Substituted tetrahydropyrans as CCR2 modulators
Compounds are provided that are modulators of the CCR2 receptor. The compounds have the general formula (I): and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of CCR2 receptors.
1. A compound haying the formula (I)
or a pharmaceutically acceptable salt, stereoisomer or rotamer thereof; wherein
A is C(R 5 )(R 6 ) or N(R 5 );
m and n are each independently 0, 1 or 2, wherein the sum of m and n is less than or equal to 3;
R 1 is selected from the group consisting of aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 5 R x substituents;
R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 4 R x substituents;
or optionally, R 1 and R 2 are combined with the nitrogen atom to which each is attached to form a 6- to 11-membered monocyclic or fused bicyclic heterocyclyl- or heteroaryl ring, wherein the —NR 1 R 2 is optionally further substituted with from 1 to 4 R x substituents;
R 3 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-4 alkyl, each of which is optionally substituted with from 1-3 R y substituents;
R 4 is selected from the group consisting of H, C 1-8 alkyl optionally substituted with 1 to 2 R y and CO 2 H;
R 5 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-8 alkylamino, di-C 1-8 alkylamino, aryl, aryloxy, arylamino, aryl-C 1-4 alkyl, heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl, each of which is optionally substituted with from 1 to 5 R z substituents;
R 6 is selected from the group consisting of H, F, OH, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy groups are optionally substituted with from 1 to 3 R z substituents;
or optionally, R 5 and R 6 are joined to form a spirocyclic 5- or 6-membered cycloalkyl ring which is optionally unsaturated, and has a fused aryl group which is optionally substituted with from 1 to 4 R z substituents;
each R x is independently selected from the group consisting of halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a , —O—X 1 —NR a R b , —O—X 1 —CO 2 R a , —O—X 1 —CONR a R b , —X 1 —OR a ,—X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , —S(O) 2 NR a R b , and 5- or 6-membered aryl or heteroaryl, wherein
each X 1 is a C 1-4 alkylene;
each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo;
each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and
optionally when two R x substituents are on adjacent atoms, are combined to form a fused 5 or 6-membered carbocyclic ring, and wherein the aryl or heteroaryl groups are optionally substituted with 1-3 members selected from halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R y is independently selected from the group consisting of halogen, —CN, —R f , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein
each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S;
each R f is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl;
and each R z is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h ,—X 1 —R j , —X 1 —NR g R h , —X 1 —CONR g R h , —X 1 —NR h C(O)R g , —NHR j , —NHCH 2 R j , and tetrazolyl; wherein
each R g and R h is independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo;
each R i is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and
each R j is selected from the group consisting of C 3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.
2. The compound of claim 1 , having the formula (I)
or a pharmaceutically acceptable salt, stereoisomer or rotamer thereof; wherein
A is C(R 5 )(R 6 ) or N(R 5 );
m and n are each independently 0, 1, or 2, wherein the sum of m and n is less than or equal to 3;
R 1 is selected from the group consisting of aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 5 R x substituents;
R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 4 R x substituents;
or optionally, R 1 and R 2 are combined with the nitrogen atom to which each is attached to form a 6- to 11-membered heterocyclyl or heteroaryl ring, optionally substituted with from 1 to 4 R x substituents;
R 3 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-4 alkyl, each of which is optionally substituted with from 1-3 R y substituents;
R 4 is selected from the group consisting of H, C 1-8 alkyl optionally substituted with 1 to 2 R y , and CO 2 H;
R 5 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-8 alkylamino, di-C 1-8 alkylamino, aryl, aryloxy, arylamino, alkyl-C 1-4 , heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl, each of which is optionally substituted with from 1 to 5 R z substituents;
R 6 is selected from the group consisting of H, F, OH, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy groups are optionally substituted with from 1 to 3 R z substituents;
or optionally, R 5 and R 6 are joined to form a spirocyclic 5- or 6-membered cycloalkyl ring which is optionally unsaturated, and has a fused aryl group which is optionally substituted with from 1 to 4 R z substituents;
each R x is independently selected from the group consisting of halogen, —CN, —R c ,—CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2R c , —NR a —C(O)NR a R b , —NR a R b , —OR a , and —S(O) 2 NR a R b ; wherein
each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo;
each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and optionally when two R x substituents are on adjacent atoms, are combined to form a fused 5 or 6-membered carbocyclic ring;
each R y is independently selected from the group consisting of halogen, —CN, —R f , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein
each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S;
each R f is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl;
and each R z is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h , —X 1 —R j , —X 1 —NR g R h , —X 1 —CONR g R h , —X 1 —NR h C(O)R g , —NHR j and —NHCH 2 R j ,
wherein X 1 is a C 1-4 alkylene;
each R g and R h is independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom can he combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo;
each R i is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and
each R j is selected from the group consisting of C 3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.
