4-azetidinyl-1-heteroaryl-cyclohexanol antagonists of CCR2

1. A compound of Formula (I)

wherein:

R 1 is

pyridyl, pyridyl-N-oxide, 1H-pyridin-2-onyl, indolyl, pyrazinyl, 3-H-thiazol-2-onyl, pyrimidyl, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiophenyl, furyl, [1,2,4]oxadiazolyl or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, pyrimidyl, pyrazolyl, imidazolyl, thiophenyl, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, CO 2 H, CONH 2 , NHCO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , NHSO 2 CH 3 , NHC(O)CF 3 , NHC (1-4) alkyl, NHCO 2 H, NHCO 2 C (1-4) alkyl, NHCOC (1-4) alkyl, NHCONH 2 , NHCONHC (1-4) alkyl, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; or wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; or wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, or wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ; or wherein said 1H-pyridin-2-onyl is optionally substituted with one substituent selected from the group consisting of CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , and CH 2 CH 2 OH, or said 1H-pyridin-2-onyl may be optionally substituted with up to 2 methyl groups; or wherein said [1,2,4]oxadiazolyl is optionally substituted on any carbon atom with CCl 3 , or pyrrolidinyl, or alternatively both hydrogens on said carbon atom of said [1,2,4]oxadiazolyl may be replaced by an oxo group;

R 2 is C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , C (3-6) cycloalkyl, heterocyclyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl;

R 3 is H, F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, or 2,3-dihydro-benzo[1,4]dioxinyl group;

R 4 is H, OC (1-4) alkyl, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

2. A compound claim 1 wherein:

R 1 is

pyridyl, pyridyl-N-oxide, 1H-pyridin-2-onyl, indolyl, pyrazinyl, 3-H-thiazol-2-onyl, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, [1,2,4]oxadiazolyl or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, CO 2 H, CONH 2 , NHCO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , NHSO 2 CH 3 , NHC(O)CH 3 , NHC(O)CF 3 , NHC (1-4) alkyl, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ; wherein said 1H-pyridin-2-onyl is optionally substituted with one substituent selected from the group consisting of CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , and CH 2 CH 2 OH, or said 1H-pyridin-2-onyl may be optionally substituted with up to 2 methyl groups; wherein said [1,2,4]oxadiazolyl is optionally substituted on any carbon atom with CCl 3 , or pyrrolidinyl, or alternatively both hydrogens on said carbon atom of said [1,2,4]oxadiazolyl may be replaced by an oxo group;

R 2 is C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , pyrrolidinyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl;

R 3 is H, F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, OCH 3 , or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

3. A compound claim 2 wherein:

R 1 is pyridyl, pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, C (1-4) alkyl, N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ;

R 2 is NH 2 , NO 2 , NHCH 2 CH 2 OH, N(CH 3 ) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , pyrrolidinyl, or OCH 3 ;

R 3 is H, F, Cl, CF 3 , or OCH 3 ; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

4. A compound claim 3 wherein:

R 1 is pyridyl, pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl or pyridyl-N-oxide is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, C (1-4) alkyl, N(C (1-4) alkyl) 2 , and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted with C (1-4) alkyl, CH 2 OH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , OH, NH 2 , N(C (1-4) alkyl) 2 , pyrrolidinyl, OC (1-4) alkyl, NHCN, or said thiazolyl may be substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

5. A compound claim 4 wherein:

R 1 is pyridyl, methoxy substituted pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl is optionally substituted with one substituent selected from the group consisting of OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OC(CH 3 ) 3 , cyclobutoxy, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 3 , N(CH 3 ) 2 , and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(CH 3 ) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted with CH 2 OH, Si(CH 3 ) 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , OH, NH 2 , N(CH 3 ) 2 , pyrrolidinyl, OCH 3 , OCH(CH 3 ) 2 , NHCN, or said thiazolyl may be substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br.(Original);

R 2 is CF 3 , F, Cl, CN, or OCH 3 ,

R 3 is H, F, Cl, or CF 3 , alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

6. A compound of claim 1 selected from the group consisting of:

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

7. A compound of claim 6 selected from the group consisting of:

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

8. A compound of the formula

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

9. A compound of Formula (Ia)

wherein:

R 1 is

pyridyl, pyridyl-N-oxide, 1H-pyridin-2-onyl, indolyl, pyrazinyl, 3-H-thiazol-2-onyl, pyrimidyl, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiophenyl, furyl, [1,2,4]oxadiazolyl or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, pyrimidyl, pyrazolyl, imidazolyl, thiophenyl, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, CO 2 H, CONH 2 , NHCO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , NHSO 2 CH 3 , NHC(O)CF 3 , NHC (1-4) alkyl, NHCO 2 H, NHCO 2 C (1-4) alkyl, NHCOC (1-4) alkyl, NHCONH 2 , NHCONHC (1-4) alkyl, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; or wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; or wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, or wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ; or wherein said 1H-pyridin-2-onyl is optionally substituted with one substituent selected from the group consisting of CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , and CH 2 CH 2 OH, or said 1H-pyridin-2-onyl may be optionally substituted with up to 2 methyl groups; or wherein said [1,2,4]oxadiazolyl is optionally substituted on any carbon atom with CCl 3 , or pyrrolidinyl, or alternatively both hydrogens on said carbon atom of said [1,2,4]oxadiazolyl may be replaced by an oxo group;

