non-limiting and are specific embodiments of the present invention.

Analysis methods A and B were performed using an Agilent 1200 Infinity Series liquid chromatography (LC) system, consisting of a HiP 1260 degasser (G4225A), a 1260 two-component pump (G1312B), a 1290 autosampler (G4226A), a temperature-compensated column compartment 1290 (G1316C) and a 1260 diode array detector (G4212B) attached to an Agilent 6150 single quadrupole mass spectrometry (MS) detector. The injection volume was set to 1 µl by default. Detection using UV (DAD) was performed at 40 Hz with scanning in the range of 190-400 nm (in 5 nm steps). A 1:1 flow split was applied before the MS detector. MS was performed with an electrospray ionization (ESI) source in both positive and negative ion mode. The pressure in the nebulizer was set to 50 psi. inch, drying gas temperature and flow at 350°C and 12 l/min respectively. Capillary voltages used were 4000 V in positive mode and 3500 V in negative mode. The MS detection range was set to 100-800 mass/charge with a step size of 0.2 mass/charge in both polarity modes. Fragmenter voltage was set to 70 (ESI+) or 120 (ESI-), gain to 0.40 (ESI+) or 1.00 (ESI-), and ion threshold to 4000 (ESI+) or 1000 (ESI-). The time for a complete MS scan cycle was 0.15 s/cycle. Data extraction was performed using the Agilent Chemstation software.

Method A. Analyzes were performed on a Phenomenex Gemini-NX C18 column, 50 mm long, 2.1 mm ID, and 3 µm particle size. The mobile phase used was: A1=water with 0.1% formic acid/B1=CH ₃ CN with 0.1% formic acid. The analysis was carried out at a temperature of 50°C and a flow rate of 1.2 ml/min, eluting in a gradient of 5% to 95% (B1) for 1.5 min followed by a hold at 95% (B1) within 0.5 min.

Method B. Analyzes were performed on a Waters XBridge C18 column, 50 mm long, 2.1 mm ID, and 3.5 µm particle size. The mobile phase used was: A2=water with 10 mM ammonium bicarbonate adjusted to pH 9 with ammonium hydroxide/B2=CH ₃ CN. The assay was run at a temperature of 50°C and a flow rate of 1.2 ml/min eluting with a gradient of 5% to 95% (B2) over 1.5 min followed by a hold at 95% (B2) within 0.5 min.

Analysis methods C and D were performed using a Waters Acquity UPLC (LC) liquid chromatography system attached to a Waters SQ Detector 2 single quadrupole mass spectrometry (MS) detector. 400 nm (with 1.2 nm resolution). MS was performed with an electrospray ionization (ESI) source in both positive and negative ion mode. Capillary voltage 3.50 (kV), cone voltage 35 (V) and desolvation temperature 550°C. Desolvation gas flow 1000 l/h, cone gas flow 50 l/h. The MS detection range was set to 100-1500 mass/charge. The MS scan cycle time was 0.5 s. Data extraction was performed using Waters Masslynx software.

Method C: Analyzes were performed on an Acquity UPLC BEH C18 column, 50 mm long, 2.1 mm id, and 1.7 km particle size. The mobile phase used was: A1=water with 0.1% formic acid/B1=CH₃CN with 0.1% formic acid. The injected volume was 0.1 μl. The analysis was carried out at a temperature of 40°C and a flow rate of 0.6 ml/min, eluting in a gradient. Method information (time (min) and B%): 0-5; 0.3-5; 2.5-95; 3.7-95; 4-5; 4.6-5.

Method D. Analyzes were performed on an Acquity UPLC BEH C18 column, 50 mm long, 2.1 mm id, and 1.7 µm particle size. The mobile phase used was: A1=water with 10 mM ammonium acetate/B1=CH₃CN with 0.1% formic acid. The injected volume was 0.1 μl. The analysis was carried out at a temperature of 45°C and a flow rate of 0.5 ml/min, eluting in a gradient. Method information (time (min) and A%): 0-98; 0.3-98; 3.2-2; 4.4-2; 4.7-98.

Example 1.1

N-[(4S)-Chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide

A mixture of 2-chloro-3-fluoro-pyridine-4-carboxylic acid (10.1 g, 56.3 mmol) and SOCl ₂ (40 ml, 547 mmol) was heated at 80°C for 2 hours. The reaction mixture was allowed to cool to rt and concentrated in vacuo . It was used directly in the next step: toluene (145 ml) and NEt ₃ (9.8 ml, 70 mmol) were added followed by the addition of ethyl 3-(dimethylamino)-prop-2-enoate (10.2 g, 69.6 mmol). The reaction mixture was heated at 80°C and stirred for 45 min. The mixture was allowed to cool to rt and filtered through Celite® (washing with EtOAc). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc and aq. 2 M HCl (150 ml each). The layers were separated and aq. the layer was extracted with EtOAc (150 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate. LCMS (method B): R _t =0.86 minutes, mass/charge = 301.00 [M+H] ⁺ .

To a solution of ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate (188 mg, 0.59 mmol) in Et ₂ O (2.4 ml) and EtOH (0.6 ml) was added 4-methoxybenzylamine (94 μl, 0.71 mmol). The reaction mixture was stirred at rt. within 15 min with the formation of a precipitate. The reaction mixture was concentrated in vacuo . The residue was triturated with cyclohexane to give ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)-methyl-amino]-prop-2-enoate. LCMS (method B): R _t =1.21 minutes, mass/charge = 393 [M+H] ⁺ .

To a solution of ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)-methyl-amino]-prop-2-enoate (214 mg, 518 µmol) in DMF (2.6 ml) was added K ₂ CO ₃ (230 mg, 1.66 mmol) at rt. The reaction mixture was heated at 40° C. and stirred for 2 hours. After cooling to rt. the reaction mixture was poured into ice water (20 ml) with the formation of a thin layer of precipitate. The precipitate was dissolved in EtOAc (20 ml) and the layers were separated. Water layer was extracted with EtOAc (2×10 ml) and the combined organic layers were washed with water (20 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to obtain ethyl-8-chloro-1-[(4-methoxyphenyl)- methyl]-4-oxo-1,7-naphthyridine-3-carboxylate. LCMS (method B): R _t =1.01 minutes, mass/charge = 373 [M+H] ⁺ .

(3,5-Dichlorophenyl)-boronic acid (110 mg, 0.56 mmol) was mixed with a complex of 1,1'-bis(diphenylphosphino)-ferrocene-Pd(II) CH ₂ Cl ₂ and Na ₂ CO ₃ (100 mg, 0.93 mmol). The vial was hermetically sealed, then pumped out and again filled with N ₂ . Ethyl 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate (186 mg, 0.47 mmol) in 1,4-dioxane (2, 4 ml, 28 mmol) followed by the addition of water (0.8 ml, 40 mmol) and the reaction mixture was heated at 100°C in a microwave oven for 1 hour. The reaction mixture was filtered through Celite® (washing with EtOAc). The filtrate was washed with water (20 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo then purified by column chromatography to give ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl) methyl]-4-oxo-1,7-naphthyridine-3-carboxylate. LCMS (method B): R _t =1.30 minutes, mass/charge = 483 [M+H] ⁺ .

To a solution of ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate (877 mg, 1.72 mmol) in CH ₂ Cl ₂ (9 ml) was added anisole (1 ml, 1.74 mmol), followed by the addition of TFA (2.5 ml, 33 mmol). The resulting reaction mixture was stirred at room temperature. within 1 hour prior to in vacuo concentration. A mixture of sat. aq. NaHCO ₃ and EtOAc (25 ml each) were added to the crude product and the resulting suspension was vigorously stirred for 15 minutes. The precipitate was isolated by filtration (washing with water then EtOAc) and dried in a vacuum oven to give ethyl 8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate. LCMS (method B): R _t =0.9 minutes, mass/charge = 363 [M+H] ⁺ .

Oxalyl _{chloride (} 17 μl, 192 μmol) followed by the addition of DMF (1 μl, 13 μmol) and the resulting mixture was stirred at rt. within 45 min. The reaction mixture was quenched by adding sat. NaHCO ₃ solution (5 ml) and the mixture was divided between water and CH ₂ Cl ₂ (10 ml each). The layers were separated. The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give ethyl 4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate. LCMS (method B): R _t =1.6 minutes, mass/charge = 381 [M+H] ⁺ .

To ethyl 4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate (59 mg, 0.12 mmol) was added dimethylamine HCl (17 mg, 0.2 mmol) in 1 4-dioxane (0.5 ml). The vial was sealed, DIPEA (73 μl, 0.41 mmol) was added and the reaction mixture was heated in a microwave oven at 100°C for 30 min. The mixture was diluted with EtOAc (10 ml), washed with aq. sat. NaHCO ₃ solution (10 ml) and brine (10 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7- naphthyridine-3-carboxylate. LCMS (method B): R _t =1.5 minutes, mass/charge = 390 [M+H] ⁺ .

To a stirred solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate (556 mg, 1.35 mmol) in THF (14 ml) was added a solution of lithium hydroxide ( 99 mg, 4.05 mmol) in water (4.5 ml) and MeOH (4.5 ml). The reaction mixture was heated at 40° C. for 2 hours and allowed to stir at rt. during the night. The mixture was then concentrated in vacuo and the residue was dissolved in water (25 ml). Water the layer was washed with EtOAc (25 ml), then brought to pH 4 by adding aq. 2 M HCl to form a suspension. The precipitate was isolated by filtration and dried in a vacuum oven overnight to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylic acid as a solid. LCMS (method B): R _t =0.78 minutes, mass/charge = 362 [M+H] ⁺ .

DIPEA (441 µl, 2 .50 mmol). HATU (282 mg, 0.72 mmol) was added and the reaction mixture was allowed to stir for 10 minutes. (4S)-chroman-4-amine HCl (156 mg, 0.81 mmol) was added and the reaction mixture was allowed to stir at rt. within 3 hours before concentrating the mixture in vacuo to give a residue. The residue was partitioned between EtOAc and sat. aq. NaHCO ₃ (20 ml each). The layers were separated and the organic layer was washed with aq. 1 M HCl (20 ml), brine (20 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography to give the title compound. LCMS (method B): R _t =1.41 minutes, mass/charge = 493 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.18 (d, J= 8.4 Hz, 1 H), 8.7 (s, 1 H), 8.65 (d, J= 5.6 Hz, 1 H), 8.09 (d, J= 2 Hz, 2 H), 8.07 (d, J= 6 Hz, 1 H), 7.73 (t, J= 2 Hz, 1 H), 7.38 (d, J= 7.6 Hz, 1 Hz), 7.18 (td, J= 8.4, 1.6 Hz, 1 H), 6.93 (td, J= 7.6, 1.2 Hz, 1 H), 6.8 (dd, J= 8.4, 0.8 Hz, 1 H), 5.24 (q, J= 6 Hz, 1 H) , 4.26(m, 2H), 3.11(s, 6H), 2.14(m, 2H).

The following compounds were obtained similarly, following the methodology of example 1.1.

Examples 1.2 and 1.3 were separated using SFC. Separation was performed on an AD-H Chiralpak® with a 250 mm x 30 mm (5 μm) column and a flow rate of 90 g/min. and a CO ₂ based mobile phase with 35% iPrOH containing 0.2% N , N -dimethylethylamine as an additive.

Example 2.1

N-[(4S)-Chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)isoquinoline-3-carboxamide

A mixture of 8-bromoisoquinoline (0.5 g, 2.43 mmol), (3,5-dichlorophenyl)boronic acid (0.46 g, 2.41 mmol), K ₂ CO ₃ (2.8 g, 20.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.12 mmol) were placed under N ₂ atmosphere and treated with 1,2-dimethoxyethane (8.69 g, 96.4 mmol) and water ( 10 ml). The reaction vessel was evacuated three times and refilled with N ₂ . The reaction mixture was then heated at 90°C for 2 hours. The mixture was cooled down to rt. before dilution with water (20 ml) and extracted with CH ₂ Cl ₂ (2 x 20 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo to give a residue which was purified by column chromatography to give 8-(3,5-dichlorophenyl)isoquinoline. LCMS (method B): R _t =1.36 minutes, mass/charge = 273.8 [M+H] ⁺ .

A mixture of 8-(3,5-dichlorophenyl)isoquinoline (0.56 g, 1.95 mmol) and N-bromosuccinimide (0.54 g, 2.94 mmol) was placed under N ₂ and treated with acetic acid (9 ml, 157.1 mmol). The resulting mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was allowed to cool to rt before being poured into water (60 ml) and extracted with CH ₂ Cl ₂ (3 x 30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo to give a residue which was purified by column chromatography to give 4-bromo-8-(3,5-dichlorophenyl)isoquinoline. LCMS (method B): R _t =1.57 minutes, mass/charge = 351.8 [M+H] ⁺ .

A mixture of 4-bromo-8-(3,5-dichlorophenyl)isoquinoline (0.46 g, 1.246 mmol), Cs ₂ CO ₃ (0.82 g, 2.53 mmol), tert-butyl carbamate (0.44 g, 3.8 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Xantphos Pd G3, 70 mg, 74 μmol) was placed under N ₂ atmosphere and treated with 1,4-dioxane (6.5 ml). The reaction vessel was evacuated three times and refilled with N ₂ . The resulting mixture was heated at 100°C for 5 hours. Then the mixture was cooled down to rt. before dilution with sat. aq. NaHCO ₃ (20 ml) and extracted with CH ₂ Cl ₂ (3×25 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography to give tert -butyl-N-[8-(3,5-dichlorophenyl)-4-isoquinolyl]carbamate. LCMS (method B): R _t =1.42 minutes, mass/charge = 389 [M+H] ⁺ .

A suspension of tert-butyl N-[8-(3,5-dichlorophenyl)-4-isoquinolyl] carbamate (0.48 g, 0.93 mmol) in CH ₂ Cl ₂ (5 mL) was placed under N ₂ and treated with TFA (2 ml, 26.45 mmol). The resulting solution was stirred at room temperature. within 2 hours. The reaction mixture was then concentrated in vacuo . The residues were diluted with sat. aq. NaHCO ₃ (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give 8-(3,5-dichlorophenyl)isoquinoline-4-amine. LCMS (method B): R _t =1.17 minutes, mass/charge = 289 [M+H] ⁺ .

