6-6 fused bicyclic heteroaryl compounds and their use as LATS inhibitors

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof

wherein

Ring A is

(a) a 5- or 6-membered monocyclic heteroaryl that is linked to the remainder of the molecule through a carbon ring member and comprises, as ring member, 1 to 4 heteroatoms that are independently selected from the group consisting of N, O and S, provided that at least one of the heteroatom ring member is an unsubstituted nitrogen (—N═) positioned at the 3- or the 4-position relative to the linking carbon ring member of the 5-membered heteroaryl or at the para ring position of the 6-membered heteroaryl; or

(b) a 9-membered fused bicyclic heteroaryl that is selected from the group consisting of:

wherein “*” represents the point of attachment of ring A to the remainder of the molecule; and

wherein ring A is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —NH 2 , C 1-6 alkylamino, di-(C 1-6 alkyl)amino, C 3-6 cycloalkyl, and phenylsulfonyl;

R 0 is hydroxyl or C 1-6 alkoxy;

R 1 is hydrogen or C 1-6 alkyl;

R 2 is selected from the group consisting of

(a) C 1-8 alkyl that is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of:

(i) halogen;

(ii) cyano;

(iii) oxo;

(iv) C 2 alkenyl;

(v) C 2 alkynyl;

(vi) C 1-6 haloalkyl;

(vii) —OR 6 , wherein R 6 is selected from hydrogen, C 1-6 alkyl that is unsubstituted or substituted by R 0 or —C(O)R 0 ;

(viii) —NR 7a R 7b , wherein R 7a is hydrogen or C 1-6 alkyl, and R 7b is selected from hydrogen, —C(O)R 0 , C 1-6 alkyl that is unsubstituted or substituted by —C(O)R 0 ;

(ix) —C(O)R 8 , wherein R 8 is R 0 or —NH—C 1-6 alkyl-C(O)R 0 ;

(x) —S(O) 2 C 1-6 alkyl;

(xi) monocyclic C 3-6 cycloalkyl or polycyclic C 7-10 cycloalkyl that are each unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 haloalkyl, R 0 , —NH 2 , C 1-6 alkylamino, and di-(C 1-6 alkyl)amino;

(xii) 6-membered heterocycloalkyl comprising, as ring members, 1 to 2 heteroatoms independently selected from the group consisting of N, O and S and that is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkylamino, and di-(Ci-6alkyl)amino;

(xiii) phenyl that is unsubstituted or substituted by halogen;

(xiv) 5- or 6-membered monocyclic heteroaryl comprising, as ring members, 1 to 4 heteroatoms independently selected from the group consisting of N and O; and

(xv) 9- or 10-membered fused bicyclic heteroaryl comprising, as ring member, 1 to 2 heteroatoms independently selected from the group consisting of N and O;

(b) —S(O) 2 C 1-6 alkyl;

(c) phenyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl and R 0 ;

(d) C 3-6 cycloalkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of C 1-6 haloalkyl, R 0 , C 1-6 alkylamino, di-(C 1-6 alkyl)amino, —C(O)R 0 , and C 1-6 alkyl that is unsubstituted or substituted by R 0 or —C(O)R 0 ; and

(e) 4-membered heterocycloalkyl comprising, as ring members, 1 to 2 heteroatoms selected from the group consisting of N, O and S and that is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of C 1-6 haloalkyl, R 0 , C 1-6 alkylamino, di-(C 1-6 alkyl)amino, —C(O)R 0 , and C 1-6 alkyl that is unsubstituted or substituted by R 0 or —C(O)R 0 ;

or, R 1 and R 2 can be taken together with the nitrogen atom to which both are bound to form a 4- to 6-membered heterocycloalkyl that can include, as ring members, 1 to 2 additional heteroatoms independently selected from the group consisting of N, O, and S, wherein the 4- to 6-membered heterocycloalkyl formed by R 1 and R 2 taken together with the nitrogen atom to which both are bound is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and R 0 ;

R 3 is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl; and

R 5 is selected from the group consisting of hydrogen, halogen and —NH-(3- to 8-membered heteroalkyl), wherein the 3- to 8-membered heteroC 3-8 alkyl of the —NH-(3- to 8-membered heteroalkyl) comprises 1 to 2 oxygen atoms as chain members and is unsubstituted or substituted by R 0 .

2. The compound according to claim 1 , wherein ring A is selected from the group consisting of

which are each unsubstituted or substituted by a substituent selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and —NH 2 ; or is

which is unsubstituted or substituted by C 1-6 alkyl.