3. The compound of claim 1 , having the formula (Ia):
4. The compound of claim 1 , having the formula (Ia2):
wherein p is 1, 2, 3, or 4.
5. The compound of claim 1 , having the formula (Ia4):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, or 4.
6. The compound of claim 1 , having the formula (Ia5):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, or 4.
7. The compound of claim 1 , having the formula (Ib1):
wherein q is 1, 2, 3, or 4, and p is 1, 2, 3, or 4.
8. The compound of claim 1 , having the formula (Ib2):
wherein q is 1, 2, 3,or 4, and p is 1, 2, 3, 4, or 5.
9. The compound of claim 1 , having the formula (Ic):
10. The compound of claim 1 , having the formula (Ic4):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, or 4.
11. The compound of claim 1 , having the formula (Ic5):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5.
12. The compound of claim 1 , having the formula (Ia1′):
wherein q is 1, 2, 3, 4, or 5, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ia1′).
13. The compound of claim 1 , having the formula (Ia2′):
wherein p is 1, 2, 3, or 4, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ia2′).
14. The compound of claim 1 , having the formula (Ia3′):
wherein p is 1, 2, 3, 4, or 5, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ia3′).
15. The compound of claim 1 , having the formula (Ia4′):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, or 4, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ia4′).
16. The compound of claim 1 , having the formula (Ia5′):
wherein q is 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ia5′).
17. The compound of claim 1 , having the formula (Ic1′):
wherein q is 1, 2, 3, 4, or 5 said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ic1′).
18. The compound of claim 1 , having the formula (Ic2′):
wherein p is 1, 2, 3, or 4, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ic2′).
19. The compound of claim 1 , having the formula (Ic3′):
wherein p is 1, 2, 3, 4, or 5, and wherein said compound is at least 90% free of other stereoisomers at each asymmetric carbon atom defined in formula (Ic3′).
20. The compound of claim 1 , wherein the ring having vertex A is represented by a formula selected from the group consisting of:
21. The compound of claim 1 , wherein A is C(R 5 )(R 6 ) wherein R 5 is selected from the group consisting of aryl, aryloxy, arylamino, aryl-C 1-4 alkyl, heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl, wherein the aryl or heteroaryl portions are selected from the group consisting of:
22. The compound of claim 21 , wherein R 5 is selected from the group consisting of aryl, aryloxy, arylamino and aryl-C 1-4 alkyl.
23. The compound of claim 21 , wherein R 5 is selected from the group consisting of heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl.
24. The compound of claim 1 , wherein A is N(R 5 ) wherein R 5 is selected from the group consisting of aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the aryl or heteroaryl portions are selected from the group consisting of:
25. The compound of claim 24 , wherein R 5 is selected from the group consisting of aryl and aryl-C 1-4 alkyl.
26. The compound of claim 24 , wherein R 5 is selected from the group consisting of heteroaryl and heteroaryl-C 1-4 alkyl.
27. The compound of claim 1 , wherein A is N(R 5 ) wherein R 5 is selected from the group consisting of:
28. The compound of claim 1 , wherein m and n are both 0.
29. The compound of claim 1 , wherein m and n are both 1.
30. The compound of claim 1 , wherein m is 1 and n is 0.
31. The compound of claim 1 , wherein in is 1 and n is 2.
32. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl.
33. The compound of claim 1 , wherein —NR 1 R 2 is selected from the group consisting of:
34. The compound of claim 1 , wherein —NR 1 R 2 is selected from the group consisting of:
35. The compound of claim 1 , wherein —NR 1 R 2 is selected from the group consisting of:
36. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
39. The pharmaceutical composition of claim 38 , further comprising one or more additional therapeutic compounds.
40. A method for inhibiting C-C chemokine receptor type 2 receptor-mediated cellular chemotaxis comprising contacting mammalian white blood cells with a compound of claim 1 .
41. A method for modulating C-C chemokine receptor type 2 receptor activity in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .
42. The method of claim 41 , wherein the mammal suffers from a disease or disorder selected from the group consisting of renal fibrosis, polycystic kidney disease, rheumatoid arthritis, atopic dermatitis, psoriasis, nephropathy, breast cancer, pancreatic cancer, and nonalcoholic steatohepatitis.
43. The method of claim 42 , wherein said disease or disorder is pancreatic cancer.
44. The method of claim 42 , wherein said disease or disorder is nonalcoholic steatohepatitis.
45. The method of claim 42 , wherein said nephropathy is diabetic nephropathy.