A solution of 8-(3,5-dichlorophenyl)isoquinoline-4-amine (0.2 g, 0.65 mmol) in DMF (5 ml) was placed under N ₂ , cooled to 0° C. in an ice bath and treated with N-bromosuccinimide (0.12 g, 0.65 mmol). The resulting mixture was stirred for 30 min at 0°C. The mixture was then poured into water (30 ml) and extracted with EtOAc (3×25 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The residue was purified by column chromatography to give 3-bromo-8-(3,5-dichlorophenyl)isoquinoline-4-amine. LCMS (method B): R _t =1.4 minutes, mass/charge = 366.8 [M+H] ⁺ .

A suspension of 3-bromo-8-(3,5-dichlorophenyl)isoquinoline-4-amine (0.15 g, 0.4 mmol) in formic acid (1.2 ml, 31 mmol) was placed under N ₂ before treatment with using formaldehyde solution (37 wt.% in water, 1.8 ml, 24.2 mmol). The resulting suspension was heated at 100°C for 3 hours. Then the reaction mixture was cooled down to rt. before careful pouring into sat. aq. NaHCO ₃ (25 ml) and extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic layers were evaporated to give a residue which was purified by column chromatography to give 3-bromo-8-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-4-amine. LCMS (method B): R _t =1.72 minutes, mass/charge=394.8 [M+H] ⁺ .

Suspension of (4S)-chroman-4-amine HCl (67 mg, 0.36 mmol) and 3-bromo-8-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-4-amine (0.12 g , 0.29 mmol) in 1,4-dioxane (10 ml) was treated with NEt ₃ (0.08 ml, 0.57 mmol) and methanesulfonate [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene )-2-(2′-amino-1,1′-biphenyl)]palladium(II) (Xantphos Pd G3, 17 mg, 170 µmol), before allowing stirring at 70° C. under CO (275 kPa) for night. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to give the title compound. LCMS (method B): R _t =1.60 minutes, mass/charge = 492.0 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.90 (d, J= 8.4 Hz, 1 H), 8.80 (s, 1 H), 8.36 (d, J= 8.6 Hz, 1 H), 7.90 (dd, J= 8.6, 7.2 Hz, 1 H), 7.77 (t, J= 2 Hz, 1 H), 7.68 (d, J= 7 Hz, 1 H), 7.62 (d, J= 2 Hz, 2 H), 7.31 (d, J= 7.6 Hz, 1 H), 7.16 (m, 1 H), 6.91 (m, 1 H), 6.87 (dd, J= 8.2, 0.8 Hz, 1 H), 5.31 (m, 1 H), 4.27 (m , 2H), 2.976(s, 6H), 2.17(m, 1H), 2.07(m, 1H).

Example 3.1

N-[(4S)-Chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-2,7-naphthyridine-3-carboxamide

A suspension of NaH (60% in mineral oil, 1.76 g, 44 mmol) in THF (26 ml) was placed under N ₂ atmosphere, cooled to 0° C. in an ice bath and treated slowly with malonic ether (6.4 ml, 42 mmol). The resulting mixture was allowed to stir at 0° C. for 15 minutes before being batch-treated with 3-bromo-4-chloro-5-nitropyridine (5.01 g, 21.1 mmol). The ice bath was removed and the resulting reaction mixture was allowed to stir for 30 min at room temperature. The mixture was then poured into ice-cold aq. NH ₄ Cl (80 ml) and extracted with EtOAc (3×60 ml). The combined organic layers were washed with brine (60 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give diethyl 2-(3-bromo-5-nitro-4-pyridyl)propanedioate (9.53 g, 21. 1 mmol), which was then treated with HCl (5 M) in water (60 ml). The resulting mixture was heated at reflux overnight. The reaction mixture was cooled down to rt. before cooling on ice and making alkaline by adding dropwise 50% NaOH solution (15 ml). Received aq. the layer was extracted with EtOAc (3×60 ml). The combined organic layers were washed with brine (80 ml) and concentrated in vacuo to give a residue which was purified by column chromatography to give 3-bromo-4-methyl-5-nitropyridine. LCMS (Method B): R _t =0.93 minutes, no significant ion mass observed.

3-Bromo-4-methyl-5-nitropyridine mixture (4.39 g, 20.2 mmol), Cyanation Kit J (J. Org. Chem. 2018, 83, 4922-4931) (5.03 g, 20. 4 mmol) and KOAc (1 g, 10.16 mmol) were placed under N ₂ atmosphere, stirred with 1,4-dioxane (20 ml) and degassed water (20 ml). The reaction vessel was evacuated three times and refilled with N ₂ . The mixture was then heated at 90° C. for 3 hours. The reaction mixture was cooled down to rt. before pouring into water (150 ml) and extracted with EtOAc (3 x 70 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The resulting residue was purified by column chromatography to give 4-methyl-5-nitropyridine-3-carbonitrile. LCMS (method B): R _t =0.94 min, mass/charge = no significant ion mass observed.

To a solution of 4-methyl-5-nitropyridine-3-carbonitrile (49 mg, 0.27 mmol) in CH ₂ Cl ₂ (0.7 ml) under N ₂ was added DMF-DMA (75 μl, 0.56 mmol) and the resulting mixture was stirred for 2 hours at 40°C. The reaction mixture was allowed to cool to rt, then concentrated in vacuo to give 4-[(E)-2-(dimethylamino)vinyl]-5-nitropyridine-3-carbonitrile (63 mg, 0.27 mmol) which was treated with acetic acid (0.75 ml, 13 mmol) and HBr (5.02 mol/l) in acetic acid (1.10 ml, 5.52 mmol) under N ₂ and the mixture was then heated at 60° C. within 45 min. After this time, the mixture was slowly added to a stirred aq. NaHCO ₃ solution (40 ml) and then extracted with EtOAc (3 × 15 ml). The combined organic layers were evaporated to give a residue which was purified by column chromatography to give 1-bromo-5-nitro-2,7-naphthyridine. LCMS (method B): R _t =0.51 minutes, mass/charge = 192.0 [M+H] ⁺ .

A mixture of 5-nitro-2H-2,7-naphthyridin-1-one (0.23 g, 1.18 mmol) and POBr ₃ (1.71 g, 5.96 mmol) in a microwave vial was placed under N ₂ and diluted with CH ₃ CN (4 ml). The resulting mixture was subjected to microwave radiation at 130°C for 1 hour. The reaction mixture was then poured into water (20 ml) and extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The resulting residue was purified by column chromatography to give 1-bromo-5-nitro-2,7-naphthyridine. LCMS (method B): R _t = 0.82 minutes, mass/charge = no significant ion mass observed.

From a sealed microwave vial containing a mixture of 1-bromo-5-nitro-2,7-naphthyridine (48 mg, 0.18 mmol), (3,5-dichlorophenyl)boronic acid (46 mg, 0.24 mmol ), chlorine(crotyl)(tri-tert-butylphosphine)Pd (II)) (5.5 mg, 13 μmol) and KF (35 mg, 0.6 mmol) were pumped out and refilled with N ₂ . The mixture was mixed with THF (0.60 ml) and then subjected to microwave radiation at 100° C. for 90 minutes. The mixture was filtered through Celite® (with washing with CH ₂ Cl ₂ ), diluted with water (30 ml) and extracted with CH ₂ Cl ₂ (4×20 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The residue was purified by column chromatography to give 1-(3,5-dichlorophenyl)-5-nitro-2,7-naphthyridine. LCMS (method B): R _t =1.29 minutes, mass/charge = 319.8 [M+H] ⁺ .

A mixture of 1-(3,5-dichlorophenyl)-5-nitro-2,7-naphthyridine (0.24 g, 0.46 mmol), NH ₄ Cl (84 mg, 1.565 mmol) and iron (85 mg, 1.49 mmol) was placed under N ₂ atmosphere and mixed with THF (2.5 ml), EtOH (2.5 ml) and water (1.2 ml) The reaction mixture was heated at 75°C and stirred for 20 min. cooling the mixture to rt before filtering through Celite® The filtrate was concentrated in vacuo to give a residue which was purified by column chromatography to give 8-(3,5-dichlorophenyl)-2,7-naphthyridine-4-amine LCMS (method B): R _t =1.01 minutes, mass/charge = 290.0 [M+H] ⁺ .

Under N ₂ in a salt/ice bath, a solution of 8-(3,5-dichlorophenyl)-2,7-naphthyridine-4-amine (0.1 g, 0.32 mmol) in DMF (2 mL) was treated with N-bromosuccinimide (57 mg, 0.32 mmol) followed by stirring for 75 minutes. After this time, the mixture was poured into water (25 ml) and extracted with CH ₂ Cl ₂ (3×20 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The resulting residue was purified by column chromatography to give 3-bromo-8-(3,5-dichlorophenyl)-2,7-naphthyridine-4-amine. LCMS (method B): R _t =1.25 minutes, mass/charge = 367.8 [M+H] ⁺ .

3-Bromo-8-(3,5-dichlorophenyl)-2,7-naphthyridine-4-amine (85 mg, 0.22 mmol) was treated with formic acid (0.6 ml, 15.9 mmol) and formaldehyde (37 wt.% solution in water, 1 ml, 13.4 mmol) under N ₂ atmosphere. The resulting suspension was heated at 120°C for 5 hours. Then the mixture was cooled down to rt. before pouring into sat. aq. NaHCO ₃ (20 ml) and extracted with CH ₂ Cl ₂ (4×10 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography to give 3-bromo-8-(3,5-dichlorophenyl)-N,N-dimethyl-2,7- naphthyridine-4-amine. LCMS (method B): R _t =1.56 minutes, mass/charge = 396 [M+H] ⁺ .

Mixture of (4S)-chroman-4-amine⋅HCl (37 mg, 0.2 mmol), 3-bromo-8-(3,5-dichlorophenyl)-N,N-dimethyl-2,7-naphthyridine-4- amine (67 mg, 0.16 mmol) and NEt ₃ (50 μl, 0.36 mmol) in 1,4-dioxane (6 ml) were treated with methanesulfonate [(4,5-bis(diphenylphosphino)-9.9 -dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (Xantphos Pd G3, 8 mg, 8 µmol). The reaction mixture was then allowed to stir at 100° C. under a CO atmosphere (380 kPa) overnight. The reaction mixture was cooled down to rt. The reaction mixture was concentrated in vacuo . The residues were subjected to column chromatography. LCMS (method B): R _t = 1.47 minutes, mass/charge = 493 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.03 (d, J= 8.4 Hz, 1 H), 9.02 (s, 1 H), 8.85 (d, J= 5.9 Hz, 1 H), 8.15 (d, J= 5.6 Hz, 1 H), 7.86 (t, J= 2 Hz, 1 H), 7.80 (d, J = 1.8 Hz, 2 H), 7.31 (d, J= 7.2 Hz, 1 H), 7.17 (td, J= 7.2, 1.2 Hz, 1 H), 6, 92 (td, J= 7.4, 1 Hz, 1 H), 6.79 (d, J= 7.4 Hz, 1 H), 5.30 (m, 1 H), 4.273 (t, J= 5.3 Hz, 2 H), 2.98 (s, 6 H), 2.18 (m, 1 H), 2.07 (m, 1 H).

Example 4.1

N-[(4S)-Chroman-4-yl]-1-(3,5-dichlorophenyl)-5-(dimethylamino)isoquinoline-6-carboxamide

1-chloroisoquinoline (1.08 g, 5.94 mmol) in a microwave vial was treated with sulfuric acid (17.8 mol/l) in water (15 ml) and nitric acid (0.1 mol/l) in water ( 0.65 ml) to ensure stirring for 20 minutes at rt. The reaction mixture was slowly added to a stirred sat. aq. NaHCO ₃ solution. Water the phase was extracted with CH ₂ Cl ₂ (3×30 ml). The combined organic layers were filtered and concentrated in vacuo to give 1-chloro-5-nitroisoquinoline. LCMS (method B): R _t =1.01 minutes, mass/charge = 208.8 [M+H] ⁺ .

From a sealed microwave vial containing a mixture of 1-chloro-5-nitroisoquinoline (0.7 g, 3.02 mmol), (3,5-dichlorophenyl)boronic acid (0.53 g, 2.72 mmol), Na ₂ CO ₃ (0.64 g, 6.05 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (0.12 g, 0.15 mmol) were pumped out and again filled with N ₂ . The mixture was treated with 1,4-dioxane (13.5 ml) and degassed water (5 ml) before being microwaved at 80° C. for 30 minutes. The reaction mixture was treated with CH ₂ Cl ₂ (40 ml) and water (40 ml) and the two layers were separated. Water the phase was extracted with additional CH ₂ Cl ₂ (3×15 ml) and the combined organic layers were filtered and concentrated in vacuo . The residues were subjected to column chromatography (eluting with 0-40% t- butyl methyl ether in cyclohexane) to give 1-(3,5-dichlorophenyl)-5-nitroisoquinoline. LCMS (method B): R _t =1.40 min, mass/charge = 319.0 [M+H] ⁺ .

A mixture of 1-(3,5-dichlorophenyl)-5-nitroisoquinoline (0.68 g, 2.02 mmol), NH ₄ Cl (0.33 g, 6.17 mmol) and iron (0.361 g, 6.33 mmol ) in the flask was placed under N ₂ atmosphere and dissolved in THF (10 ml), EtOH (10 ml) and water (5 ml). The resulting suspension was heated to 75°C and stirred for 20 minutes. The reaction mixture was cooled down to rt. before filtering through Celite® and concentrated in vacuo . The residues were treated with 5% MeOH in CH ₂ Cl ₂ and the resulting precipitate was filtered and dried under vacuum to give 1-(3,5-dichlorophenyl)isoquinoline-5-amine. LCMS (method B): R _t =1.24 min, mass/charge = 289.0 [M+H] ⁺ .

A suspension of 1-(3,5-dichlorophenyl)isoquinoline-5-amine (0.45 g, 1.43 mmol) in DMF (6 ml) in a flask was placed under N ₂ atmosphere, cooled in an ice/brine bath and treated with N-bromosuccinimide (0.26 g, 1.44 mmol). Provided stirring the resulting dark brown solution at -10°C for 1 hour. Water and CH ₂ Cl ₂ were added (10 ml each). Two phases were extracted with additional CH ₂ Cl ₂ (3×10 ml). The combined organic phases were filtered and concentrated in vacuo . The residues were subjected to column chromatography (0-50% EtOAc in cyclohexane) to give 6-bromo-1-(3,5-dichlorophenyl)isoquinoline-5-amine. LCMS (method B): R _t =1.44 min, mass/charge = 366.8 [M+H] ⁺ .