R 2 is C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , C (3-6) cycloalkyl, heterocyclyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl;

R 3 is H, F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, or 2,3-dihydro-benzo[1,4]dioxinyl group;

R 4 is H, OC (1-4) alkyl, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

10. A compound claim 9 wherein:

R 1 is

pyridyl, pyridyl-N-oxide, 1H-pyridin-2-onyl, indolyl, pyrazinyl, 3-H-thiazol-2-onyl, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, [1,2,4]oxadiazolyl or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, CO 2 H, CONH 2 , NHCO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , NHSO 2 CH 3 , NHC(O)CH 3 , NHC(O)CF 3 , NHC (1-4) alkyl, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ; wherein said 1H-pyridin-2-onyl is optionally substituted with one substituent selected from the group consisting of CH 2 CN, C (1-4) alkyl, CH 2 CF 3 , and CH 2 CH 2 OH, or said 1H-pyridin-2-onyl may be optionally substituted with up to 2 methyl groups; wherein said [1,2,4]oxadiazolyl is optionally substituted on any carbon atom with CCl 3 , or pyrrolidinyl, or alternatively both hydrogens on said carbon atom of said [1,2,4]oxadiazolyl may be replaced by an oxo group;

R 2 is C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , pyrrolidinyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl;

R 3 is H, F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, OCH 3 , or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

11. A compound claim 10 wherein:

R 1 is pyridyl, pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl, pyridyl-N-oxide, or thiazolyl is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, C (1-4) alkyl, N(C (1-4) alkyl) 2 , C (1-4) alkylOH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , pyrrolidinyl, OH, NH 2 , NHCN, and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br or OCH 3 ;

R 2 is NH 2 , NO 2 , NHCH 2 CH 2 OH, N(CH 3 ) 2 , N(SO 2 CH 3 ) 2 , CN, F, Cl, Br, CF 3 , pyrrolidinyl, or OCH 3 ;

R 3 is H, F, Cl, CF 3 , or OCH 3 ; alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

12. A compound claim 11 wherein:

R 1 is pyridyl, pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl or pyridyl-N-oxide is optionally substituted with one substituent selected from the group consisting of OC (1-4) alkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , OCH 2 Ph, F, CN, C (1-4) alkyl, N(C (1-4) alkyl) 2 , and Br;

or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(C (1-4) alkyl) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted with C (1-4) alkyl, CH 2 OH, Si(CH 3 ) 3 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , OH, NH 2 , N(C (1-4) alkyl) 2 , pyrrolidinyl, OC (1-4) alkyl, NHCN, or said thiazolyl may be substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

13. A compound claim 12 wherein:

R 1 is pyridyl, methoxy substituted pyridyl-N-oxide, pyrimidyl, methyl substituted imidazolyl, methyl substituted pyrazolyl optionally substituted with Br, thiophenyl optionally substituted with Br, benzooxazolyl, oxazolyl, thiazolyl, isothiazolyl, or [1,3,4]thiadiazolyl; wherein said pyridyl is optionally substituted with one substituent selected from the group consisting of OCH 3 ,

OCH 2 CH 3 , OCH(CH 3 ) 2 , OC(CH 3 ) 3 , cyclobutoxy, OCH 2 CF 3 , OCH 2 Ph, F, CN, CH 3 , N(CH 3 ) 2 , and Br; or said pyridyl may be substituted with one OCH 3 group and one CH 3 ; wherein said pyrimidyl is optionally substituted with one N(CH 3 ) 2 group or one or two OCH 3 groups; wherein said thiazolyl is optionally substituted with CH 2 OH, Si(CH 3 ) 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , —C≡CH, SCH 3 , S(O)CH 3 , SO 2 CH 3 , OH, NH 2 , N(CH 3 ) 2 , pyrrolidinyl, OCH 3 , OCH(CH 3 ) 2 , NHCN, or said thiazolyl may be substituted on two adjacent carbon atoms to form fused bicyclic system benzothiazol-2-yl, wherein said benzothiazol-2-yl is optionally substituted with Br;

R 2 is CF 3 , F, Cl, CN, or OCH 3 ,

R 3 is H, F, Cl, or CF 3 , alternatively, R 2 and R 3 may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;

R 4 is H, or F;

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

14. A compound of claim 9 selected from the group consisting of:

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

15. A compound of the formula

and hydrates, tautomers, and pharmaceutically acceptable salts thereof.

16. A compound of claim 15 of the formula

17. A crystalline compound of claim 16 having the following XRPD °20Θ peaks:

Position [°2θ]

7.0

7.4

9.3

11.0

12.6

14.3

14.4

14.8

15.3

17.1

17.4

18.3

18.7

19.2

19.7

21.3

21.8

22.2

22.9

23.5

23.9

24.5

24.7

25.3

26.3

28.2

28.8

29.5

18. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

20. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition, comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition made by mixing a compound of claim 9 and a pharmaceutically acceptable carrier.

23. A process for making a pharmaceutical composition comprising mixing a compound of claim 9 and a pharmaceutically acceptable carrier.

24. A method of treating a disorder selected from the group consisting of: rheumatoid arthritis, type I diabetes, type II diabetes, diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, obesity, obesity-associated insulin resistance, metabolic syndrome, asthma, and allergic asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

25. A method of treating a disorder selected from the group consisting of type II diabetes, obesity and asthma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .