Substituted isoquinolines as CRTH2 receptor modulators

1. A compound of the Formula (I)

wherein:

Z is a bond or —N(H)—;

R A is —OH, —N(H)—S(O) 2 —R A1 , or —N(H)—S(O) 2 —N(H)R A1

R A1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl, wherein R A1 is unsubstituted or substituted by 1 to 3 fluoro or C 1 -C 3 alkyl;

the subscript n is 1, 2, 3, or 4;

M is a bond or C 1 -C 3 alkylene;

ring AH is

A phenyl; or

B a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S;

each R 2 is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, and —CN;

the subscript b is 0, 1, 2, 3, 4, or 5;

R q1 , R q2 , R q3 , and R q4 are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl;

R 1 is

A group of the formula —C(O)N(R 3 )(R 4 ), wherein

1) R 3 and R 4 are independently

(a) H, or

(b) —Z—R 5C , wherein

 Z is a bond or C 1 -C 3 alkylene;

 R 5C is

 (i) C 5 -C 10 mono or bicyclic carbocyclyl,

 (ii) 5- to 10-membered mono- or bicyclic heterocyclyl containing 1 to 3 heteroatoms selected from N and O;

 (iii) 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 3 heteroatoms selected from N and O;

 wherein said carbocyclyl, heterocyclyl, and heteroaryl of R 5C is unsubstituted or substituted by 1 to 4 R 5A moieties selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, and —CN; or

2) R 3 and R 4 together with the N atom to which they are attached form R 5H , wherein R 5H is selected from the group consisting of:

ring A r is aryl, pyridyl, or pyrimidyl;

each R 7 is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, and —CN;

each R 8 is independently selected from the group consisting of H and C 1 -C 3 alkyl;

the subscript u1 is 0, 1 or 2;

the subscript u2 is 0, 1, 2, or 3; or

B) a moiety selected from the group consisting of:

Y is a bond or C 1 -C 3 alkylene;

R 6 is H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl;

R cy is:

1) C 6 -C 10 mono or bicyclic carbocyclyl;

2) 5- to 9-membered mono- or bicyclic heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N and O;

3) 5- to 9-membered mono- or bicyclic heteroaryl containing 1 to 3 heteroatoms selected N and O;

 wherein R cy is unsubstituted or substituted by 1 to 3 R 9 moieties which are independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, and —CN, or wherein two R 9 moieties are geminally substituted on a common ring carbon of R cy , the two geminally substituted R 9 moieties, together with said common carbon atom, form —C(O)—;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is the group of the formula —C(O)N(R 3 )(R 4 ).

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is —Z—R 5C and R 4 is H.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein

Z is a bond or

and

R 5C is C 6 -C 10 carbocyclyl, wherein said C 6 -C 10 carbocyclyl is unsubstituted or substituted by 1 to 4 R 5A moieties.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein said C 6 -C 10 carbocyclyl is selected from the group consisting of phenyl, indanyl or tetrahydronaphthalenyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the N atom to which they are attached form R 5H .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof,

wherein R 5H is

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is a moiety selected from the group consisting of:

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein

Y is a direct bond, —CH 2 —, or

and

R cy is phenyl, indanyl, or benzoxazolyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is a bond or —CH 2 —.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a bond and the subscript n is 4.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R A is —OH or

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R q1 , R q2 , R q3 , and R q4 are each H.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the Formula (IA),

wherein

R A is —OH or

M is a bond or —CH 2 —; and

R 1 , R 2 , and the subscript b are as set forth in claim 1 .

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

5-(2-(4-fluorophenyl)-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid;

5-(6-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid;

3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide;

5-(2-(4-fluorophenyl)-6-(2-methyl-4-phenylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid;

5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid;

5-(6-(5-(4-fluorobenzyl)-1,2,4-oxadiazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid; and

N-(cyclopropylsulfonyl)-5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanamide.

17. A pharmaceutical formulation comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A method for treating a disease or condition selected from asthma, allergic rhinitis, or COPD comprising administering to a patient in need of such treatment a therapeutically amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method for treating asthma comprising administering to a patient in need of such treatment a therapeutically amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and montelukast.