A solution of 6-bromo-1-(3,5-dichlorophenyl)isoquinoline-5-amine (0.39 g, 0.96 mmol) in formic acid (2.3 ml, 61 mmol) in a flask was placed under N ₂ and treated with a solution of formaldehyde (37 wt.% in water) (4.7 g, 58 mmol, 4.3 ml). The resulting mixture was heated to 100° C. and stirred for 2.5 hours. The reaction mixture was cooled to RT before quenching with sat. aq. NaHCO ₃ (30 ml) and extracted with CH ₂ Cl ₂ (3×0 ml). The combined organic layers were filtered and concentrated in vacuo . The residues were subjected to column chromatography (0-20% tert -butyl methyl ether in cyclohexane) to give 6-bromo-1-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-5-amine. LCMS (method B): R _t =1.73 min, mass/charge = 395.0 [M+H] ⁺ .

Solution of 6-bromo-1-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-5-amine (0.36 g, 0.81 mmol), (4S)-chroman-4-amine⋅HCl (0. 18 g, 0.99 mmol) and NEt ₃ (0.23 ml, 1.65 mmol) in 1,4-dioxane (11 ml) in a flask was treated with methanesulfonate [(4,5-bis(diphenylphosphino)-9 ,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (Xantphos Pd G3, (0.048 g, 0.048 mmol) before stirring under CO (379 kPa) at 100 °C overnight The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml) The combined organic layers were washed with brine (30 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . the residue was purified by column chromatography to give the title compound LCMS (method B): R _t = 1.50 min, mass/charge = 492.0 [M+H] ^{+ .1} H-NMR (400 MHz, DMSO -d ₆ ) δ [ppm]: 9.10 (d, J=8.20 Hz, 1 H), 8.63 (d, J= 5.9 Hz, 1 H), 8.12 (d, J = 5.9 Hz, 1 H), 7.81 (t, J= 2.0 Hz, 1 H), 7.69-7.67 (m, 3 H), 7.54 (d, J= 8 .6 Hz, 1 H), 7.34 (d, J= 7.2 Hz, 1 H), 7.17 (td, J= 8.4, 1.2 Hz, 1 H), 6.93 ( td, J= 7.4, 1 Hz, 1 H), 6.81-6.79 (m, 1 H), 5.29-5.25 (m, 1 H), 4.30-4.23 (m, 2H), 2.97 (s, 6H), 2.24-2.18 (m, 2H).

Example 5.1

(4S)-Chroman-4-yl]-5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxamide

A mixture of 1-bromo-5-nitronaphthalene (1.04 g, 4.13 mmol), (3,5-dichlorophenyl)boronic acid (0.7 g, 3.60 mmol), Na ₂ CO ₃ (0.862 g, 8 .10 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (0.156 g, 0.20 mmol) were degassed and refilled with N ₂ three times. The mixture was treated with 1,4-dioxane (20 ml) and degassed water (6 ml), heated to 80° C. and stirred for 45 minutes. The reaction mixture was cooled down to rt. before dilution with water (40 ml) and extracted with CH ₂ Cl ₂ (3×30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residues were purified by column chromatography (0-25% tert -butyl methyl ether in cyclohexane) to give 1-(3,5-dichlorophenyl)-5-nitronaphthalene. LCMS (Method A): R _t =1.61 minutes, no significant ion mass was observed.

A mixture of 1-(3,5-dichlorophenyl)-5-nitronaphthalene (0.928 g, 2.77 mmol), NH ₄ Cl (0.468 g, 8.72 mmol) and iron (0.47 g, 8.28 mmol) was placed under N ₂ atmosphere before adding THF (14 ml), EtOH (14 ml) and water (7 ml). The resulting mixture was heated to 75° C. and allowed to stir for 45 minutes to form a black mixture. The reaction mixture was cooled down to rt. before filtering through Celite® (with washing with CH ₂ Cl ₂ ). The filtrate was concentrated in vacuo , treated with sat. aq. NaHCO ₃ (50 ml) and extracted with CH ₂ Cl ₂ (3×25 ml). The combined organic layers were filtered through Celite® and concentrated in vacuo to give 5-(3,5-dichlorophenyl)naphthalene-1-amine. LCMS (method B): R _t =1.49 min, mass/charge = 288.0 [M+H] ⁺ .

A solution of 5-(3,5-dichlorophenyl)naphthalene-1-amine (0.88 g, 2.60 mmol) in DMF (10 ml) was placed under N ₂ , cooled in an ice/salt bath to approximately -5° C and treated with N-bromosuccinimide (0.47 g, 2.58 mmol). The reaction mixture was stirred for 30 min. The reaction mixture was treated with sat. aq. NaHCO ₃ solution (50 ml). The mixture was extracted with CH ₂ Cl ₂ (3×30 ml) and the combined organic phases were concentrated in vacuo . The residues were purified by column chromatography (0-30% EtOAc in cyclohexane) to give 2-bromo-5-(3,5-dichlorophenyl)naphthalene-1-amine. LCMS (method B): R _t =1.64 minutes, mass/charge = 365.8 [M+H] ⁺ .

A suspension of 2-bromo-5-(3,5-dichlorophenyl)naphthalene-1-amine (0.73 g, 1.79 mmol) in formic acid (6 ml, 160 mmol) in a 100 ml round bottom flask was placed under N2 atmosphere. and treated with a solution of formaldehyde (37 wt.% in water) (8 ml, 110 mmol). The resulting suspension was heated to 100° C. and stirred for 1 hour. The reaction mixture was cooled down to rt. before adding sat. aq. NaHCO ₃ (60 ml). The mixture was then extracted with CH ₂ Cl ₂ (3×20 ml) and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residues were purified by column chromatography (0-5% tert -butyl methyl ether in cyclohexane) to give 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethylnaphthalene-1-amine. LCMS (method B): R _t =1.93 minutes, mass/charge = 393.8 [M+H] ⁺ .

A solution of 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethylnaphthalene-1-amine (532 mg, 1.279 mmol) in 1,4-dioxane (10 ml) was treated with MeOH (10 ml), NEt ₃ (0.54 ml, 3.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (0.103 g, 0.134 mmol) before stirring at 100° C. under atmosphere CO(0.036 g, 1.28 mmol, 50 psi) for 16 hours. The reaction mixture was allowed to cool to rt. The reaction mixture was filtered and concentrated in vacuo . The residue was purified by column chromatography (0-10% tert -butyl methyl ether in cyclohexane) to give methyl 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate. LCMS (method B): R _t =1.75 minutes, mass/charge = 374.0 [M+H] ⁺ .

A solution of methyl 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate (0.42 g, 1.01 mmol) in THF (10 mL) was treated with 1,4-dioxane (15 ml), water (5 ml) and lithium hydroxide (0.26 g, 10.23 mmol). The reaction mixture was heated to 85° C. and stirred for 2 hours. The reaction mixture was cooled to rt. before treatment with 2 M HCl (up to pH 8). Water the phase was extracted with CH ₂ Cl ₂ (3×25 ml). The combined organic layers were filtered, concentrated in vacuo and dried to give 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid. LCMS (method B): R _t =1.10 minutes, mass/charge = 358.0 [MH] ^- .

A mixture of 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid (0.225 g, 0.5 mmol), (4S)-chroman-4-amine⋅HCl (0.11 g, 0 .58 mmol) and PyBOP (0.414 g, 0.78 mmol) in a 50 ml round bottom flask were placed under N ₂ and treated with THF (5 ml) and NEt ₃ (1.8 mmol, 0.25 ml). The resulting reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into sat. aq. NaHCO ₃ (20 ml) and extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residues were purified by column chromatography (0-15% EtOAc in cyclohexane) to give the title compound. LCMS (method B): R _t = 1.63 minutes, mass/charge = 491.0 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 9.03 (d, J= 8.4 Hz, 1 H), 8.33 (d, J= 8 Hz, 1 H), 7, 77 (t, J= 2 Hz, 1 H), 7.64 (d, J= 7.2 Hz, 1 H), 7.62 (d, J= 6.8 Hz, 1 H), 7.51 (d, J= 7.2 Hz, 1 H), 7.49 (m, 2 H), 7.45 (s, 2 H), 7.33 (d, J= 7.2 Hz, 1 H) , 7.16 (t, J= 8.4 Hz, 1 H), 6.92 (t, J= 8.4 Hz, 1 H), 6.79 (d, J= 8 Hz, 1 H), 5.28 (q, J= 8 Hz, 1 H), 4.27 (t, J= 4.8 Hz, 2 H), 2.96 (s, 6 H), 2.10 (m, 2 H ).

Example 6.1

N-[(4S)-Chroman-4-yl]-4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxamide

A solution of 4-bromoquinoline (0.81 g, 3.89 mmol) in sulfuric acid (17.82 mol/l) in water (10 ml) was treated with nitric acid (70 w/w%) in water (0 .30 ml) and allowed to stir for 1.5 hours at rt. The reaction mixture was diluted with water (200 ml) and treated slowly with solid K ₂ CO ₃ until foaming ceased. Water the phase was extracted with CH ₂ Cl ₂ (3×30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residue was purified by column chromatography (100% CH ₂ Cl ₂ ) to give 4-bromo-8-nitroquinoline. LCMS (method B): R _t =1.03 minutes, mass/charge = 253.0 [M+H] ⁺ .

A mixture of 4-bromo-8-nitroquinoline (0.83 g, 3.12 mmol), (3,5-dichlorophenyl)boronic acid (0.61 g, 3.13 mmol), Na ₂ CO ₃ (0.66 g , 6.24 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (0.12 g, 0.16 mmol) were placed under N ₂ and treated with 1, 4-dioxane (15 ml) and degassed water (5 ml). The reaction vessel was evacuated three times and refilled with N ₂ before the reaction mixture was heated to 80° C. and allowed to stir for 30 minutes. The reaction mixture was cooled down to rt. before dilution with water (40 ml) and extracted with CH ₂ Cl ₂ (3×25 ml). The combined organic layers were filtered and concentrated in vacuo . The residues were purified by column chromatography (0-25% EtOAc in cyclohexane) to give 4-(3,5-dichlorophenyl)-8-nitroquinoline. LCMS (method B): R _t =1.37 minutes, mass/charge = 319.0 [M+H] ⁺ .

A solution of 4-(3,5-dichlorophenyl)-8-nitroquinoline (0.99 g, 2.8 mmol) in THF (14 mL) was placed under N ₂ and treated with EtOH (14 mL), NH ₄ Cl ( 0.45 g, 8.4 mmol), iron (0.488 g, 8.56 mmol) and water (7 ml). The resulting reaction mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to rt. before filtering through Celite® (with washing with CH ₂ Cl ₂ ). The filtrate was washed with water (30 ml) and aq. the phase was extracted with CH ₂ Cl ₂ (3×20 ml). The combined organic phases were passed through Celite® and concentrated in vacuo . The residue was purified by column chromatography (0-50% EtOAc in cyclohexane) to give 4-(3,5-dichlorophenyl)quinoline-8-amine. LCMS (method B): R _t =1.43 minutes, mass/charge = 289.0 [M+H] ⁺ .

A solution of 4-(3,5-dichlorophenyl)quinoline-8-amine (0.86 g, 2.52 mmol) in DMF (10 ml) was placed under N ₂ and cooled on ice before treatment with N-bromosuccinimide (0 .45 g, 2.52 mmol). The reaction mixture was stirred for 15 min at 0°C. The reaction mixture was diluted with sat. aq. NaHCO ₃ (40 ml) and extracted with CH ₂ Cl ₂ (3×25 ml). The combined organic layers were filtered through Celite® and concentrated in vacuo . The residues were purified by column chromatography (0-20% EtOAc in cyclohexane) to give 7-bromo-4-(3,5-dichlorophenyl)quinoline-8-amine. LCMS (method B): R _t =1.64 minutes, mass/charge = 366.8 [M+H] ⁺ .

A mixture of 7-bromo-4-(3,5-dichlorophenyl)quinoline-8-amine (0.74 g, 1.9 mmol) and Na ₂ CO ₃ (0.8 g, 5.78 mmol) was placed under N ₂ and treated with DMF (6.5 ml) and iodomethane (0.40 ml, 6.4 mmol). The resulting mixture was heated to 100° C. and stirred for 45 minutes. The reaction mixture was cooled down to rt. before dilution with sat. aq. NaHCO ₃ (30 ml) and extracted with tert-butyl methyl ether (3×20 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo . The residues were purified by column chromatography (0-20% tert-butyl methyl ether in cyclohexane) to give 7-bromo-4-(3,5-dichlorophenyl)-N,N-dimethylquinoline-8-amine. LCMS (method B): R _t =1.74 minutes, mass/charge = 395.0 8 [M+H] ⁺ .

A solution of 7-bromo-4-(3,5-dichlorophenyl)-N,N-dimethylquinoline-8-amine (0.73 g, 1.47 mmol) in 1,4-dioxane (10 mL) was treated with MeOH ( 10 ml), NEt ₃ (0.62 ml, 4.45 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (0.12 g, 0.15 mmol) before stirring at 100° C. under CO (0.041 g, 1.48 mmol, 56 psi) overnight. The reaction mixture was filtered and concentrated in vacuo . The residue was purified by column chromatography (0-40% EtOAc in cyclohexane) to give methyl 4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxylate. LCMS (method B): R _t =1.57 minutes, mass/charge = 375.0 [M+H] ⁺ .

A solution of methyl 4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxylate (0.46 g, 1.11 mmol) in 1,4-dioxane (15 mL) was treated with water (6 ml) and lithium hydroxide (0.57 g, 22.57 mmol) before stirring for 1 hour at 100°C. The reaction mixture was concentrated to approximately half volume before treatment with 2 M HCl (to pH 3) and was extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic phases were filtered through Celite® and concentrated in vacuo to give 4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxylic acid. LCMS (method B): R _t =1.11 minutes, mass/charge = 358.8 [MH] ^- .

