Cyclohexyl-azetidinyl antagonists of CCR2

1. A compound of Formula I

wherein:

A is

X is N;

Z is N;

J is N or CH;

Q is C—R 5 , provided that J is N, or Q is N, provided that J is CH;

R 1 is H, phenyl, heteroaryl, CF 3 , —CH═CH 2 , CO 2 C (1-4) alkyl, NHBOC, NHC (1-4) alkyl, N(C (1-4) alkyl)CO 2 CH 2 Ph, NR b C(O)R bb , NR b SO 2 R bb , C(O)N(CH 3 )OCH 3 , C(O)NR b C (1-4) alkyl, C(O)NHCH 2 Ph(OCH 3 ) 2 , —C(OH)(CH 2 CH═CH 2 ) 2 , 3,6-dihydropyran-2-yl, 2,5-dihydrofuran-2-yl, tetrahydropyranyl, cyclopentenyl, cyclopentanyl, cyclohexenyl, cyclohexanyl, tetrahydrofuran-2-yl, cycloheptanyl,

or unsubstituted or substituted C (1-6) alkyl wherein said alkyl may be substituted with up to two substituents wherein one substituent is selected from the group consisting of OH, C (2-4) alkenyl, C (3-6) cycloalkyl, NH 2 , NHBOC, N(C (1-4) alkyl) 2 , NHSO 2 R b , NR b C(O)R bb , NHCO 2 R b , NHCONR b R bb , OC (1-2) alkyl, OC(O)C (1-4) alkyl, OC(O)NR b R bb , CO 2 C (1-4) alkyl, C(O)NR b R bb , C (2) alkylnyl, thiazolyl, oxazolyl, furyl, CF 3 , CF 2 CF 2 CF 3 , CH 2 NHCOC (1-3) alkyl, N 3 , SCH 3 , S(O)CH 3 , SO 2 CH 3 and —CN, and the second substituent on the C (1-6) alkyl is OH, and wherein said phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of: OH, —CN, CH 2 OH, OC (1-4) alkyl, NH 2 , NHC (1-4) alkyl, OC (1-4) alkyl, C(O)C (1-4) alkyl, CO 2 C (1-4) alkyl, C(O)NHC (1-4) alkyl, CO 2 NHC (1-4) alkyl, SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, SO 2 NHC (1-4) alkyl, NHSO 2 C (1-4) alkyl, NHCO 2 C (1-4) alkyl, NHC(O)C (1-4) alkyl, NO 2 , and C (1-4) alkyl;

R 2 is H, or OH;

or R 1 and R 2 may together form a carbonyl;

R 3 is H, C (1-4) alkyl, —CN, CHF 2 , or CF 3 ;

R 4 is H or CH 3 ;

R 5 is H or deuterium;

R a is H, or CH 3 ;

R b is H, C (1-4) alkyl, or CF 3 ;

R bb is H, C (1-4) alkyl, or CF 3 ;

and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 wherein:

A is

Q is C—R 5 ;

and pharmaceutically acceptable salts thereof.

3. A compound of claim 2 wherein:

R 1 is pyridyl, pyrimidyl, pyrazyl, pyranyl, furyl, isoxazolyl, oxazolyl, phenyl, thiazolyl, isothiazolyl, CF 3 , —CH═CH 2 , CO 2 C (1-4) alkyl, NHBOC, N(C (1-4) alkyl)CO 2 CH 2 Ph, NR b C(O)R bb , C(O)N(CH 3 )OCH 3 , C(O)NHC (1-4) alkyl, C(O)NHCH 2 Ph(OCH 3 ) 2 , —C(OH)(CH 2 CH═CH 2 ) 2 , 3,6-dihydropyran-2-yl, 2,5-dihydrofuran-2-yl, tetrahydropyranyl, cyclopentenyl, cyclopentanyl, cyclohexenyl, tetrahydrofuran-2-yl, cycloheptanyl,

or unsubstituted or substituted C (1-6) alkyl wherein said alkyl may be substituted with up to two substituents wherein one substituent is selected from the group consisting of OH, C (3-6) cycloalkyl, C (2-4) alkenyl, NHBOC, N(C (1-4) alkyl) 2 , NHSO 2 R b , NR b C(O)R bb , NHCO 2 R b , NHCONR b R bb , OC (1-2) alkyl, OC(O)C (1-4) alkyl, OC(O)NR b R bb , CO 2 C (1-4) alkyl, C(O)NR b R bb , C (2) alkylnyl, thiazolyl, oxazolyl, CF 3 , CF 2 CF 2 CF 3 , CH 2 NHCOC (1-3) alkyl, N 3 , SCH 3 and S(O)CH 3 , and the second substituent on the C (1-6) alkyl is OH, and wherein said pyridyl, pyrimidyl, pyrazyl, pyranyl, furyl, isoxazolyl, oxazolyl, phenyl, or thiazolyl is optionally substituted with one substituent selected from the group consisting of: OH, —CN, CH 2 OH, OC (1-4) alkyl, NH 2 , NHC (1-4) alkyl, OC (1-4) alkyl, C(O)C (1-4) alkyl, CO 2 C (1-4) alkyl, C(O)NHC (1-4) alkyl, CO 2 NHC (1-4) alkyl, SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, SO 2 NHC (1-4) alkyl, NHSO 2 C (1-4) alkyl, NHCO 2 C (1-4) alkyl, NHC(O)C (1-4) alkyl, and C (1-4) alkyl;

and pharmaceutically acceptable salts thereof.

4. A compound of claim 3 wherein:

R 1 is pyridyl, pyrimidyl, pyrazyl, oxazolyl, phenyl, thiazolyl, isothiazolyl, CF 3 , —CH═CH 2 , CO 2 C (1-4) alkyl, NHBOC, N(C (1-4) alkyl)CO 2 CH 2 Ph, NR b C(O)R bb , C(O)N(CH 3 )OCH 3 , C(O)NHC (1-4) alkyl, C(O)NHCH 2 Ph(OCH 3 ) 2 , —C(OH)(CH 2 CH═CH 2 ) 2 , 3,6-dihydropyran-2-yl, 2,5-dihydrofuran-2-yl, tetrahydropyranyl, cyclopentenyl, cyclopentanyl, cyclohexenyl, tetrahydrofuran-2-yl, cycloheptanyl,

or unsubstituted or substituted C (1-6) alkyl wherein said alkyl may be substituted with up to two substituents wherein one substituent is selected from the group consisting of OH, C (3-6) cycloalkyl, C (2-4) alkenyl, NHBOC, N(C (1-4) alkyl) 2 , NHSO 2 R b , NR b C(O)R bb , NHCO 2 R b , NHCONR b R bb , OC (1-2) alkyl, OC(O)C (1-4) alkyl, OC(O)NR b R bb , CO 2 C (1-4) alkyl, C(O)NR b R bb , C (2) alkylnyl, thiazolyl, oxazolyl, CF 3 , CF 2 CF 2 CF 3 , CH 2 NHCOC (1-3) alkyl, N 3 , SCH 3 , S(O)CH 3 and SO 2 CH 3 , and the second substituent on the C (1-6) alkyl is OH, and wherein said pyridyl, pyrimidyl, pyrazyl, oxazolyl, phenyl, or thiazolyl is optionally substituted with one substituent selected from the group consisting of: OH, —CN, CH 2 OH, OC (1-4) alkyl, NH 2 , NHC (1-4) alkyl, OC (1-4) alkyl, C(O)C (1-4) alkyl, CO 2 C (1-4) alkyl, C(O)NHC (1-4) alkyl, CO 2 NHC (1-4) alkyl, SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, SO 2 NHC (1-4) alkyl, NHSO 2 C (1-4) alkyl, NHCO 2 C (1-4) alkyl, NHC(O)C (1-4) alkyl, and C (1-4) alkyl;

and pharmaceutically acceptable salts thereof.