3. The compound according to claim 1 , wherein ring A is

4. The compound according to claim 1 , wherein R 2 is selected from the group consisting of:

(a) C 1-8 alkyl that is unsubstituted or substituted by A1 to A3 substituents independently selected from the group consisting of

(i) cyano;

(ii) C 2 alkynyl;

(iii) C 1-6 haloalkyl;

(iv) —OR 6 , wherein R 6 is selected from the group consisting of hydrogen, and C 1-6 alkyl that is unsubstituted or substituted by R 0 or —C(O)R 0 ;

(v) —NR 7a R 7b , wherein R 7a is hydrogen or C 1-6 alkyl, and R 7b is selected from the group consisting of hydrogen, —C(O)R 0 , and C 1-6 alkyl that is unsubstituted or substituted by —C(O)R 0 ;

(vi) —C(O)R 8 , wherein R 8 is R 0 ;

(vii) —S(0)2C 1-4 alkyl;

(viii) monocyclic C 3-6 cycloalkyl that is unsubstituted or substituted by a substituent selected from the group consisting of C 1-6 alkyl, hydroxyC 1-6 alkyl and R 0 ;

(ix) 6-membered heterocycloalkyl comprising, as ring members, 1 to 2 heteroatoms independently selected from the group consisting of N and O, and wherein the 6-membered heterocycloalkyl is unsubstituted or substituted by C 1-6 alkyl;

(x) phenyl that is unsubstituted or substituted by halogen; and

(b) C 3-6 cycloalkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from C 1-6 haloalkyl, R 0 , C 1-6 alkylamino, —C(O)R 0 , C 1-6 alkyl that is unsubstituted or substituted by —R 0 or —C(O)R 0 .

5. The compound according to claim 1 , wherein R 2 is selected from the group consisting of:

n-propyl, isopropyl, t-butyl,

6. The compound according to claim 1 , wherein the compound is of Formula A3:

wherein

X 1 is CH;

Ring A is

each of which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —NH 2 ;

R 1 is hydrogen or unsubstituted C 1-6 alkyl; and

R 2 is

(a) C 1-8 alkyl that is unsubstituted or substituted by 1 substituents selected from the group consisting of

(i) C 1-4 haloalkyl; and

(ii) —OR 6 , wherein R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl that is unsubstituted or substituted by hydroxyl; or

(b) monocyclic C 3-6 cycloalkyl that is unsubstituted or substituted by C 1-6 alkyl or C 1-6 haloalkyl and R 0 .

7. A compound, or a salt thereof, selected from the group consisting of: N (4 methoxy-2-methylbutan-2-yl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-[2-methyl-1-(propan-2-yloxy)propan-2-yl]-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-[(2S)-butan-2-yl]-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-[(2R)-butan-2-yl]-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-(1-methoxy-2-methylpropan-2-yl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-methyl-N-(propan-2-yl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; 3-methyl-3-{[2-(pyridin-4-yl )-1,7-naphthyridin-4-yl]amino}butan-1-ol; N-tert-butyl-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; 2,2-dimethyl-1-[2-(pyridin-4-yl)-1,7-naphthyridin-4-yl]piperidin-4-ol; 2,4-dimethyl-4-{[2-(pyridin-4-yl)-1,7-naphthyridin-4-yl]amino pentan-2-ol; N-cyclopentyl-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; dimethyl(3-methyl-3-{[2-(pyridin-4-yl)-1,7-naphthyridin-4-yl]amino}butyl)amine; N,N-diethyl-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; 2-methyl-1-(2-methyl-2-{[2-(pyridin-4-yl)-1,7-naphthyridin-4-yl]amino}propoxy)propan-2-ol; N-propyl-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-tert-butyl-2-(3-methyl-1H-pyrazol-4-yl)-1,7-naphthyridin-4-amine; N-tert-butyl-2-(pyrimidin-4-yl)-1,7-naphthyridin-4-amine; 2-(2-aminopyrimidin-4-yl)-N-tert-butyl-1,7-naphthyridin-4-amine; N-tert-butyl-2-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1,7-naphthyridin-4-amine; N-tert-butyl-2-(pyridazin-4-yl)-1,7-naphthyridin-4-amine; 2-(2-aminopyridin-4-yl)-N-tert-butyl-1,7-naphthyridin-4-amine; N,N-diethyl-2-(3-fluoropyridin-4-yl)-1,7-naphthyridin-4-amine; (3-{[2-(3-fluoropyridin-4-yl)-1,7-naphthyridin-4-yl]amino}-3-methylbutyl)dimethylamine; 2-(3-fluoropyridin-4-yl)-N-methyl-N-(propan-2-yl)-1,7-naphthyridin-4-amine; N-tert-butyl-2-(3-fluoropyridin-4-yl)-1,7-naphthyridin-4-amine; 2-(3-fluoropyridin-4-yl)-N-(2-methylbutan-2-yl)-1,7-naphthyridin-4-amine; 2-{[2-(3-fluoropyridin-4-yl)-1,7-naphthyridin-4-yl]amino}-2-methylpropan-1-ol; 2 (3 fluoropyridin-4-yl)-N-[2-methyl-1-(morpholin-4-yl)propan-2-yl]-1,7-naphthyridin-4-amine; N-tert-butyl-2-(3-chloropyridin-4-yl)-1,7-naphthyridin-4-amine; 2 (pyridin-4-yl)-N-(1-(trifluoromethyl)cyclobutyl)-1,7-naphthyridin-4-amine; 2-methyl-N1-(2-(pyridin-4-yl)-1,7-naphthyridin-4-yl)propane-1,2-diamine; N-(oxetan-3-yl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-(1-methylcyclopropyl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-(1 methylcyclobutyl)-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; 2,2-dimethyl-N1-(2-(pyridin-4-yl)-1,7-naphthyridin-4-yl)propane-1,3-diamine; N 2 ,N 2 ,2-trimethyl-N 1 -(2-(pyridin-4-yl)-1,7-naphthyridin-4-yl)propane-1,2-diamine; 4-(2-methylpiperazin-1-yl)-2-(pyridin-4-yl)-1,7-naphthyridine; 2-methyl-N 1 -(2-(pyridin-4-yl)-1,7-naphthyridin-4-yl)propane-1,3-diamine; N-(tert-butyl)-N-methyl-2-(pyridin-4-yl)-1,7-naphthyridin-4-amine; N-(1-methylcyclobutyl)-2-(pyrimidin-4-yl)-1,7-naphthyridin-4-amine; and (S)-1,1,1-trifluoro-2-methyl-3-((2-(pyridin-4-yl)-1,7-naphthyridin-4-yl)amino)propan-2-ol; 2-(3-chloropyridin-4-yl)-N,N-diethyl-1,7-naphthyridin-4-amine.

8. A pharmaceutical composition comprising a compound of claim 1 as an active ingredient and at least one pharmaceutically acceptable excipient.

9. The compound according to claim 1 , wherein Ring A is a 5- or 6-membered monocyclic heteroaryl that is linked to the remainder of the molecule through a carbon ring member and comprises, as ring member, 1 to 2 heteroatoms that are selected from N, provided that at least one of the nitrogen atom ring member is an unsubstituted nitrogen (—N═) positioned at the 3- or the 4-position relative to the linking carbon ring member of the 5-membered heteroaryl or at the para ring position of the 6-membered heteroaryl.

10. The compound according to claim 1 , wherein ring A is selected from

11. The compound according to claim 1 , wherein

R 2 is selected from

(a) C 1-8 alkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from

(i) cyano;

(ii) C 2 alkynyl;

(iii) C 1-6 haloalkyl;

(iv) —OR 6 , wherein R 6 is selected from hydrogen, C 1-6 alkyl that is unsubstituted or substituted by hydroxyl or —C(O)H;

(v) —NR 7a R 7b , wherein R 7a is hydrogen or C 1-6 alkyl, and R 7b is selected from hydrogen, —C(O)—C 1-6 alkoxy, and C 1-6 alkyl that is unsubstituted or substituted by — C(O)OH; and

(vi)monocyclic C 3-6 cycloalkyl that is unsubstituted or substituted by a hydroxyl; and

(b) C 3-6 cycloalkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from C 1-6 haloalkyl, R 0 , C 1-6 alkylamino, and C 1-6 alkyl that is unsubstituted or substituted by hydroxyl or —C(O)—C 1-6 alkoxy.

12. The compound according to claim 1 , wherein

R 2 is selected from

(a) C 1-8 alkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from

(i) C 1-6 haloalkyl;

(ii) —OR 6 , wherein R 6 is selected from hydrogen, and C 1-6 alkyl that is unsubstituted or substituted by hydroxyl; and

(iii) monocyclic C 3-6 cycloalkyl that is unsubstituted or substituted by hydroxyl; and

(b) C 3-6 cycloalkyl that is unsubstituted or substituted by 1 to 2 substituents independently selected from C 1-6 haloalkyl, R 0 , C 1-6 alkylamino, and C 1-6 alkyl that is unsubstituted or substituted by hydroxyl.

13. The compound according to claim 1 , wherein ring A is

and R 2 is selected from ethyl,

14. The compound according to claim 1 , wherein R 2 is tert-butyl.