4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxylic acid mixture (0.16 g, 0.36 mmol), (4S)-chroman-4-amine⋅HCl (0.083 g, 0.434 mmol) and PyBOP (0.29 g, 0.55 mmol) were placed under N ₂ atmosphere and treated with THF (0.5 ml) and NEt ₃ (0.11 g, 0.15 ml). The resulting reaction mixture was stirred for 30 min at room temperature. The reaction mixture was poured into sat. aq. NaHCO ₃ (25 ml) and extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered through Celite® and concentrated in vacuo . The residue was purified by column chromatography (0-20% EtOAc in cyclohexane) to give the title compound. LCMS (method B): R _t =1.66 minutes, mass/charge = 492.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.37 (d, J= 8 Hz, 1 H), 9.01 (d, J= 4.4 Hz, 1 H), 7, 94 (d, J= 9.2 Hz, 1 H), 7.82 (d, J= 2 Hz, 1 H), 7.61 (m, 3 H), 7.55 (d, J= 4, 4 Hz, 1H), 7.38 (d, J= 6.8 Hz, 1 H), 7.18 (td, J= 8, 1.2 Hz, 1 H), 76.99 (td, J= 7.6, 0.8 Hz, 1 H), 6.81 (dd, J= 8, 0.8 Hz, 1 H), 5.28 (m, 1 H), 4.30 (m, 2 H ), 3.03 (s, 6H), 2.15 (m, 2H).

Example 7.1

N-[(4S)-Chroman-4-yl]-4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxamide

To a degassed solution of 4-bromo-8-nitroisoquinoline (864 mg, 3.24 mmol), (3,5-dichlorophenyl)boronic acid (650 mg, 3.34 mmol) and Na ₂ CO ₃ (729 mg, 6.85 mmol) in 1,4-dioxane (15 ml) and water (5 ml) under N ₂ at room temperature. 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ complex (255 mg, 0.33 mmol) was added. The mixture was again degassed and stirred under N ₂ atmosphere, then heated to 80°C for 3 hours. The reaction mixture was cooled to rt, diluted with EtOAc (25 ml) and filtered through a layer of Celite®. Celite® was washed with EtOAc (50 ml). The combined organic filtrates were then washed with sat. NaHCO ₃ (50 ml) and brine (2×50 ml), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residues were purified by column chromatography (10-100% CH ₂ Cl ₂ in cyclohexane to 0-5% MeOH in CH ₂ Cl ₂ ) to give 4-(3,5-dichlorophenyl)-8-nitroisoquinoline. LCMS (method B) R _t =1.35 minutes, mass/charge = 319 [M+H] ⁺ .

Mixture of 4-(3,5-dichlorophenyl)-8-nitroisoquinoline (881 mg, 2.62 mmol), iron (458 mg, 8.04 mmol) and NH ₄ Cl (428 mg, 7.97 mmol) under N atmosphere ₂ at r.t. was dissolved in THF (13 ml), EtOH (13 ml) and water (6.5 ml) and heated to 75 C for 1.5 hours. The reaction mixture was cooled to rt. and filtered through a layer of Celite®. Celite® was then washed with MeOH (100 ml). The combined filtrates were concentrated in vacuo then dissolved in a mixture of CH ₂ Cl ₂ (100 ml) and sat. aq. NaHCO ₃ (100 ml). Water the layer was separated and extracted with CH ₂ Cl ₂ (3×50 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4-(3,5-dichlorophenyl)isoquinoline-8-amine. LCMS (method B) R _t =1.24 minutes, mass/charge = 289 [M+H] ⁺ .

A solution of 4-(3,5-dichlorophenyl)isoquinoline-8-amine (0.59 g, 1.96 mmol) in DMF (25 ml) under N ₂ was cooled to -10° C. using an ice/NaCl bath. N-bromosuccinimide (372 mg, 2.03 mmol) was added and the mixture was stirred at rt. within 2 hours. The reaction mixture was poured into water (150 ml) and extracted with CH ₂ Cl ₂ (4×100 ml) and 10% MeOH in CH ₂ Cl ₂ (100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo . The residue was dissolved in EtOH (30 ml) and heated to 100°C. The mixture was allowed to cool to rt, then filtered to remove solids. The solid was then dried in vacuo at 60°C for 1 hour to give 7-bromo-4-(3,5-dichlorophenyl)isoquinoline-8-amine. LCMS (method B) Rt=1.42 minutes, mass/charge=367 [M+H] ⁺ .

To a solution of 7-bromo-4-(3,5-dichlorophenyl)isoquinoline-8-amine (132 mg, 0.34 mmol) in formic acid (2.6 ml, 69 mmol) at r.t. formaldehyde solution (37 wt.% in water) (5 ml, 67 mmol, 37 wt.%) was added under N ₂ atmosphere. The resulting mixture was heated to 100°C for 24 hours. To the reaction mixture, the basicity of which was then increased basicity with sat. aq. NaHCO ₃ (75 ml), ice (50 g) was added and extracted with CH ₂ Cl ₂ (3×50 ml). The combined organic layers were concentrated in vacuo . The oil was purified by column chromatography (5-5% EtOAc in cyclohexane) to give 7-bromo-4-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-8-amine. LCMS (method B) R _t =1.67 min, mass/charge=395 [M+H] ⁺ .

To a solution of 7-bromo-4-(3,5-dichlorophenyl)-N,N-dimethylisoquinoline-8-amine (0.126 g, 0.304 mmol), NEt ₃ (0.13 ml, 0.93 mmol) in MeOH (5 ml) and 1,4-dioxane (5 ml) complex 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)⋅CH ₂ Cl ₂ ) (45.8 mg, 0.0595 mmol) was added. The reaction mixture was placed under a CO atmosphere (0.304 mmol, 42 psi) and heated to 100° C. for 22 hours. The reaction mixture was filtered through a pad of Celite®. Celite® was washed with EtOAc (25 ml). The combined organic filtrates were concentrated in vacuo then purified by column chromatography (10-25% EtOAc in cyclohexane) to give methyl 4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxylate. LCMS (method B) R _t =1.48 minutes, mass/charge = 375 [M+H] ⁺ .

A solution of methyl 4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxylate (71.5 mg, 0.181 mmol) and lithium hydroxide (96.8 mg, 3.84 mmol) in 1.4 -dioxane (5 ml) and water (1 ml) in an atmosphere of N ₂ was heated to 100°C for 2.5 hours. The reaction mixture was cooled to rt and then concentrated in vacuo . The solid was then dissolved in water (5 ml) and acidified with 2 M HCl (aq., 3.5 ml) to pH=1 and extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxylic acid. LCMS (method B) R _t =0.82 minutes, mass/charge=361 [M+H] ⁺ .

A stirred suspension of 4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxylic acid (78.7 mg, 0.218 mmol) in DMF (2.5 ml) was added to NEt ₃ (0.13 ml, 0.92 mmol) followed by the addition of (4S)-chroman-4-amine⋅HCl (50 mg, 0.27 mmol) and PyBOP (181 mg, 0.34 mmol). The reaction mixture was stirred at rt. in N ₂ atmosphere for 2 hours. The reaction mixture was diluted with brine (25 ml) and extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic layers were concentrated in vacuo . The residue was purified by preparative HPLC (Phenomenex Gemini 5 micron 30*100 mm C-18) (CH ₃ CN and water pH adjusted to 9 with conc ammonium hydroxide, 30% to 100% CH ₃ CN for 9 min at 60 ml/min to give the title compound LCMS (method B) Rt=1.41 minutes, mass/charge=492 [M+H] ⁺ .

Experiment details for compounds in tables:

