Claims for Patent: 8,445,515

Summary for Patent: 8,445,515

Title:	C5aR antagonists
Abstract:	Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of C5a receptors.
Inventor(s):	Fan; Pingchen (Fremont, CA), Greenman; Kevin Lloyd (Sunnyvale, CA), Leleti; Manmohan Reddy (Sunnyvale, CA), Li; Yandong (San Jose, CA), Powers; Jay (Pacifica, CA), Tanaka; Hiroko (Foster City, CA), Yang; Ju (Cupertino, CA), Zeng; Yibin (Foster City, CA)
Assignee:	Chemocentryx, Inc. (Mountain View, CA)
Application Number:	12/643,229
Patent Claims:	1. A compound having the formula ##STR00037## and pharmaceutically acceptable salts and rotamers thereof; wherein C.sup.1 is phenyl optionally substituted with from 1 to 3 R.sup.1 substituents; C.sup.2 is phenyl optionally substituted with from 1 to 3 R.sup.2 substituents; C.sup.3 is selected from the group consisting of C.sub.3-8 cycloalkyl and phenyl, and each C.sup.3 is optionally substituted with from 1-3 R.sup.3 substituents; each R.sup.1 is independently selected from the group consisting of halogen, --CN, --R.sup.c, --CO.sub.2R.sup.a, --CONR.sup.aR.sup.b, --C(O)R.sup.a, --OC(O)NR.sup.aR.sup.b, --NR.sup.bC(O)R.sup.a, --NR.sup.bC(O).sub.2R.sup.c, --NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aR.sup.b, --OR.sup.a, and --S(O).sub.2NR.sup.aR.sup.b; wherein each R.sup.a and R.sup.b is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R.sup.c is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R.sup.a, R.sup.b and R.sup.c are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R.sup.1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R.sup.2 is independently selected from the group consisting of halogen, --CN, --R.sup.f, --CO.sub.2R.sup.d, --CONR.sup.dR.sup.e, --C(O)R.sup.d, --OC(O)NR.sup.dR.sup.e, --NR.sup.eC(O)R.sup.d, --NR.sup.eC(O).sub.2R.sup.f, --NR.sup.dC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)NR.sup.dR.sup.e, --NR.sup.dR.sup.e, --OR.sup.d, and --S(O).sub.2NR.sup.dR.sup.e; wherein each R.sup.d and R.sup.e is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R.sup.f is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R.sup.d, R.sup.e and R.sup.f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R.sup.3 is independently selected from the group consisting of halogen, --CN, --R.sup.i, --CO.sub.2R.sup.g, --CONR.sup.gR.sup.h, --C(O)R.sup.g, --OC(O)NR.sup.gR.sup.h, --NR.sup.hC(O)R.sup.g, --NR.sup.hC(O).sub.2R.sup.i, --NR.sup.gC(O)NR.sup.gR.sup.h, --NR.sup.gR.sup.h, --S(O).sub.2NR.sup.gR.sup.h, --X.sup.4--R.sup.j, --X.sup.4--NR.sup.gR.sup.h, --X.sup.4--CONR.sup.gR.sup.h, --X.sup.4--NR.sup.hC(O)R.sup.g, --NHR.sup.j and --NHCH.sub.2R.sup.j, wherein X.sup.4 is a C.sub.1-4 alkylene; each R.sup.g and R.sup.h is independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-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.sup.i is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R.sup.j is selected from the group consisting of C.sub.3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R.sup.g, R.sup.h, R.sup.i and R.sup.j are optionally further substituted with from one to three halogen, methyl, CF.sub.3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH.sub.3. 2. The compound of claim 1, wherein X is hydrogen. 3. The compound of claim 1, having the formula: ##STR00038## 4. The compound of claim 1, having the formula: ##STR00039## 5. The compound of claim 1, having the formula: ##STR00040## wherein X.sup.1 is selected from the group consisting of CH and CR.sup.1; the subscript n is an integer of from 0 to 2; X.sup.2 is selected from the group consisting of CH and CR.sup.2; and the subscript m is an integer of from 0 to 2. 6. The compound of claim 1, having the formula: ##STR00041## wherein X.sup.1 is selected from the group consisting of CH and CR.sup.1; the subscript n is an integer of from 0 to 2; X.sup.2 is selected from the group consisting of CH and CR.sup.2; and the subscript m is an integer of from 0 to 2. 7. The compound of claim 1, having the formula: ##STR00042## wherein the subscript p is an integer of from 0 to 3; X.sup.1 is selected from the group consisting of CH and CR.sup.1; the subscript n is an integer of from 0 to 2; X.sup.2 is selected from the group consisting of CH and CR.sup.2; and the subscript m is an integer of from 0 to 2. 8. The compound of claim 1, having the formula: ##STR00043## 9. The compound of claim 1, having the formula: ##STR00044## 10. The compound of claim 1, having the formula: ##STR00045## 11. The compound of claim 1, having the formula: ##STR00046## 12. The compound of claim 1, having the formula: ##STR00047## 13. The compound of claim 1, having the formula: ##STR00048## 14. The compound of claim 1, having the formula: ##STR00049## wherein R.sup.3 is a member selected from the group consisting of --NR.sup.gR.sup.h, --NHR.sup.j and --NHCH.sub.2R.sup.j. 15. The compound of claim 1, having the formula: ##STR00050## wherein R.sup.3 is a member selected from the group consisting of --X.sup.4--NR.sup.gR.sup.h, --X.sup.4--R.sup.j and --X.sup.4--NR.sup.hCOR.sup.g. 16. The compound of claim 1, wherein C.sup.3 is selected from the group consisting of C.sub.3-6 cycloalkyl, and phenyl, each of which is optionally substituted with from 1 to 3 R.sup.3 substituents. 