CXCR3 receptor agonists

1. A compound having the structure of Formula I:

or a stereoisomer, isotope or pharmaceutically acceptable salt thereof, wherein:

R is hydrogen, hydroxy, cyano, halo or —OS(═O) 2 R 6 ;

R 1 is aryl or heteroaryl and substituted with 0-4 R 4 groups;

R 2 is aryl or heteroaryl and substituted with 0-3 R 5 groups,

or R 2 is —NR 8 R 9 ;

R 3a is hydrogen or alkyl and R 3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen,

or R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen;

R 4 and R 5 are, at each occurrence, cyano, halo, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, heterocyclyl, —S(═O) 2 R 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 N 7 or —NR 6 R 7 ;

R 6 and R 7 are, at each occurrence, hydrogen or alkyl; and

R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0-4 R 4 groups,

or R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-4 R 4 groups and optionally substituted with oxo (═O) or thioxo (═S).

2. The compound of claim 1 , wherein R 1 is aryl substituted with 0-4 R 4 groups.

3. The compound of claim 1 , wherein R 1 is heteroaryl substituted with 0-4 R 4 groups.

4. The compound of claim 1 , wherein R 2 is aryl substituted with 0-3 R 5 groups.

5. The compound of claim 1 , wherein R 2 is heteroaryl substituted with 0-3 R 5 groups.

6. The compound of claim 1 , wherein R 1 and R 2 are phenyl, and the compound has the structure of Formula II, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

7. The compound of claim 1 , wherein R 1 is substituted with at least two R 4 groups.

8. The compound of claim 1 , wherein R 1 is substituted with at least three R 4 groups.

9. The compound of claim 1 , wherein R 1 is substituted with at least three R 4 groups individually selected from halo and alkyl.

10. The compound of claim 1 , wherein R 2 is substituted with zero R 5 groups.

11. The compound of claim 1 , wherein R 1 and R 2 are phenyl, R 3a is hydrogen, and the compound has the structure of Formula III, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

12. The compound of claim 1 , wherein R 1 and R 2 are phenyl, R 3a is hydrogen, and the compound has the structure of Formula IV, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

13. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and the compound has the structure of Formula V, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

14. The compound of claim 13 , wherein R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0-4 R 4 groups.

15. The compound of claim 13 , wherein R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-4 R 4 groups and optionally substituted with oxo (═O) or thioxo (═S).

16. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VI, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

17. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VII, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

18. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VIII, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

19. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula IX, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

20. The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula X, or a stereoisomer, isotope or pharmaceutically acceptable salt thereof:

wherein R 14 is H or R 4 .

21. The compound of claim 1 , wherein R 3a is hydrogen and R 3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.

22. The compound of claim 21 , wherein R 3b is a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups, or wherein R 3b is alkyl substituted with —NR 10 R 11 , —N + R 10 R 11 R 12 , —NR 12 C(═O)NR 10 R 11 , —C(═O)NR 10 R 11 , —NR 12 C(═O)CH 2 NR 10 R 11 , —NR 12 N(═NR 13 )NR 10 R 11 , —NR 10 SO 2 R 11 , or a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups, and wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, alkyl or haloalkyl.

23. The compound of claim 22 , wherein R 3b is alkyl substituted with —NR 10 R 11 or N + R 10 R 11 R 12 .

24. The compound of claim 23 , wherein R 3b is —(CH 2 ) 2-4 NH 2 .

25. The compound of claim 22 , wherein R 3b is alkyl substituted with —NR 12 N(═NR 13 )NR 10 R 11 .

26. The compound of claim 22 , wherein R 3b is alkyl substituted with —C(═O)NR 10 R 11 , —NR 12 C(═O)NR 10 R 11 or —NR 12 C(═O)CH 2 NR 10 R 11 .

27. The compound of claim 22 , wherein R 3b is alkyl substituted with a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups.

28. The compound of claim 1 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.

29. The compound of claim 28 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups.

30. The compound of claim 1 , wherein the compound is a compound of Table A:

TABLE A

Structure

Cpd. No.

 1-1

 1-2

 1-3

 1-5

 1-6

 1-7

 1-8

 1-9

 1-10

 1-11

 1-12

 1-13

 1-14

 1-15

 1-16

 1-17

 1-18

 1-19

 1-20

 1-21

 1-22

 1-23

 1-24

 1-25

 1-26

 1-27

 1-28

 1-29

 1-30

 1-31

 1-32

 1-33

 1-34

 1-35

 1-36

 1-37

 1-38

 1-39

 2-1

 2-2

 2-3

 2-4

 2-5

 2-6

 2-7

 2-8

 2-9

 2-10

 2-11

 2-12

 2-13

 2-14

 2-15

 2-16

 2-17

 2-18

 2-19

 2-20

 2-21

 2-22

 2-23

 2-24

 2-25

 2-26

 2-27

 2-28

 2-29

 2-30

 2-31

 2-32

 2-33

 2-34

 2-35

 2-36

 2-37

 2-38

 2-39

 2-40

 2-41

 2-42

 2-43

 2-44

 2-45

 2-46

 2-47

 2-48

 2-49

 2-50

 2-51

 2-52

 2-53

 2-54

 2-55

 2-56

 2-57

 2-58

 2-59

 2-60

 2-61

 2-62

 2-63

 2-64

 2-65

 2-66

 2-67

 2-68

 2-69

 2-70

 2-71

 2-72

 2-73

 2-74

 2-75

 2-76

 2-77

 2-78

 2-79

 2-80

 2-81

 2-82

 3-1

 3-2

 3-3

 3-4

 3-5

 3-6

 3-7

 3-8

 3-9

 3-10

 3-11

 3-12

 3-13

 3-14

 4-2

 4-3

 4-4

 4-5

 4-6

 4-7

 4-8

 4-9

 4-10

 4-11

 4-12

 4-13

 4-14

 4-15

 4-16

 4-17

 4-18

 4-19

 4-20

 5-1

 5-2

 5-3

 5-4

 6-1

 6-2

 6-3

 6-4

 6-5

 6-6

 6-7

 7-1

 7-2

 7-3

 7-4

 7-5

 7-6

 7-7

 7-8

 7-9

 8-1

 8-2

 8-3

 8-4

 8-5

 8-6

 8-7

 9-1

10-1

10-2

10-3

10-4

10-5

10-6

10-7

10-8

10-9

10-10

10-11

10-12

11-1

11-2

11-3

11-4

11-5

11-6

12-1

12-2

12-3

12-4

12-5

12-6

12-7

12-8

12-9

12-10

12-11

12-12

12-13

12-14

12-15

12-16

12-17

12-18

12-19

12-20

12-21

12-22

12-23

12-24

12-25

12-26

12-27

12-28

12-29

12-30

12-31

12-32

12-33

12-34

12-35

12-36

12-37

12-38

12-39

12-40

12-41

12-42

12-43

12-44

12-45

12-46

12-47

12-48

12-49

12-50

12-51

12-52

12-53

12-54

12-55

12-56

12-57

12-58

12-59

12-60

12-61

12-62

12-63

12-64

12-65

12-66

12-67

12-68

12-69

12-70

12-71

12-72

12-73

12-74

12-75

12-76

12-77

12-78

12-79

12-80

12-81

12-82

12-83

12-84

12-85

12-86

12-87

12-88

12-89

12-90

12-91

12-92

12-93

12-94

12-95

12-96

12-97

12-98

12-99

12-100

12-101

12-102

12-103

12-104

12-105

12-106

12-107

12-108

12-109

12-110

12-111

12-112

12-113

12-114

12-115

12-116

12-117

12-118

12-119

12-120

12-121

12-122

12-123

12-124

12-125

12-126

12-127

12-128

12-129

12-130

12-131

12-132

12-133

12-134

12-135

12-136

12-137

12-138

12-139

12-140

12-141

12-142

12-143

12-144

12-145

12-146

12-147

12-148

12-149

12-150

12-151

12-152

12-153

12-154

12-155

12-156

12-157

12-158

12-159

13-1

13-2

13-3

13-4

13-5

13-6

13-7

14-1

14-2

14-3

14-4

14-5

14-6

14-7

14-8

14-9

14-10

14-11

14-12

14-13

14-14

14-15

14-16

14-17

14-18

14-19

14-20

14-21

14-23

14-24

14-25

14-26

14-27

14-28

14-29

15-1

15-2

15-3

15-4

15-5

15-6

15-7

15-8

15-9

15-10

15-11

15-12

15-13

15-14

15-15

15-16

15-17

15-18

15-19

15-20

15-21

15-22

15-23

15-24

15-25

15-26

15-27

15-28

15-29

15-30

15-31

15-32

15-33

15-34

15-35

15-36

15-37

15-38

15-39

15-40

15-41

15-42

15-43

15-44

15-45

15-46

15-47

15-48

15-49

15-50

15-51

15-52

15-53

15-54

15-55

15-56

15-57

15-58

15-59

15-60

15-61

15-62

15-63

15-64

16-1

17-1

17-2

17-3

17-4

18-1

19-1

20-1

21-1

22-1

22-2

22-3

23-1

23-2

23-3

23-4

23-5

23-6

23-7

23-8

23-9

24-1

24-2

25-1

25-2

25-3

26-1

26-2

26-3

27-1

27-2

27-3

27-4

27-5

27-6

27-7

28-1

28-2

28-3

29-1

30-1

31-1

32-1

32-2

33-1

34-1

35-2

35-1.

31. The compound of claim 1 , wherein the compound is a compound of Table B:

TABLE B

Cpd.

Structure

No.

1-14

1-18

1-29

1-35

1-36

1-37

1-38

1-39

2-2

2-15

2-22

2-24

2-25

2-39

2-57

4-12

4-14

8-4

10-3

12-73

12-88

12- 104

12- 131

12- 136

13-1

14-3

14-6

14-18

15-3

15-6

18-1.

32. The compound of claim 1 , wherein R 3a is H and the compound of claim 1 is a stereoisomer having the structure of Formula XI:

or an isotope or pharmaceutically acceptable salt thereof.

33. The compound of claim 1 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen, and the compound of claim 1 is a stereoisomer having the structure of Formula XII:

or an isotope or pharmaceutically acceptable salt thereof.

34. The compound of claim 1 wherein R is hydrogen.

35. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

36. A method for agonizing a chemokine receptor of a cell comprising contacting the cell with a compound of claim 1 , wherein the chemokine receptor is CXCR3.