Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of:

(i) C 1 -C 3 alkyl; and

(ii) C 1 -C 3 fluoroalkyl;

R 2 is ring C B , wherein ring C B is selected from the group consisting of

(a) a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S;

(b) phenyl; and

(c) cyclohexenyl;

wherein ring C B is unsubstituted or substituted with 1 to 3 R 7 , wherein each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —CN, —CH 2 —O—C 1 -C 3 alkyl, —S(O)—C 1 -C 3 alkyl, —S(O) 2 —C 1 -C 3 alkyl, amino, —N(H)—C 1 -C 3 alkyl, —N(C 1 -C 3 alkyl) 2 , —C(O)NH 2 , —C(O)N(H)-C 1 -C 3 alkyl, —C(O)N(C 1 -C 3 alkyl) 2 , or —C(O)N(H)-cyclopropyl;

R 3 is selected from the group of H and halo;

R 5 is —C(O)OR A or —C(O)NH 2 ;

R 6 is C 1 -C 3 alkyl

the subscript r is 0, 1, or 2;

the subscript s is 0 or 1;

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

the subscript x is 0, 1, or 2;

R A is independently selected from the group consisting of:

(a) H;

(b) C 1 -C 8 alkyl;

(c) a group of the formula -M-R CH , wherein

M is a bond or —(CH 2 ) n1 -, wherein the subscript n1 is 1 or 2;

R CH is (a) aryl or C 3 -C 6 cycloalkyl optionally substituted with 1-3 groups independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of R CH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C 1-3 alkyl;

(d) a group of the formula —(CH 2 ) n1 —R m or —(CH 2 ) 2 —O—(CH 2 ) 2 —R m wherein R m is —CO 2 R m , —C(O)N(R m2 ) 2 , or —O(CO)R m1 ;

R m1 is C 1 -C 4 alkyl; and

R m2 is H or C 1 -C 4 alkyl;

(e) a group of the formula —(CH 2 ) 2 —R n ,

R n is —OH, —O—(C 1 -C 4 alkyl), —O—(CH 2 ) 2 —O—(C 1 -C 4 alkyl), —NH 2 , —N(H)(C 1 -C 4 alkyl) or —N(C 1 -C 4 alkyl) 2 ;

(f) a group of the formula

 wherein

R o is H or C 1 -C 4 alkyl; and

R p is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; and,

(g) a group of the formula

 wherein R o and R p are as set forth above.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein ring C B is pyrazolyl, tetrazolyl, thienyl, thiazolyl, phenyl, pyridyl, or cyclohexenyl; and

wherein ring C B is unsubstituted or substituted with 1 to 2 R 7 moieties.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein each R 7 is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, amino, methoxy, methoxymethyl, —CN, —S(O) 2 CH 3 , and —C(O)N(H)-cyclopropyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein the subscript r is 0 or 2.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein the group

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 5 is —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , or —C(O)NH 2 .

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 .

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

wherein

R 2 is

ring C B , wherein ring C B is pyrazolyl, tetrazolyl, thienyl, thiazolyl, phenyl, pyridyl, or cyclohexenyl:

wherein ring C B is unsubstituted or substituted with 1 to 2 R 7 , wherein each R 7 is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, amino, methoxy, methoxymethyl, —CN, —S(O) 2 CH 3 , and —C(O)N(H)-cyclopropyl;

R 5 is —C(O)OR A or —C(O)NH 2 ; and

R 6a and R 6b are independently H or methyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)OR A .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R A is H.

11. The compound of claim 1 selected from the group consisting of:

ethyl 4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylate;

4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylic acid;

4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxamide;

1-(5-(3-(1H-tetrazol-5-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclobutanol;

4-hydroxy-2,2-dimethyl-4-(5-(3-(1-methyl-1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylic acid;

4-{5-[3-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(3-[1-(1-methylethyl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-{5-[3-(1-ethyl-1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(3-pyridin-4-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-[5-(4′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-4-{5-[3-(6-methoxypyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(3-thiophen-3-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-{5-[3′-(cyclopropylcarbamoyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-{5-[3-(1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-{5-[3-(1H-pyrazol-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid;

4-[5-(3′-fluoro-4′-methoxy-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-4-{5-[4′-(methoxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylic acid;

4-[5-(2′,3′-difluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-{5-[3-(5-fluoropyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-[5-(4′-fluoro-3′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-{5-[2′-(methylsulfinyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid;

4-[5-(2′-chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-{5-[3-(6-aminopyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(2′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-[5-(3-cyclohex-1-en-1-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-[5-(2′-fluoro-5′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-{5-[3-(3-methylthiophen-2-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-{5-[3-(4-methylthiophen-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid;

4-[5-(2′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-(5-(3-(thiazol-2-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(3-thiophen-2-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; and

4-[5-(4′-cyano-3′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)OR A .

13. The compound of claim 12 , or pharmaceutically acceptable salt thereof, wherein R A is H.

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceuticallly acceptable carrier.