17. The compound of claim 1, wherein each R.sup.1 is independently selected from the group consisting of halogen, --CN, --R.sup.c, --NR.sup.aR.sup.b and --OR.sup.a, and wherein each R.sup.a and R.sup.b is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each R.sup.c is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl and C.sub.3-6 cycloalkyl, and wherein the aliphatic and cyclic portions of R.sup.a, R.sup.b and R.sup.c are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R.sup.1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring. 18. The compound of claim 1, wherein each R.sup.2 is independently selected from the group consisting of halogen, --R.sup.f and --OR.sup.d; wherein each R.sup.d is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl; each R.sup.f is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of R.sup.d and R.sup.f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups. 19. The compound of claim 16, wherein each R.sup.3 is independently selected from the group consisting of halogen, --R.sup.i, --CO.sub.2R.sup.g, --CONR.sup.gR.sup.h, --NR.sup.hC(O)R.sup.g, --NR.sup.hC(O).sub.2R.sup.i, --NR.sup.gR.sup.h, --OR.sup.g, --X.sup.4--R.sup.j, --X.sup.4--NR.sup.gR.sup.h, --X.sup.4--CONR.sup.gR.sup.h, --X.sup.4--NR.sup.hC(O)R.sup.g, --NHR.sup.j and --NHCH.sub.2R.sup.j, wherein X.sup.4 is a C.sub.1-3 alkylene; each R.sup.g and R.sup.h is independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 1 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R.sup.i is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R.sup.j is selected from the group consisting of C.sub.3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R.sup.g, R.sup.h, R.sup.i and R.sup.j are optionally further substituted with from one to three halogen, methyl, CF.sub.3, hydroxy, amino, alkylamino and dialkylamino groups. 20. The compound of claim 18, wherein C.sup.2 is selected from the group consisting of: ##STR00051## 21. The compound of claim 17, wherein C.sup.1 is selected from the group consisting of: ##STR00052## ##STR00053## 22. The compound of claim 1, wherein C.sup.3 is selected from the group consisting of: ##STR00054## ##STR00055## 23. The compound of claim 1, wherein C.sup.3 is selected from the group consisting of: ##STR00056## ##STR00057## 24. The compound of claim 1, wherein said compound is selected from the group consisting of ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising a compound a pharmaceutically acceptable carrier and a compound having formula ##STR00103## and pharmaceutically acceptable salts and rotamers thereof; wherein C.sup.1 is phenyl optionally substituted with from 1 to 3 R.sup.1 substituents; C.sup.2 is phenyl optionally substituted with from 1 to 3 R.sup.2 substituents; C.sup.3 is selected from the group consisting of C.sub.3-8 cycloalkyl and phenyl, and each C.sup.3 is optionally substituted with from 1-3 R.sup.3 substituents; each R.sup.1 is independently selected from the group consisting of halogen, --CN, --R.sup.c, --CO.sub.2R.sup.a, --CONR.sup.aR.sup.b, --C(O)R.sup.a, --OC(O)NR.sup.aR.sup.b, --NR.sup.bC(O)R.sup.a, --NR.sup.bC(O).sub.2R.sup.c, --NR.sup.a--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aR.sup.b, --OR.sup.a, and --S(O).sub.2NR.sup.aR.sup.b; wherein each R.sup.a and R.sup.b is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R.sup.c is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R.sup.a, R.sup.b and R.sup.c are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R.sup.1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R.sup.2 is independently selected from the group consisting of halogen, --CN, --R.sup.f, --CO.sub.2R.sup.d, --CONR.sup.dR.sup.e, --C(O)R.sup.d, --OC(O)NR.sup.dR.sup.e, --NR.sup.eC(O)R.sup.d, --NR.sup.eC(O).sub.2R.sup.f, --NR.sup.dC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)NR.sup.dR.sup.e, --NR.sup.dR.sup.e, --OR.sup.d, and --S(O).sub.2NR.sup.dR.sup.e; wherein each R.sup.d and R.sup.e is independently selected from hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R.sup.f is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R.sup.d, R.sup.e and R.sup.f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R.sup.3 is independently selected from the group consisting of halogen, --CN, --R.sup.i, --CO.sub.2R.sup.g, --CONR.sup.gR.sup.h, --C(O)R.sup.g, --OC(O)NR.sup.gR.sup.h, --NR.sup.hC(O)R.sup.g, --NR.sup.hC(O).sub.2R.sup.i, --NR.sup.gC(O)NR.sup.gR.sup.h, --NR.sup.gR.sup.h, --OR.sup.g, --S(O).sub.2NR.sup.gR.sup.h, --X.sup.4--R.sup.j, --X.sup.4--NR.sup.gR.sup.h, --X.sup.4--CONR.sup.gR.sup.h, --X.sup.4--NR.sup.hC(O)R.sup.g, --NHR.sup.j and --NHCH.sub.2R.sup.j, wherein X.sup.4 is a C.sub.1-4 alkylene; each R.sup.g and R.sup.h is independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl and C.sub.1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-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.sup.i is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R.sup.j is selected from the group consisting of C.sub.3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R.sup.g, R.sup.h, R.sup.i and R.sup.j are optionally further substituted with from one to three halogen, methyl, CF.sub.3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH.sub.3.