Etc. HPLC NMR 1.2 _Rt = 1.32; mass/charge (ES+)= 479.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.99 (s, 1 H), 8.51 (d, J= 6 Hz, 1 H), 7.72 (d, J= 6 Hz, 1 H), 7.22 (t, J= 8 Hz, 2 H), 7.14 (d, J= 7.6 Hz, 1 H), 7.06 (m, 2 H), 6, 93 (q, J= 7.6 Hz, 2 H), 6.88 (d, J= 8 Hz, 1 H), 6.55 (d, J= 7.6 Hz, 1 H), 5.86 (t, J= 7.2 Hz, 1 H), 5.39 (q, J= 7.2 Hz, 1 H), 4.36 (m, 1 H), 4.21 (m, 1 H) , 3.14(s, 6H), 3.05(m, 1H), 2.9(m, 1H), 2.41(m, 1H), 2.23(m, 2H) , 2.02 (m, 2 H) 1.3 _Rt = 1.32; mass/charge (ES+)= 479.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.99 (s, 1 H), 8.51 (d, J= 6 Hz, 1 H), 7.72 (d, J= 6 Hz, 1 H), 7.22 (t, J= 8 Hz, 2 H), 7.14 (d, J= 7.6 Hz, 1 H), 7.06 (m, 2 H), 6, 93 (q, J= 7.6 Hz, 2 H), 6.88 (d, J= 8 Hz, 1 H), 6.55 (d, J= 7.6 Hz, 1 H), 5.86 (t, J= 7.2 Hz, 1 H), 5.39 (q, J= 7.2 Hz, 1 H), 4.36 (m, 1 H), 4.21 (m, 1 H) , 3.14(s, 6H), 3.05(m, 1H), 2.9(m, 1H), 2.41(m, 1H), 2.23(m, 2H) , 2.02 (m, 2 H) 1.4 R _t = 1.17; mass/charge (ES+)= 477.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.81 (s, 1 H), 8.62 (d, J= 5 Hz, 1 H), 7.88 (d, J= 6 Hz, 1 H), 7.27 (m, 1 H), 7.20 (m, 1 H), 7.09 (t, J= 7.6 Hz, 1 H), 6.92 (m, 1 H), 6.85 (d, J= 8.4 Hz, 1 H), 3.674 (d, J= 7.2 Hz, 1 H), 6.41 (d, J= 7.6 Hz, 1 H ), 6.30 (t, J= 4.4 Hz, 1 H), 5.35 (q, J= 7.2 Hz, 1 H), 4.33 (m, 1 H), 4.17 ( m, 1 H), 3.17 (s, 6 H), 3.00 (d, J= 8 Hz, 1 H), 2.6 (m, 2 H), 2.20 (m, 2 H) 1.5 _Rt = 1.43; mass/charge (ES+)= 472.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.11 (dd, J= 3.6, 4.8 Hz, 1 H), 8.45 (s, 1 H), 7 .97 (d, J= 5.6 Hz, 1 H), 7.34 (m, 1 Hz), 7.17 (m, 2 H), 6.94 (m, 1 H), 6.80 ( dd, J= 2.0, 8 Hz, 1 H), 5.25 (m, 1 H), 4.26 (m, 3 H), 3.51 (q, J= 8.8 Hz, 1 H ), 3.28 (m, 1 H), 3.00 (s, 3 H), 2.98 (s, 3 h), 2.73 (d, J= 11.2 Hz, 1 H), 1 .68-2.51(m, 7H), 1.37(m, 4H), 1.02(m, 1H) 1.6 R _t = 1.45; mass/charge (ES+)= 472.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.11 (t, J= 8 Hz, 1 H), 8.45 (d, J= 4 Hz, 1 H), 7, 91 (d, J= 5 Hz, 1 H), 7.35 (t, J= 9.2 Hz, 1 Hz), 7.17 (t, J= 7.6 Hz, 1 H), 6.96 (m, 2 H), 6.80 (d, J= 8.4 Hz, 1 H), 5.23 (m, 1 H), 4.97 (br s , 1 H), 4.26 (m , 2 H), 4.08 (m, 1 H), 3.78 (m, 1 H), 3.17 (d, J= 5.2 Hz, 1 H), 2.97 (s, 3 h ), 2.96 (s, 3 h), 2.3 (m, 1 H), 2.19 (m, 1 H), 2.03 (m, 2H), 1.15-1.86 (m , 8H) 1.7 R _t = 1.37; mass/charge (ES+)= 500.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.81 (s, 1 H), 8.16 (d, J= 5.7 Hz, 1 H), 7.38 (d, J = 5.9 Hz, 1 H), 7.30 (d, J= 8.6 Hz, 2 H), 7.22 (m, 1H), 7.16 (m, 2 H), 7.04 ( dd, J= 8.8, 2.2 Hz, 1 H), 6.94 (td, J= 7.4, 1 Hz, 1 H), 6.87 (d, J= 8.2 Hz, 1 H), 5.38(m, 1H), 4.55(m, 2H), 4.36(m, 1H), 4.20(m, 1H), 3.18(t, J = 8.2Hz, 2H), 3.11(s, 6H), 2.40(m, 1H), 2.21(m, 1H) 1.8 _Rt = 1.36; mass/charge (ES+)= 498.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.82 (s, 1 H), 8.45 (d, J=5.9 Hz, 1 H), 8.04 (d, J = 3.5 Hz, 1 H), 7.92 (d, J= 8.8 Hz, 1 H), 7.78 (d, J= 5.9 Hz, 1 H), 7.61 (d, J= 2.2 Hz, 1 H), 7.28 (d, J= 7.8 Hz, 1 H), 7.20 (m, 2 H), 6.93 (td, J= 7.4, 0.8 Hz, 1 H), 6.86 (d, J= 8.2 Hz, 1 H), 6.78 (d, J= 7.6 Hz, 1 H), 6.64 (d, J = 3.3 Hz, 1 H), 5.37 (m, 1 H), 4.34 (m, 1 H), 4.18 (m, 1 H), 3.17 (s, 6 H), 2.39(m, 1H), 2.19(m, 1H) 1.9 _Rt = 1.35; mass/charge (ES+)= 535.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.95 (s, 1 H), 8.70 (d, J= 5.7 Hz, 1 H), 7.99 (d, J = 1.8 Hz, 2 H), 7.94 (d, J= 5.9 Hz, 1 H), 7.47 (t, J= 2 Hz, 1 H), 7.31 (m, 1 H ), 7.22 (m, 1 H), 6.96 (m, 1 H), 6.94 (d, J= 8.2 Hz, 1 H), 6.73 (m, 1 H), 5 .40 (m, 1 H), 4.38 (m, 1 H), 4.21 (m, 1 H), 3.94 (m, 4 H), 3.44 (m, 4 H), 2 .43 (m, 1H), 2.25 (m, 1H) 1.10 _Rt = 1.20; mass/charge (ES+)= 499.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.25 (d, J= 8 Hz, 1 H), 8.74 (s, 1 H), 8.20 (d, J = 5.9 Hz, 1 H), 7.60 (m, 3 H), 7.48 (m, 3 H), 7.40 (d, J= 7.6 Hz, 1 H), 7.19 (td, J= 6.8, 1.6 Hz, 1 H), 6.96 (td, J= 7.6, 1 Hz, 1 H), 6.82 (d, J= 8.2 Hz, 1 H), 5.27 (m, 1 H), 4.27 (m, 2 H), 3.84 (m, 4 H), 3.28 (m, 4 H), 2.24 (m, 1H), 2.08(m, 1H) 1.11 _Rt = 1.02; mass/charge (ES+)= 531.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.27 (d, J= 8 Hz, 1 H), 8.81 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H), 8.26 (d, J= 5.7 Hz, 1 H), 8.04 (m, 2 H), 7.72 (m, 1 H), 7.63 (m, 2 H), 7.39 (d, J= 7.2 Hz, 1 H), 7.19 (m, 1 H), 6.95 (m, 1 H), 6.81 (d, J= 8.2Hz, 1H), 5.24(m, 1H), 4.25(m, 2H), 3.85(m, 4H), 3.28(m, 4H) , 2.22(m, 1H), 2.06(m, 1H) 1.12 _Rt = 1.36; mass/charge (ES+)= 465.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (d, J= 8 Hz, 1 H), 8.98 (s, 1 H), 8.64 (d, J = 5.7 Hz, 1 H), 8.60 (br s, 2 H), 8.32 (d, J= 5.7 Hz, 1 H), 8.18 (d, J= 2.1 Hz , 2 H), 7.70 (t, J= 2 Hz, 1 H), 7.25 (d, J= 7.4 Hz, 1 H), 7.17 (m, 1 H), 6.89 (m, 1 H), 6.81 (d, J= 8.2 Hz, 1 H), 5.32 (m, 1 H), 4.29 (m, 2 H), 2.13 (m, 2H) 1.13 _Rt = 1.54; mass/charge (ES+)= 508.00 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.31 (d, J= 8 Hz, 1 H), 8.98 (s, 1 H), 8.76 (d, J = 5.6 Hz, 1 H), 8.14 (m, 3 H), 7.76 (t, J= 2 Hz, 1 H), 7.37 (d, J= 8 Hz, 1 H), 7.19 (td, J= 1.6, 8.4 Hz, 1 H), 6.94 (td, J= 1.2, 7.6 Hz, 1 H), 6.81 (dd, J= 1.2, 7.6Hz, 1H), 5.27(m, 1H), 4.94(m, 1H), 4.27(m, 2H), 2.04-2.24 (m, 2H), 1.32-1.36 (m, 6H) 1.14 R _t = 1.33; mass/charge (ES+)= 548.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.08 (s, 1 H), 8.65 (d, J= 5.6 Hz, 1 H), 7.98 (d, J = 2 Hz, 2 H), 7.95 (d, J= 6 Hz, 1 H), 7.53 (br s , 1 H), 7.45 (t, J= 1.6 Hz, 1 H) , 7.30 (d, J= 7.6 Hz, 1 H), 7.22 (t, J= 8.4 Hz, 2 H), 6.95 t, J= 7.6 Hz, 1 H) , 6.88 (d, J= 8.4 Hz, 1 H), 5.6 (d, J= 6.8 Hz, 1 H), 4.36 (m, 1 H), 4.21 (m , 1 H), 3.44 (t, J= 438Hz, 4 H), 2.22-2.6 (m, 6 H), 1.6 (s, 2 H) 1.15 _Rt = 1.08; mass/charge (ES+)= 461.0 [M+H] ⁺ / method A ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.15 (d, J= 8.2 Hz, 1 H), 8.67 (d, J= 6.2 Hz, 1 H ), 8.60 (s, 1 H), 8.13 (d, J= 5.9 Hz, 1 H), 7.58 (m, 1 H), 7.35 (d, J= 7.6 Hz, 1 H), 7.25-7.14 (m, 3 H), 6.91 (t, J= 8 Hz, 1 H), 6.79 (d, J= 8 Hz, 1H), 5 .25-5.21(m, 1H), 4.30-4.19(m, 2H), 3.13(s, 6H), 2.24-2.16(m, 1H) , 2.07-1.99 (m, 1H) 1.16 R _t = 1.37; mass/charge (ES+)= 519.2 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.79 (s, 1 H), 8.51 (d, J= 5.9 Hz, 1 H), 7.95 (d, J = 2 Hz, 2 H), 7.91 (d, J= 5.9 Hz, 1 H), 7.43 (t, J= 2 Hz, 1 H), 7.29-7.29 (m, 1 H), 7.24-7.20 (m, 1 H), 6.94 (td, J= 7.5, 1 Hz, 1 H), 6.89-6.85 (m, 2 H) , 5.37-5.33(m, 1H), 4.36(m, 1H), 4.23-4.17(m, 1H), 3.80-3.73(m, 4 H), 2.42-2.37 (m, 1 H), 2.23-2.17 (m, 1 H), 2.05-2.01 (m, 4 H) 1.17 _Rt = 1.40; mass/charge (ES+)= 511 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.16 (d, J= 8 Hz, 1 H), 8.74 (s, 1 H), 8.65 (d, J = 6 Hz, 1 H), 8.09 (d, J= 2 Hz, 1 H), 8.07 (d, J= 5.6 Hz, 1 H), 7.73 (t, J= 2 Hz , 1 H), 7.04 (t, J= 6.8 Hz, 1 H), 6.78 (td, J= 2.8, 8.4 Hz, 1 H), 6.67 (dd, J = 2.4, 10.4Hz, 1H), 5.21(m, 1H), 4.28(m, 2H), 3.1(s, 6H), 2.1(m, 2 h) 1.18 _Rt = 1.01; mass/charge (ES+)= 464.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.90 (s, 1H), 8.70 (d, J= 5.9 Hz, 1H), 8.25 (s, 1H), 7.88 (d, J= 5.9 Hz, 1H), 7.53-7.47 (m, 2H), 7.35-7.26 (m, 2H), 7.22-7.18 ( m, 2H), 7.00-6.90 (m, 3H), 6.41 (s, 1H), 5.39-5.35 (m, 1H), 4.36-4.31 (m, 1H), 4.21-4.15(m, 1H), 3.18(s, 6H), 2.42-2.35(m, 1H), 2.23-2.14(m, 1H) 1.19 _Rt = 1.49; mass/charge (ES+)= 526.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.35 (s, 1 H), 8.66 (d, J= 5.9 Hz, 1 H), 8.07 (d, J = 1.8 Hz, 2 H), 7.58-7.55 (m, 3 H), 7.50 (t, J= 1.9 Hz, 1 H), 7.45-7.41 (m , 3 H), 7.15-7.11 (m, 1 H), 6.80-6.71 (m, 3 H), 5.63-5.59 (m, 1 H), 5.11 (dt, J= 7.6, 5.0 Hz, 1 H), 4.07 (m, 1 H), 3.59-3.53 (m, 1 H), 2.12-2.05 ( m, 1H), 1.76-1.71 (m, 1H) 1.20 _Rt = 1.42; mass/charge (ES+)= 490.0 [M+H] ⁺ / method B ¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.00 (s, 1 H), 8.76 (d, J= 5.9 Hz, 1 H), 8.25 (d, J = 5.7 Hz, 1 H), 7.99 (d, J= 1.8 Hz, 2 H), 7.47 (t, J= 1.9 Hz, 1 H), 7.31 (d, J= 7.6 Hz, 1 H), 7.23-7.19 (m, 1 H), 6.96-6.92 (m, 1 H), 6.86 (d, J= 8.2 Hz, 1 H), 6.29 (d, J= 7.4 Hz, 1 H), 5.44-5.39 (m, 1 H), 4.40-4.35 (m, 1 H) , 4.24-4.18(m, 1H), 2.47-2.40(m, 1H), 2.33-2.26(m, 2H), 1.34-1.25 (m, 2H), 0.88-0.80 (m, 2H) 1.21 R _t = 1.45; mass/charge (ES+)= 477.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.89 (s, 1H), 8.63 (d, J= 5.9 Hz, 1H), 7.98 (d, J= 2 Hz , 2H), 7.91 (d, J= 5.9 Hz, 1H), 7.45 (t, J= 2 Hz, 1H), 7.39 (d, J= 6.6 Hz, 1H), 7.30-7.22 (m, 3H), 6.52 (d, J= 8.4 Hz, 1H), 5.73 (q, J= 7.5 Hz, 1H), 3.19 (s , 6H), 3.10-3.02 (m, 2H), 2.81-2.74 (m, 1H), 2.04-1.95 (m, 1H) 1.22 _Rt = 1.35; mass/charge (ES+)= 518.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.93 (s, 1H), 8.65 (d, J= 5.9 Hz, 1H), 7.98 (d, J= 2 Hz , 2H), 7.91 (d, J= 5.7 Hz, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.50-7.45 (m, 2H), 7 .04-7.00 (m, 1H), 6.95 (d, J= 8.6 Hz, 1H), 5.44-5.39 (m, 1H), 4.48-4.33 (m , 2H), 3.18 (s, 6H), 2.45-2.38 (m, 2H) 1.23 _Rt = 1.48; mass/charge (ES+)= 527.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.89 (s, 1H), 8.63 (d, J= 5.9 Hz, 1H), 7.97 (d, J= 2 Hz , 2H), 7.89 (d, J= 5.9 Hz, 1H), 7.45 (t, J= 1.9 Hz, 1H), 7.23 (d, J= 8.2 Hz, 1H ), 6.94-6.85 (m, 3H), 5.38-5.33 (m, 1H), 4.36 (ddd, J= 11.2, 6.1, 3.5 Hz, 1H ), 4.23-4.17(m, 1H), 3.16(s, 6H), 2.42-2.35(m, 1H), 2.23-2.17(m, 1H) 1.24 _Rt = 1.11; mass/charge (ES+)= 491.2 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.15 (d, J= 8.2 Hz, 1H), 8.66 (d, J= 5.9 Hz, 1H), 8 .60 (s, 1H), 8.12 (d, J= 5.9 Hz, 1H), 7.35-7.27 (m, 2H), 7.18-7.12 (m, 2H), 6.93-6.89(m, 1H), 6.79(d, J=8.2Hz, 1H), 5.25-5.21(m, 1H), 4.30-4.24( m, 2H), 3.89 (d, J= 3.7 Hz, 3H), 3.13 (s, 6H), 2.24-2.16 (m, 1H), 2.07-2.00 (m, 1H) 1.25a R _t = 1.38; mass/charge (ES+)= 523.2 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.88 (s, 1 H), 8.63 (d, J= 5.9 Hz, 1 H), 7.97 (d, J= 1.8 Hz, 2 H), 7.90 (d, J= 5.9 Hz, 1 H), 7.45 (t, J= 1.9 Hz, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 6.69 (d, J= 7.2 Hz, 1 H), 6.54 (dd, J= 2.5, 8.6 Hz, 1 H), 6, 40 (d, J= 2.5 Hz, 1 H), 5.32-5.28 (m, 1 H), 4.38-4.32 (m, 1 H), 4.20-4.14 (m, 1 H), 3.77 (s, 3 H), 3.17 (s, 6 H), 2.41-2.34 (m, 1 H), 2.24-2.19 (m , 1H) 1.25b R _t = 1.38; mass/charge (ES+)= 523.2 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.88 (s, 1 H), 8.63 (d, J= 5.9 Hz, 1 H), 7.97 (d, J= 1.8 Hz, 2 H), 7.90 (d, J= 5.9 Hz, 1 H), 7.45 (t, J= 1.9 Hz, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 6.69 (d, J= 7.2 Hz, 1 H), 6.54 (dd, J= 2.5, 8.6 Hz, 1 H), 6, 40 (d, J= 2.5 Hz, 1 H), 5.32-5.28 (m, 1 H), 4.38-4.32 (m, 1 H), 4.20-4.14 (m, 1 H), 3.77 (s, 3 H), 3.17 (s, 6 H), 2.41-2.34 (m, 1 H), 2.24-2.19 (m , 1H) 1.26a _Rt = 1.43; mass/charge (ES+)= 507.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.91 (s, 1H), 8.63 (d, J= 5.9 Hz, 1H), 7.97 (d, J= 2 Hz , 2H), 7.88 (d, J= 5.7 Hz, 1H), 7.45-7.41 (m, 2H), 7.24-7.19 (m, 1H), 6.98- 6.94 (m, 1H), 6.88 (dd, J= 0.9, 8.3 Hz, 1H), 6.75 (s, 1H), 4.31-4.28 (m, 2H) , 3.13 (s, 6H), 3.08-3.03 (m, 1H), 2.30-2.23 (m, 1H), 2.01-1.99 (m, 3H) 1.26b _Rt = 1.43; mass/charge (ES+)= 507.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.91 (s, 1H), 8.63 (d, J= 5.9 Hz, 1H), 7.97 (d, J= 2 Hz , 2H), 7.88 (d, J= 5.7 Hz, 1H), 7.45-7.41 (m, 2H), 7.24-7.19 (m, 1H), 6.98- 6.94 (m, 1H), 6.88 (dd, J= 0.9, 8.3 Hz, 1H), 6.75 (s, 1H), 4.31-4.28 (m, 2H) , 3.13 (s, 6H), 3.08-3.03 (m, 1H), 2.30-2.23 (m, 1H), 2.01-1.99 (m, 3H) 1.27a R _t = 1.25; mass/charge (ES+)=492.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.90 (s, 1H), 8.65 (d, J= 5.7 Hz, 1H), 8.49 (dd, J= 1, 4, 4.7 Hz, 1H), 7.98 (d, J= 2 Hz, 2H), 7.91 (d, J= 5.7 Hz, 1H), 7.75 (d, J= 7, 8 Hz, 1H), 7.47-7.44 (m, 1H), 7.18 (dd, J= 4.7, 7.8 Hz, 1H), 6.69-6.65 (m, 1H ), 5.53-5.48 (m, 1H), 3.18 (s, 6H), 3.07-2.96 (m, 2H), 2.28-2.22 (m, 1H), 2.07-1.97 (m, 3H) 1.27b R _t = 1.25; mass/charge (ES+)=492.