5. A compound of claim 4 wherein:

R 1 is pyridyl, phenyl, thiazolyl, isothiazolyl, CF 3 , —CH═CH 2 , CO 2 C (1-4) alkyl, NHBOC, N(C (1-3) alkyl)CO 2 CH 2 Ph, NR b C(O)R bb , C(O)N(CH 3 )OCH 3 , C(O)NHC (1-4) alkyl, C(O)NHCH 2 Ph(OCH 3 ) 2 , —C(OH)(CH 2 CH═CH 2 ) 2 , 3,6-dihydropyran-2-yl, 2,5-dihydrofuran-2-yl, tetrahydropyranyl, cyclopentenyl, cyclopentanyl, tetrahydrofuran-2-yl, cycloheptanyl,

or unsubstituted or substituted C (1-6) alkyl wherein said alkyl may be substituted with up to two substituents wherein one substituent is selected from the group consisting of OH, C (3-5) cycloalkyl-C (2) alkenyl, NHBOC, N(C (1-4) alkyl) 2 , NHSO 2 R b , NR b C(O)R bb , NHCO 2 R b , NHCONR b R bb , OC (1-2) alkyl, OC(O)C (1-4 )alkyl, OC(O)NR b R bb , CO 2 C (1-4) alkyl, C(O)NR b R bb , C (2) alkylnyl, cyclopentyl, thiazolyl, oxazolyl, CF 3 , CF 2 CF 2 CF 3 , CH 2 NHCOC (1-3) alkyl, N 3 , SCH 3 and S(O)CH 3 , and the second substituent on the C (1-6) alkyl is OH, and wherein said phenyl, pyridyl or thiazolyl is optionally substituted with one substituent selected from the group consisting of: OH, —CN, CH 2 OH, OCH 3 , NH 2 , NHCH 3 , and C (1-4) alkyl;

and pharmaceutically acceptable salts thereof.

6. A compound of claim 5 wherein:

R 1 is H, pyridyl, phenyl, thiazolyl, isothiazolyl, CF 3 , —CH═CH 2 , CO 2 CH 2 CH 3 , NHBOC, N(C (1-3) alkyl)CO 2 CH 2 Ph, NR b C(O)R bb , C(O)N(CH 3 )OCH 3 , C(O)NHCH 2 CH 3 , C(O)NHCH 2 Ph(OCH 3 ) 2 , —C(OH)(CH 2 CH═CH 2 ) 2 , 3,6-dihydropyran-2-yl, 2,5-dihydrofuran-2-yl, tetrahydropyranyl, cyclopentenyl, cyclopentanyl, tetrahydrofuran-2-yl, cycloheptanyl,

or unsubstituted or substituted C (1-5) alkyl wherein said alkyl may be substituted with up to two substituents wherein one substituent is selected from the group consisting of OH, cyclopropyl, cyclopentyl, C (2) alkenyl, NHBOC, N(CH 3 ) 2 , NHSO 2 R b , NR b C(O)R bb , NHCO 2 R b , NHCONR b R bb , OC (1-2) alkyl, OC(O)CH 3 , OC(O)N(CH 3 ) 2 , CO 2 CH 2 CH 3 , C(O)N(CH 3 ) 2 , C (2) alkylnyl, cyclopentyl, thiazolyl, CF 3 , CF 2 CF 2 CF 3 , CH 2 NHCOC (1-3) alkyl, N 3 , SCH 3 and S(O)CH 3 , and the second substituent on the C (1-5) alkyl is OH, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of: OH, —CN, and CH 2 OH; wherein said pyridyl is optionally substituted with one substituent selected from the group consisting of: OCH 3 , OH, NH 2 , NHCH 3 , and CH 3 ; wherein said thiazolyl is optionally substituted with one substituent selected from the group consisting of isopropyl, and methyl;

R 3 is H, CH 3 , —CN, CH(CH 3 ) 2 , or CF 3 ;

and pharmaceutically acceptable salts thereof.

7. A compound of claim 1 selected from

and pharmaceutically acceptable salts thereof.

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

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

10. 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 .