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.90 (s, 1H), 8.65 (d, J= 5.7 Hz, 1H), 8.49 (dd, J= 1, 4, 4.7 Hz, 1H), 7.98 (d, J= 2 Hz, 2H), 7.91 (d, J= 5.7 Hz, 1H), 7.75 (d, J= 7, 8 Hz, 1H), 7.47-7.44 (m, 1H), 7.18 (dd, J= 4.7, 7.8 Hz, 1H), 6.69-6.65 (m, 1H ), 5.53-5.48 (m, 1H), 3.18 (s, 6H), 3.07-2.96 (m, 2H), 2.28-2.22 (m, 1H), 2.07-1.97 (m, 3H) 1.28 _Rt = 1.14; mass/charge (ES+)=480.2 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.16 (d, J= 8 Hz, 1H), 8.61-8.58 (m, 2H), 7.98 (d, J= 5.9 Hz, 1H), 7.35 (d, J= 7.4 Hz, 1H), 7.20-7.09 (m, 2H), 6.92 (t, J= 7.3 Hz, 1H), 6.81-6.78 (m, 2H), 6.59 (d, J= 7.8 Hz, 1H), 5.27-5.22 (m, 1H), 4.30 -4.20 (m, 2H), 3.18 (t, J= 8.1 Hz, 2H), 3.10 (s, 6H), 2.74 (s, 3H), 2.66 (t, J= 8Hz, 2H), 2.23-2.18(m, 1H), 2.10-2.03(m, 1H) 1.29 _Rt = 1.07; mass/charge (ES+)=494.0 [M+H] ⁺ / method A ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.79 (s, 1H), 8.68 (d, J= 5.9 Hz, 1H), 8.51 (s, 1H), 8 .00 (d, J= 5.9 Hz, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.26 (m, 2H), 6.95-6.91 (m, 1H), 6.86 (d, J= 8.2 Hz, 1H), 6.81 (s, 1H), 5.40-5.35 (m, 1H), 4.37-4.32 (m , 1H), 4.22-4.16(m, 1H), 3.19(s, 6H), 2.43-2.36(m, 1H), 2.22-2.17(m, 1H ) 1.30 _Rt = 1.43; mass/charge (ES+)=484.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.17 (s, 1 H), 8.85 (d, J= 5.7 Hz, 1 H), 8.10 (d, J= 5.7 Hz, 1 H), 8.03 (d, J= 1.8 Hz, 2 H), 7.50 (t, J= 1.9 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.25-7.21 (m, 1 H), 6.96 (td, J= 7.5, 0.9 Hz, 1 H), 6.89-6 .87 (m, 1 H), 6.55 (d, J= 7.4 Hz, 1 H), 5.46-5.42 (m, 1 H), 4.40-4.35 (m, 1 H), 4.27-4.21 (m, 1 H), 2.46-2.40 (m, 1 H), 2.33-2.28 (m, 1 H) 1.31 R _t = 1.38; mass/charge (ES+)=509.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.15 (s, 1H), 8.70 (d, J= 5.9 Hz, 1H), 8.09 (d, J= 5, 7 Hz, 1H), 8.00 (d, J= 1.8 Hz, 2H), 7.47 (t, J= 2 Hz, 1H), 7.36-7.34 (m, 1H), 7 .24-7.19 (m, 2H), 6.95 (td, J= 7.5, 0.9 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 5, 40-5.36 (m, 1H), 4.37 (ddd, J= 11, 5.8, 3.5 Hz, 1H), 4.25-4.19 (m, 1H), 3.59 ( s, 3H), 3.33(s, 3H), 2.43-2.36(m, 1H), 2.28-2.23(m, 1H) 1.32 _Rt = 1.48; mass/charge (ES+)=491.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.86 (s, 1H), 8.63 (d, J= 5.9 Hz, 1H), 7.97 (d, J= 2 Hz , 2H), 7.90 (d, J= 5.9 Hz, 1H), 7.44 (t, J= 2 Hz, 1H), 7.40-7.36 (m, 1H), 7.24 -7.20 (m, 2H), 7.16-7.13 (m, 1H), 6.51 (d, J= 8.2 Hz, 1H), 5.42 (dt, J= 8.5 .6 Hz, 1H), 3.19 (s, 6H), 2.89-2.82 (m, 2H), 2.24-2.18 (m, 1H), 2.07-2.00 ( m, 3H) 1.33 _Rt = 1.43; mass/charge (ES+)= 480.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.37 (d, J= 8 Hz, 1H), 8.94 (s, 1H), 8.76 (d, J= 5, 7 Hz, 1H), 8.15-8.14 (m, 3H), 7.76 (t, J= 2 Hz, 1H), 7.39 (d, J= 7 Hz, 1H), 7.21 -7.17(m, 1H), 6.96-6.92(m, 1H), 6.81(d, J=8.2Hz, 1H), 5.31-5.26(m, 1H ), 4.22 (s, 5H), 2.26-2.12 (m, 2H) 1.34 R _t = 1.44; mass/charge (ES+)= 477.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.87 (s, 1H), 8.62 (d, J= 5.9 Hz, 1H), 7.98 (d, J= 1, 8 Hz, 2H), 7.90 (d, J= 5.9 Hz, 1H), 7.44 (t, J= 2 Hz, 1H), 7.39 (d, J= 6.6 Hz, 1H ), 7.29-7.26 (m, 3H), 6.55 (d, J= 8.2 Hz, 1H), 5.72 (q, J= 7.5 Hz, 1H), 3.18 (s, 6H), 3.10-3.00 (m, 2H), 2.80-2.73 (m, 1H), 2.04-1.92 (m, 1H) 1.35 _Rt = 1.48; mass/charge (ES+)= 491.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.85 (s, 1H), 8.62 (d, J= 5.9 Hz, 1H), 7.97 (d, J= 2 Hz , 2H), 7.90 (d, J= 5.9 Hz, 1H), 7.44 (t, J= 2 Hz, 1H), 7.40-7.36 (m, 1H), 7.24 -7.20 (m, 2H), 7.16-7.12 (m, 1H), 6.52 (d, J= 8.2 Hz, 1H), 5.42 (dt, J= 8.2 , 5.5 Hz, 1H), 2.89-2.81 (m, 2H), 2.24-2.18 (m, 1H), 2.07-1.99 (m, 3H) 1.36a _Rt = 1.20; mass/charge (ES+)= 478.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.92 (s, 1H), 8.65 (d, J= 5.9 Hz, 1H), 8.51 (d, J= 4, 7 Hz, 1H), 7.99 (d, J= 1.8 Hz, 2H), 7.91 (d, J= 5.9 Hz, 1H), 7.77-7.74 (m, 1H) , 7.45 (t, J= 2 Hz, 1H), 7.22-7.17 (m, 1H), 6.71-6.66 (m, 1H), 5.78 (q, J= 7 .5 Hz, 1H), 3.19 (m, 8H), 2.87-2.80 (m, 1H), 2.07-1.99 (m, 1H) 1.36b _Rt = 1.20; mass/charge (ES+)= 478.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.92 (s, 1H), 8.65 (d, J= 5.9 Hz, 1H), 8.51 (d, J= 4, 7 Hz, 1H), 7.99 (d, J= 1.8 Hz, 2H), 7.91 (d, J= 5.9 Hz, 1H), 7.77-7.74 (m, 1H) , 7.45 (t, J= 2 Hz, 1H), 7.22-7.17 (m, 1H), 6.71-6.66 (m, 1H), 5.78 (q, J= 7 .5 Hz, 1H), 3.19 (m, 8H), 2.87-2.80 (m, 1H), 2.07-1.99 (m, 1H) 1.37 _Rt = 1.13; mass/charge (ES+)= 534 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.05 (s, 1 H), 8.71 (d, J= 5.9 Hz, 1 H), 7.99 (d, J= 2 Hz, 2 H), 7.85 (d, J= 5.9 Hz, 1 H), 7.47 (t, J= 2 Hz, 1 H), 7.30 (d, J= 7.8 Hz, 1 H), 7.24-7.21 (m, 1 H), 7.00-6.94 (m, 2 H), 6.89 (d, J= 8.4 Hz, 1 H) , 6.26 (s, 1 H), 5.42-5.37 (m, 1 H), 5.06 (s, 2 H), 4.40-4.34 (m, 1 H), 4 .24-4.18(m, 1H), 4.12-4.11(m, 2H), 2.47-2.40(m, 1H), 2.25-2.19(m , 1H) 1.38 _Rt = 1.36; mass/charge (ES+)= 489.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO d6-) δ [ppm]: 9.51 (d, J= 7.8 Hz, 1 H), 9.19 (s, 1 H), 8.91 (d, J = 5.9 Hz, 1 H), 8.32 (d, J= 5.9 Hz, 1 H), 8.09 (d, J= 2 Hz, 2 H), 7.79 (t, J= 2 Hz, 1 H), 7.42 (d, J= 7 Hz, 1 H), 7.21-7.17 (m, 1 H), 6.94-6.91 (m, 1 H), 6.82 (d, J= 8 Hz, 1 H), 5.33-5.28 (m, 1 H), 4.71 (s, 2 H), 4.33-4.23 (m, 2 H), 2.28-2.21(m, 2H) 1.39 R _t = 1.44; mass/charge (ES+)= 507 [M+H] ⁺ / method A ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.92-8.91 (m, 1H), 8.65-8.63 (m, 1 H), 7.97-7.96 ( m, 2 H), 7.92-7.90 (m, 1 H), 7.45 (t, J= 1.9 Hz, 1 H), 7.29 (d, J= 7.8 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.00-6.93 (m, 1 H), 6.87 (d, J= 8.2 Hz, 1 H), 6 .70-6.61 (m, 1 H), 5.52 (dd, J= 4.8, 9.1 Hz, 0.4 H), 5.09 (dd, J= 6.5, 7, 5 Hz, 0.6 H), 4.26-4.19 (m, 1 H), 4.08-4.03 (m, 0.6 H), 3.86 (dd, J= 9.6 , 11.1 Hz, 0.4 H), 3.19-3.18 (m, 6 H), 2.57-2.53 (m, 0.4 H), 2.35-2.29 ( m, 0.6H), 1.20-1.15 (m, 3H) 1.40 R _t = 1.55; mass/charge (ES+)= 475.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.51 (s, 1 H), 8.89-8.84 (m, 2 H), 8.43 (s, 1 H), 8 .05 (d, J= 1.8 Hz, 2 H), 7.51 (t, J= 2 Hz, 1 H), 7.26 (d, J= 15.8 Hz, 1 H), 7, 03 (d, J= 7.6 Hz, 1 H), 6.98 (d, J= 8.4 Hz, 1 H), 6.91 (t, J= 7.5 Hz, 1 H), 5 .91 (dd, J= 7, 10.3 Hz, 1 H), 4.49 (dt, J= 11.5, 3.5 Hz, 1 H), 4.33 (td, J= 11.5 , 2 Hz, 1 H), 2.56-2.46 (m, 1 H), 2.37-2.29 (m, 1 H) 1.41 _Rt = 1.16; mass/charge (ES+)= 477.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.97 (s, 1H), 7.96 (d, J= 5.9 Hz, 1H), 7.57 (d, J= 6 Hz , 1H), 7.31 (d, J= 7.6 Hz, 1H), 7.24-7.19 (m, 2H), 7.07-6.97 (m, 5H), 5.41- 5.37(m, 1H), 4.39-4.23(m, 2H), 3.14(s, 6H), 2.46-2.39(m, 2H) 1.42 Rt= 1.45; mass/charge (ES+)= 492.2 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.24 (d, J= 8.2 Hz, 1H), 8.94 (s, 1H), 8.75 (d, J= 5 .9 Hz, 1H), 8.31 (d, J= 5.9 Hz, 1H), 8.04 (d, J= 2 Hz, 2H), 7.76 (t, J= 2 Hz, 1H) , 7.38 (d, J= 7 Hz, 1H), 7.18 (td, J= 8.4, 1.2 Hz, 1H), 6.94 (td, J= 7.5, 1 Hz, 1H), 6.80 (dd, J= 0.8, 8.2 Hz, 1H), 5.31-5.26 (m, 1H), 4.32-4.25 (m, 2H), 3 .86-3.79(m, 1H), 2.26-2.19(m, 2H), 1.49-1.58(m, 6H) 1.43 Rt= 1.06; mass/charge (ES+)= 504.2 [M+H] ⁺ / method A ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.89 (s, 1H), 8.71 (d, J= 5.9 Hz, 1H), 7.98 (d, J= 5, 9 Hz, 1H), 7.30-7.18 (m, 2H), 7.07-7.05 (m, 1H), 6.96-6.91 (m, 2H), 6.86 (d , J= 8.2 Hz, 1H), 6.77-6.73 (m, 1H), 5.39-5.35 (m, 1H), 4.37-4.32 (m, 1H), 4.21-4.15(m, 1H), 3.19(s, 6H), 2.85-2.83(m, 6H), 2.43-2.36(m, 1H), 2, 24-2.19(m, 1H) 1.44 Rt=1.40; mass/charge (ES+)= 493.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 9.10 (s, 1H), 8.68 (d, J= 5.9 Hz, 1H), 8.22 (s, 1H), 8 .01 (d, J= 1.8 Hz, 2H), 7.94 (d, J= 5.9 Hz, 1H), 7.56-7.52 (m, 1H), 7.46 (t, J= 1.9 Hz, 1H), 7.19 (t, J= 8.2 Hz, 1H), 6.76 (d, J= 8.2 Hz, 1H), 4.20-4.18 ( m, 2H), 3.24 (s, 6H), 2.72 (t, J= 6.5 Hz, 2H), 2.11-2.05 (m, 2H) 1.45 Rt= 1.44; mass/charge (ES+)= 507.0 [M+H] ⁺ / method B ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.13 (d, J= 8.2 Hz, 1H), 8.72 (s, 1H), 8.65 (d, J= 5 .9 Hz, 1H), 8.09 (d, J= 2 Hz, 2H), 8.06 (d, J= 5.7 Hz, 1H), 7.73 (t, J= 2 Hz, 1H) , 7.25 (d, J= 7.8 Hz, 1H), 6.75 (dd, J= 1, 7.8 Hz, 1H), 6.62 (s, 1H), 5.22-5, 17 (m, 1H), 4.28-4.19 (m, 2H), 3.10 (s, 6H), 2.00-2.27 (m, 5H) 1.46 Rt= 1.37; mass/charge (ES+)= 499.0 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.89 (s, 1 H), 8.64 (d, J= 6 Hz, 1 H), 7.98 (d, J= 1, 6 Hz, 1 H), 7.91 (d, J= 5.6 Hz, 1 H), 7.45 (t, J= 2 Hz, 1 H), 7.16 (d, J= 5.2 Hz, 1 H), 6.77 (d, J= 7.2 Hz, 1 H), 6.65 (d, J= 5.6 Hz, 1 H), 5.4 (m, 1 H), 4.37(m, 1H), 4.17(m, 1H), 3.2(s, 6H), 2.45(m, 1H), 2.22(m, 1H) 1.47 Rt= 1.37; mass/charge (ES+)= 499.0 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.89 (s, 1 H), 8.64 (d, J= 6 Hz, 1 H), 7.98 (d, J= 1, 6 Hz, 1 H), 7.91 (d, J= 5.6 Hz, 1 H), 7.45 (t, J= 2 Hz, 1 H), 7.16 (d, J= 5.2 Hz, 1 H), 6.77 (d, J= 7.2 Hz, 1 H), 6.65 (d, J= 5.6 Hz, 1 H), 5.4 (m, 1 H), 4.37(m, 1H), 4.17(m, 1H), 3.2(s, 6H), 2.45(m, 1H), 2.22(m, 1H) 1.48 Rt= 1.20; mass/charge (ES+)= 461.2 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.19 (d, J=8.2 Hz, 1 H), 8.73 (s, 1 H), 8.65 (d, J = 5.7 Hz, 1 H), 8.06 (d, J=5.9 Hz, 1 H), 7.84-7.76 (m, 2 H), 7.41-7.33 (m , 2 H), 7.21-7.15 (m, 1 H), 6.96-6.90 (m, 1 H), 6.80 (dd, J= 8.2, 1 Hz, 1H) , 5.30-5.22(m, 1H), 4.33-4.18(m, 2H), 1.24(s, 6H), 2.27-2.16(m, 1 H), 2.11-2.02(m, 1H) 1.49 Rt= 1.07; mass/charge (ES+)= 443.2 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.90 (s, 1 H), 8.67 (d, J= 5.9 Hz, 1 H), 7.93 (d, J= 5.9Hz, 1H), 7.64-7.57(m, 1H), 7.50-7.43(m, 1H), 7.32-7.25(m, 2H) , 7.24-7.16 (m, 2 H), 6.96-6.90 (m, 1 H), 6.86 (d, J= 8.4 Hz, 1 H), 6.8 ( d, J=7.6 Hz, 1 H), 5.37 (q, J= 7.2 Hz, 1 H), 4.38-4.30 (m, 1 H), 4.22-4, 14(m, 1H), 3.18(s, 6H), 2.43-2.34(m, 1H), 2.24-2.15(m, 1H) 1.50 Rt=1.19; mass/charge (ES+)= 479.0 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.86 (s, 1H), 8.67 (d, J= 6 Hz, 1 H), 7.98 (d, J= 6 Hz, 1 H), 7.26-7.29 (m, 2 H), 7.21 (td, J= 1.2, 8.4 Hz, 1 H), 7.01-7.15 (m, 1 H), 6.93 (td, J= 1.2, 8.4 Hz, 1 H), 6.87 (dd, J= 0.4, 8 Hz, 1 H) 6.66 (d, J= 7.6 Hz, 1 H), 5.37 (q, J= 5.2 Hz, 1 H), 4.32-4.38 (m, 1 H), 4.16-4.22 (m, 1 H), 3.2 (s, 6 H), 2.38-2.46 (m, 1 H), 2.19-2.26 (m, 1 H) 1.51 Rt=1.30; mass/charge (ES+)= 479.0 [M+H] ⁺ / Method B ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.90 (s, 1 H), 8.63 (d, J= 5.6 Hz, 1 H), 7.89 (t, J= 6 Hz, 2 H), 7.86 (d, J= 6.8 Hz, 1 H), 7.30 (d, J= 7.6 Hz, 1 H), 7.23 (t, J= 8 .4 Hz, 1 H), 6.95 (td, J= 1.2, 7.6 Hz, 1 H), 6.88 (d, J= 8.4 Hz, 1 H), 6.73 ( d, J= 7.2 Hz, 1 H), 5.39 (q, J= 7.2 Hz, 1 H), 4.18-4.39 (m, 2 H), 3.18 (s, 6H), 2.19-2.45(m, 2H) 1.52 Rt=1.43; mass/charge (ES-)= 559.2 [MH] ^- / Method B ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.21 (d, J= 8 Hz, 1 H), 8.76 (s, 2 H), 8.72 (s, 1 H) , 8.71 (d, J= 6 Hz, 1 H), 8.27 (s, 1 H), 8.12 (d, J= 5.6 Hz, 1 H), 7.38 (d, J = 7.6 Hz, 1 H), 7.18 (td, J= 1.6, 8.4 Hz, 1 H), 6.93 (td, J= 1.2, 8.4 Hz, 1 H ), 6.80 (dd, J= 0.8, 8 Hz, 1 H), 5.24 (q, J= 7.6 Hz, 1 H), 4.20-4.32 (m, 2 H ), 3.12(s, 6H), 2.03-2.25(m, 2H) 1.53 Rt= 1.16; mass/charge (ES-)= 494.0 [MH] ^- / Method B ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.23 (d, J= 8 Hz, 1H), 8.77 (s, 1 H), 8.65 (d, J= 5, 6 Hz, 1 H), 8.49 (s, 1 H), 8.25 (d, J= 5.6 Hz, 1 H), 8.25 (d, J= 5.6 Hz, 1 H) , 8.09 (d, J= 2 Hz, 1 H), 8.07 (d, J= 5.6 Hz, 1 H), 7.73 (t, J= 2 Hz, 1 H), 6, 83 (d, J= 5.6 Hz, 1 H), 5.28 (q, J= 7.2 Hz, 1 H), 4.29-4.43 (m, 2 H), 3.10 ( s, 6H), 2.09-2.27(m, 2H) 1.54 Rt=2.93; mass/charge (ES-)= 493.0 [M+H] ⁺ / Method C ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.15 (d, J= 8.4 Hz, 1 H), 8.62 (d, J= 6 Hz, 1 H), 8, 58 (s, 1 H), 8.09 (d, J= 5.6 Hz, 1 H), 7.73 (d, J= 2 Hz, 1 H), 7.53-7.55 (m, 2 H), 7.34 (d, J= 6.8 Hz, 1 H), 7.16 (td, J= 1.6, 8.8 Hz, 1 H), 6.91 (td, J= 1.2 , 7.6 Hz, 1 H), 3.81 (d, J= 7 Hz, 1 H), 5.22 (q, J= 5.6 Hz, 1 H), 4.19-4 .30 (m, 2 H), 3.11 (s, 6 H), 2.16-2.23 (m, 1 H), 2.01-2.07 (m, 1 H) 1.55 Rt=2.89; mass/charge (ES-)= 493.0 [M+H] ⁺ / Method C ¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.15 (d, J= 8.4 Hz, 1 H), 8.62 (d, J= 6 Hz, 1 H), 8, 59 (s, 1 H), 8.10 (d, J= 6 Hz, 1 H), 7.73 (dd, J= 1.6, 8 Hz, 1 H), 7.48 (t, J= 7.6 Hz, 1 H), 7.39-7.42 (m 1 H), 7.34 (d, J= 6.8 Hz, 1 H), 7.16 (td, J= 1.6 , 8.4 Hz, 1 H), 6.90 (td, J= 0.8, 8.4 Hz, 1 H), 6.79 (d, J= 8 Hz, 1 H), 5.22 ( q, J= 5.6 Hz, 1 H), 4.21-4.27 (m, 2 H), 3.12 (s, 6 H), 2.15-2.22 (m, 1 H) , 2.00-2.06 (m, 1H)

The compounds of formula (I) of the present invention are useful in the treatment and/or control, in particular of helminths, when endoparasitic nematodes and flukes can cause serious diseases in mammals and poultry. Representative nematodes by this definition are Filariidae , Setariidae , Haemonchus , Trichostrongylus , Ostertagia , Nematodirus , Cooperia , Ascaris , Bunostonum , Oesophagostonum , Charbertia , Trichuris , Strongylus , Trichonema , Dictyocaulus , Capillaria , Heterakis , Toxocara , Ascarid ia, Oxyuris , Ancylostoma , Uncinaria , Toxascaris and Parascaris . Trematodes include in particular the family Fasciolideae , especially Fasciola hepatica .

Some parasite speciesNematodirus,cooperia AndOesophagostonum affect the intestinal tract of the host animal, while others, speciesHaemonchus AndOstretagia, parasitize in the stomach, and parasites, which are speciesDictyocaulusparasitize in lung tissue. Parasites from these families can also be found in the internal tissue and organs, for example, in the heart, blood vessels, lymphatics and subcutaneous tissue. In particular, a notable parasite is the dog heartworm,Dirofilaria imitis.

Parasites that can be treated and/or controlled by compounds of formula (I),

also includes parasites from the classCestoda (tapeworms), for example, familiesMesocestoidae, especially the kindMesocestoides, in particularM. lineatus;

Dipylidiidae , especially Dipylidium caninum , Joyeuxiella spp., in particular Joyeuxiella pasquali , and Diplopylidium spp., and Taeniidae , especially Taenia pisformis , Taenia cervi , Taenia ovis , Taeneia hydatigena , Taenia multiceps , Taenia taeniaeformis , Taenia serialis , and Echinococcus spp., most specifically Taneia hydatigena , Taenia ovis , Taenia multiceps , Taenia serialis ; Echinococcus granulosus and Echinococcus multilocularis .

In addition, the compounds of formula (I) are suitable for the treatment of human pathogenic parasites and/or the control of human pathogenic parasites. Of these, typical representatives that inhabit the digestive tract are parasites from the genera Ancylostoma , Necator , Ascaris , Strongyloides , Trichinella , Capillaria , Trichuris , and Enterobius . The compounds of the present invention are also effective against parasites from the genera Wuchereria , Brugia , Onchocerca and Loa from the family Dracunculus and parasites from the genera Strongyloides and Trichinella , which infect in particular the gastrointestinal tract.

A particular parasite that is treated and/or controlled by the compounds of the present invention is the heartworm ( Dirofilaria immitis ). Specific subjects for such treatment are dogs and cats.

The compounds of the present invention may be administered alone or in the form of a composition. In practice, the compounds of the present invention are usually administered in the form of compositions, ie in admixture with at least one suitable excipient. The ratio and nature of any suitable excipient(s) will be determined based on the properties of the selected compound of the present invention, the chosen route of administration, and standard practice in both the veterinary and pharmaceutical fields.

In one embodiment, the present invention provides compositions containing a compound of the present invention and at least one acceptable excipient.

To effect such treatment and/or control, the compound of the present invention may be administered in any form and by any route that promotes the bioavailability of the compound. The compounds of the present invention can be administered in a variety of ways, including orally, in particular tablets and capsules. The compounds of the present invention may be administered by parenteral routes, more specifically by inhalation, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, vaginal, ocular, topical, sublingual and buccal, intraperitoneal, intraadipose, intrathecal, and by topical delivery, e.g. using a catheter or stent.

The person skilled in the art can readily select the appropriate form and route of administration depending on the specific characteristics of the selected compound, the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances. Pharmaceutical compositions of the present invention may be administered to a subject, for example, in the form of tablets, capsules, cachets, paper-backed drugs, lozenges, cachets, tinctures, ointments, transdermal patches, aerosols, inhalers, suppositories, liquid oral dosage forms. applications, solutions and suspensions.

The term "acceptable excipient" refers to those commonly used in the preparation of veterinary and pharmaceutical compositions and which must be pure and non-toxic in the amounts used. In general, they are a solid, semi-solid or liquid material which together can serve as a carrier or medium for the active ingredient. Some examples of acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, carrier media, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavoring agents, bases for gels, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, colorants, propellants, coating agents and others.

In one embodiment, the composition is adapted for oral administration, in the form of, for example, a tablet or capsule, or a liquid formulation, such as a solution or suspension, adapted for oral administration. In one embodiment, the composition is adapted for oral administration, such as a chewable composition adapted for oral administration. In yet another embodiment, the composition is a liquid or semi-solid formulation, such as a solution or suspension or paste, adapted for parenteral administration.

Particular compositions for use in relation to subjects in the course of treatment and/or control of nematodes/helminths contain solutions; emulsions, including classic emulsions, microemulsions, and self-emulsifying compositions, which are anhydrous organic, preferably oily, compositions that form emulsions with body fluids when added to a subject's body; suspensions (liquid dosage forms for oral administration); pourable compositions; nutritional supplements; powders; tablets, including effervescent tablets; boluses; capsules, including microcapsules; and chewables for treatment. Particular forms of the composition are tablets, capsules, dietary supplements or chewable medications.

The compositions of the present invention are prepared in a manner well known in the veterinary and pharmaceutical arts and include at least one of the compounds of the present invention as an active ingredient. The amount of a compound of the present invention may vary depending on its particular form and conveniently may range from 1% to about 50% by weight of the single dosage form. The pharmaceutical compositions of the present invention are preferably formulated as a single dosage form, with each dose typically containing from about 0.5 mg to about 100 mg of the compounds of the present invention. You can take one or more single(s) dosage(s) form(s) for the introduction of the required dose for treatment.

In one embodiment, the present invention also provides a method of treating parasites comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

In one embodiment, the present invention also provides a method of controlling parasites comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

In one embodiment, the present invention also provides a method of treating or controlling parasites, comprising contacting the subject's environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound. .

Thus, the present invention provides for the use of the compounds of the present invention as a medicinal product, including for the manufacture of a medicinal product. In one embodiment, the present invention provides for the manufacture of a medicament containing a compound of formula (I), or a salt thereof, for the treatment of parasites. In one embodiment, the present invention provides for the manufacture of a medicament containing a compound of the present invention, or a salt thereof, for the control of parasites.

[001] The terms "treating," "treating," "treatable," or "treatment" include, without limitation, restraining, slowing, stopping, reducing, ameliorating, reversing the progression or severity of an existing symptom, or preventing a disorder, condition, or disease. For example, an adult heartworm infection will be treated by administering a compound of the present invention. The treatment agent may be used or administered therapeutically.

The terms "control", "exercising control" or "under control" refer to the following, including without limitation reducing, reducing or reducing the risk of developing a symptom, disorder, condition or disease and protecting the animal from the symptom, disorder, condition or disease. The exercise of control may refer to therapeutic, prophylactic or preventive administration. It is understood that infection with immature heartworm larvae can be asymptomatic, and infection with mature parasites is symptomatic and/or severe, therefore, for example, heartworm infection will be controlled by targeting the larvae or the immature parasite, preventing the infection from progressing to infection with mature parasites. .

Thus, the use of the compounds of the present invention in the treatment and/or control of parasites, in particular helminths, among which endoparasitic nematodes and trematodes, refers to the use of the compounds of the present invention to act on various forms of parasites throughout their life cycle, regardless of in addition, the subject exhibits a symptom, including morbidity or mortality, and regardless of the phase(s) of the parasitic infection.

[002] As used herein, "subject administration" includes, without limitation, dermal, subcutaneous, intramuscular, mucosal, submucosal, transdermal, oral, or intranasal administration. Administration may include injection or topical administration.

[003] The terms "subject" and "patient" refer to humans and non-human mammals such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. It is known that a more specific subject is a human. Also, a more specific subject is mammalian domestic or companion animals such as dogs and cats, as well as mice, guinea pigs, ferrets and rabbits.

[004] The term "effective amount" refers to an amount that provides the desired beneficial effect to the subject, and includes the introduction for the implementation of both treatment and control. The amount will vary from one individual subject to another and will depend on a number of factors, including the general physical condition of the subject and the severity of the underlying cause of the condition being treated, the concomitant treatment, and the amount of a compound of the present invention used to maintain the desired response at a favorable level.

An effective amount can be readily determined by consulting a diagnostician, one of skill in the art, by applying known techniques and by observing results obtained under similar circumstances. In determining the effective amount, dose, several factors are considered at the time of referral to the diagnostician, including, without limitation, the type of patient; its size, age and general health; the specific condition, disorder, infection, or disease involved in the pathological process; the degree or involvement in the pathological process, or the severity of the condition, disorder or disease, the response of the individual patient; the particular compound being administered; method of administration; bioavailability, characteristics of the administered drug; the selected scheme of administration; the use of concomitant medications; and other significant circumstances. It is assumed that the effective amount of the present invention, the required dose for treatment, is in the range from 0.5 mg to 100 mg. Specific amounts can be determined by a person skilled in the art. While such doses are based on the characteristics of a subject weighing from about 1 kg to about 20 kg, the diagnostician will be able to determine the appropriate dose for a subject whose weight falls outside this weight range. It is assumed that the effective amount of the present invention, the required dose for treatment, is in the range from 0.1 mg to 10 mg/kg of the subject. It is contemplated that the administration schedule is daily, weekly or monthly administration.

The compounds of the present invention can be combined with one or more other active compounds or therapies for the treatment of one or more disorders, diseases or conditions, including the treatment of parasites, for which they are indicated. The compounds of the present invention may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for the treatment of parasites and other disorders.

For example, when used to treat parasites, including heartworm, a compound of the present invention can be combined with a macrocyclic lactone such as ivermectin, moxidectin, or milbemycin oxime, or with imidacloprid. Specific combinations for the treatment of parasites include the compound of the present invention and ivermectin. Another specific parasite treatment combination includes a compound of the present invention and milbemycin oxime.

Thus, the compositions and methods of the present invention are known to optionally comprise an effective amount of at least one additional active compound.

The activity of compounds as antiparasitic agents can be determined by various methods, including in vitro and in vivo methods.

Example A

Heartworm microfilariae in dogs

D. immitis microfilariae were isolated by filtration from the blood of a beagle dog that was an infected donor and allowed to incubate in a suitable medium. Test compounds were diluted in DMSO and added to a 96-well plate containing parasitic organisms. The plates were incubated for the required time and motility was assessed using an imaging system with an LCD camera. Serum effect was tested by adding no more than 20% fetal bovine serum to the assay. Percent mobility inhibition values were obtained relative to the average of wells containing only DMSO.

In this test, for example, the following compounds from the preparation examples showed EC50 <0.1 µg/ml: 1.1, 1.8, 1.9, 1.12, 1.15, 1.17, 1.20, 1.21, 1.24, 1.30, 1.31, 1.32, 1.33, 1.37, 1.38 , 1.39, 1.42, 1.45, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.54, 1.55, 2.1, 4.1, 5.1, 6.1, and 7.1.

Example B

Gastrointestinal infection of ruminants ( H. contortus ( Hc .))

Hc . eggs isolated from lamb faeces were hatched overnight in an incubator. Test compounds were diluted in DMSO and added to a 96-well plate containing the appropriate medium. Hc larvae. was added to each well and the plates were incubated for the required time. Mobility was assessed using an imaging system with an LCD camera. Percent mobility inhibition values were obtained relative to the average of wells containing only DMSO.

In this test, for example, the following compounds from the preparation examples showed EC50 <0.1 μg/ml: 1.1, 1.7, 1.8, 1.9, 1.12, 1.17, 1.20, 1.21, 1.24, 1.25, 1.31. 1.32, 1.33, 1.37, 1.38, 1.39, 1.42, 1.45, 1.47, 1.48, 1.50, 1.51, 1.54, 1.55, 2.1, 3.1, 4.1, 5.1, 6.1, and 7.1.

Example C

Gastrointestinal nematode infection

Gerbils ( Meriones unguiculatus ) were artificially infected by force-feeding with a probe with third-stage larvae of each of T. colubriformis and H. contortus . Then, on day 6 post challenge, treated orally with a test compound formulated in, for example, DMSO/PEG 2/1 at a dose that ranges from 1 x 3 mg/kg to not more than 1 x 32 mg/kg. Three days after treatment, the gerbils were euthanized and dissected to remove H. contortus from the stomach and T. colubriformis from the small intestine. Efficacy was expressed as a % reduction in worms compared to the placebo treated group using Abbott's formula. Compound Nos. 1.1, 1.9, 1.20, 1.21 and 1.31 showed an efficiency of >90% in this model. Compound #1.50 showed >90% efficiency with respect to Hc in this model.

Example D

Nematodes causing filariasis

Av Model: Gerbils injected subcutaneously with infective A. viteae larvae were sequentially treated with test preparations formulated in e.g. mg/kg up to a maximum of 5 x 32 mg/kg (one dose per day for 5 consecutive days). During necropsy of animals 12 weeks post-challenge, efficacy was expressed as a % reduction in worm counts compared to the placebo-treated group using Abbott's formula. Compound Nos. 1.1, 1.9, 1.20, 1.31, 1.32, 1.42, and 5.1 demonstrated >80% efficiency in this model.

Example E

Ls model

Mice injected subcutaneously with L. sigmodontis infective larvae were sequentially treated with test preparations formulated in, for example, DMSO/PEG 2/1 by oral gavage feeding at a dose that ranged from 1 x 3 mg/kg up to no more than 5 × 32 mg/kg (one dose per day for 5 consecutive days). During necropsy of animals 5 weeks after challenge, efficacy was calculated by counting developed larvae versus untreated animals using Abbott's formula. Compound 1.8 showed >70% efficiency in this model.

Claims (109)

1. Compound of formula (I), Where n is 0 or 1; X ₁ is N; X ₂ is CR ₂ ; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is N; X ₁ is CR ₁ ; X ₂ is CR ₂ ; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is N; and X ₆ is CR ₆ ; X ₁ is N; X ₂ is CR ₂ ; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is N; and X ₆ is CR ₆ ; X ₁ is N; X ₂ is CR ₂ ; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is CR ₆ ; X ₁ is CR ₁ ; X ₂ is CR ₂ ; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is CR ₆ ; X ₁ is CR ₁ ; X ₂ is CR ₂ ; X ₃ is N; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is CR ₆ ; X ₁ is CR ₁ ; X ₂ is N; X ₃ is CR ₃ ; X ₄ is CR ₄ ; X ₅ is CR ₅ ; and X ₆ is CR ₆ ; G is a group ; Y ₁ is selected from the group consisting of CR ₈ R ₉ , O, and S; Y ₂ is selected from the group consisting of CR ₈ R ₉ , O, and S; where at least one of the groups Y ₁ or Y ₂ represents CR ₈ R ₉ ; Z ₁ is selected from the group consisting of N and CR ₁₁ ; Z ₂ is CR ₁₁ ; Z ₃ is absent or selected from the group consisting of N and CR ₁₁ ; Z ₄ is selected from the group consisting of O, S and CR ₁₁ ; and Z ₃ is absent only if Z ₄ is O or S; R ₁ is hydrogen; R ₂ is hydrogen; R ₃ is hydrogen; R ₄ is selected from the group consisting of halogen, cyano, hydroxyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), - N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkoxy), 6-membered aryl; and a monocyclic heterocycle selected from the group consisting of a 4-7 membered heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, a 5-membered heteroaryl containing one nitrogen atom, through which the 5-membered the heteroaryl ring is attached to the rest of the molecule; 6-membered heteroaryl containing one nitrogen atom; each of the aryl, heterocycloalkyl and heteroaryl rings in R ₄ is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, hydroxyl, oxo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₄ haloalkyl, C ₁ -C ₄ alkoxy; and where each of C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₄ alkoxy in R ₄ may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , cyano and C ₁ -C ₄ alkoxy; R ₅ is hydrogen; R ₆ is hydrogen; R ₇ is hydrogen; R ₈ is hydrogen; R ₉ is hydrogen; R ₁₁ is at each occurrence independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl; And Q is selected from the group consisting of 6- or 10-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -NH(C ₃ -C ₆ cycloalkyl), -N(C ₁ -C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), where a 6- or 10-membered aryl is optionally fused to a 4-7-membered heterocycloalkyl containing 1 or 2 N heteroatoms, and where the carbon atoms of the heterocycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ) ₂ , and any N in heterocycloalkyl, if valency permits, is substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; 5-10 membered heteroaryl containing 1 or 2 N heteroatoms, and wherein the carbon atoms of the 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heteroaryl, if valence permits, optionally substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; 4-7 membered heterocycloalkyl containing 1 or 2 N heteroatoms, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbon atoms of the 4-7 membered heterocycloalkyl or optionally benzo-fused 4-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ , and any N in heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; 6- or 10-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ - C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ ; 6- or 10-membered arylthiooxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ - C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ ; excluding connections N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3,5-trifluorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide; And N-[(4S)-chroman-4-yl]-8-(2,3,5-trichlorophenyl)-4-(morpholin-4-yl)-1,7-naphthyridine-3-carboxamide; or a veterinarily or pharmaceutically acceptable salt thereof. 2. Connection according to claim 1, where Q is a 6-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -NH (C ₃ -C ₆ cycloalkyl), -N (C ₁ - C ₄ alkyl)(C ₃ -C ₆ cycloalkyl), where a 6-membered aryl is fused to a 4-7-membered heterocycloalkyl containing 1 or 2 N heteroatoms, and where the carbon atoms of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), and -N(C ₁ -C ₄ alkyl) ₂ and any N in the heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl; or a veterinarily or pharmaceutically acceptable salt thereof. 3. Connection under item 1, where n is 1; or a veterinarily or pharmaceutically acceptable salt thereof. 4. Connection under item 1, where Y ₁ represents CR ₈ R ₉ and Y ₂ represents O; or a veterinarily or pharmaceutically acceptable salt thereof. 5. Connection according to any one of paragraphs. 1-4, where R ₄ is selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -N(C ₁ -C ₄ alkyl) ₂ and 4-7-membered heterocycloalkyl containing one or two a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; or a veterinarily or pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, selected from the group consisting of N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[(1R)-tetralin-1-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[(1S)-tetralin-1-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[(1R or S)-tetralin-1-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(1,2-dihydronaphthalen-1-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; trans- 8-(2,3,3a,4,5,6,7,7a-octahydroindol-1-yl)-N-[(4S)-chroman-4-yl]-4-(dimethylamino)-1, 7-naphthyridine-3-carboxamide; cis- 8-(2,3,3a,4,5,6,7,7a-octahydroindol-1-yl)-N-[(4S)-chroman-4-yl]-4-(dimethylamino)-1, 7-naphthyridine-3-carboxamide; 8-(5-chloroindolin-1-yl)-N-[(4S)-chroman-4-yl]-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-(5-chloroindol-1-yl)-N-[(4S)-chroman-4-yl]-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-morpholino-8-phenylsulfanyl-1,7-naphthyridine-3-carboxamide; 4-amino-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-isopropoxy-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(4-methylpiperazin-1-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,6-difluorophenyl)-4-(4-methylpiperazin-1-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-pyrrolidin-1-yl-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(4S)-7-fluorochroman-4-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(1H-indol-4-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-phenyl-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-cyclopropyl-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(1S)-indan-1-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-6-cyanochroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-((4S)-7-chlorochroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-((4R)-7-chlorochroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,6-difluoro-3-methoxy-phenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; 8-((4S)-3,5-dichlorophenyl)-4-(dimethylamino)-N-(7-methoxychroman-4-yl)-1,7-naphthyridine-3-carboxamide; 8-((4R)-3,5-dichlorophenyl)-4-(dimethylamino)-N-(7-methoxychroman-4-yl)-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-((8S)-5,6,7,8-tetrahydroquinolin-5-yl)-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-((8R)-5,6,7,8-tetrahydroquinolin-5-yl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichloro-2-pyridyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; 4-chloro-N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-[methoxy(methyl)amino]-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(1S)-tetralin-1-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-methoxy-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(1R)-indan-1-yl]-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(1R)-tetralin-1-yl]-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-((8S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-4-(dimethylamino)-1,7-naphthyridine-3- carboxamide; 8-(3,5-dichlorophenyl)-N-((8R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-4-(dimethylamino)-1,7-naphthyridine-3- carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(4-oxo-imidazolidin-1-yl)-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[rac-(3R,4S)-3-methylchroman-4-yl]-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-cyano-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-isopropyl-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-[3-(dimethylamino)-2,6-difluorophenyl]-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-4-(dimethylamino)-N-[(4S)-7-methylchroman-4-yl]-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-[(7S)-6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl]-4-(dimethylamino)-1,7- naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-[(7R)-6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl]-4-(dimethylamino)-1,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-difluorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2-fluorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-4-(dimethylamino)-8-(3,4,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; 8-[3,5-bis(trifluoromethyl)phenyl]-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)-1,7- naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,4-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(2,3-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)isoquinoline-3-carboxamide; N-[(4S)-chroman-4-yl]-8-(3,5-dichlorophenyl)-4-(dimethylamino)-2,7-naphthyridine-3-carboxamide; N-[(4S)-chroman-4-yl]-1-(3,5-dichlorophenyl)-5-(dimethylamino)isoquinoline-6-carboxamide; (4S)-chroman-4-yl]-5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxamide; N-[(4S)-chroman-4-yl]-4-(3,5-dichlorophenyl)-8-(dimethylamino)quinoline-7-carboxamide; N-[(4S)-chroman-4-yl]-4-(3,5-dichlorophenyl)-8-(dimethylamino)isoquinoline-7-carboxamide or a veterinarily or pharmaceutically acceptable salt of each of the above compounds. 7. The use of a compound according to any one of paragraphs. 1-6 or a veterinarily or pharmaceutically acceptable salt thereof as a medicament for the treatment and/or control of D. immitis, H. contortus, T. colubriformis, A. viteae, or L. sigmodontis . 8. The use of a compound according to any one of paragraphs. 1-6 or a veterinarily or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or control of D. immitis, H. contortus, T. colubriformis, A. viteae, or L. sigmodontis .