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):	Pingchen Fan, Kevin Lloyd Greenman, Manmohan Reddy Leleti, Yandong Li, Jay Powers, Hiroko Tanaka, Ju Yang, Yibin Zeng
Assignee:	Chemocentryx Inc
Application Number:	US12/643,229
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,445,515
Patent Claims:	1. A compound having the formula and pharmaceutically acceptable salts and rotamers thereof; wherein C1 is phenyl optionally substituted with from 1 to 3 R1 substituents; C2 is phenyl optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of C3-8 cycloalkyl and phenyl, and each C3 is optionally substituted with from 1-3 R3 substituents; each R1 is independently selected from the group consisting of halogen, —CN, —Rc, —CO2Ra, —CONRaRb, —C(O)Ra, —OC(O)NRaRb, —NRbC(O)Ra, —NRbC(O)2Rc, —NRaC(O)NRaRb, —NRaRb, —ORa, and —S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 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 Rc is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, —CN, —Rf, —CO2Rd, —CONRdRe, —C(O)Rd, —OC(O)NRdRe, —NReC(O)Rd, —NReC(O)2Rf, —NRdC(O)NRdRe, —NRdC(O)NRdRe, —NRdRe, —ORd, and —S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 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 Rf is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R3 is independently selected from the group consisting of halogen, —CN, —Ri, —CO2Rg, —CONRgRh, —C(O)Rg, —OC(O)NRgRh, —NRhC(O)Rg, —NRhC(O)2Ri, —NRgC(O)NRgRh, —NRgRh, —S(O)2NRgRh, —X4—Rj, —X4—NRgRh, —X4—CONRgRh, —X4—NRhC(O)Rg, —NHRj and —NHCH2Rj, wherein X4 is a C1-4 alkylene; each Rg and Rh is independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl and C1-8 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 Ri is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, Ri and Rj are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3. 2. The compound of claim 1, wherein X is hydrogen. 3. The compound of claim 1, having the formula: 4. The compound of claim 1, having the formula: 5. The compound of claim 1, having the formula: wherein X1 is selected from the group consisting of CH and CR1; the subscript n is an integer of from 0 to 2; X2 is selected from the group consisting of CH and CR2; and the subscript m is an integer of from 0 to 2. 6. The compound of claim 1, having the formula: wherein X1 is selected from the group consisting of CH and CR1; the subscript n is an integer of from 0 to 2; X2 is selected from the group consisting of CH and CR2; and the subscript m is an integer of from 0 to 2. 7. The compound of claim 1, having the formula: wherein the subscript p is an integer of from 0 to 3; X1 is selected from the group consisting of CH and CR1; the subscript n is an integer of from 0 to 2; X2 is selected from the group consisting of CH and CR2; and the subscript m is an integer of from 0 to 2. 8. The compound of claim 1, having the formula: 9. The compound of claim 1, having the formula: 10. The compound of claim 1, having the formula: 11. The compound of claim 1, having the formula: 12. The compound of claim 1, having the formula: 13. The compound of claim 1, having the formula: 14. The compound of claim 1, having the formula: wherein R3 is a member selected from the group consisting of —NRgRh, —NHRj and —NHCH2Rj. 15. The compound of claim 1, having the formula: wherein R3 is a member selected from the group consisting of —X4—NRgRh, —X4—Rj and —X4—NRhCORg. 16. The compound of claim 1, wherein C3 is selected from the group consisting of C3-6 cycloalkyl, and phenyl, each of which is optionally substituted with from 1 to 3 R3 substituents. 17. The compound of claim 1, wherein each R1 is independently selected from the group consisting of halogen, —CN, —Rc, —NRaRb and —ORa, and wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each Rc is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 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 R2 is independently selected from the group consisting of halogen, —Rf and —ORd; wherein each Rd is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd and Rf 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 R3 is independently selected from the group consisting of halogen, —Ri, —CO2Rg, —CONRgRh, —NRhC(O)Rg, —NRhC(O)2Ri, —NRgRh, —ORg, —X4—Rj, —X4—NRgRh, —X4—CONRgRh, —X4—NRhC(O)Rg, —NHRj and —NHCH2Rj, wherein X4 is a C1-3 alkylene; each Rg and Rh is independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl and C1-8 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 Ri is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, Ri and Rj are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups. 20. The compound of claim 18, wherein C2 is selected from the group consisting of: 21. The compound of claim 17, wherein C1 is selected from the group consisting of: 22. The compound of claim 1, wherein C3 is selected from the group consisting of: 23. The compound of claim 1, wherein C3 is selected from the group consisting of: 24. The compound of claim 1, wherein said compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising a compound a pharmaceutically acceptable carrier and a compound having formula and pharmaceutically acceptable salts and rotamers thereof; wherein C1 is phenyl optionally substituted with from 1 to 3 R1 substituents; C2 is phenyl optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of C3-8 cycloalkyl and phenyl, and each C3 is optionally substituted with from 1-3 R3 substituents; each R1 is independently selected from the group consisting of halogen, —CN, —Rc, —CO2Ra, —CONRaRb, —C(O)Ra, —OC(O)NRaRb, —NRbC(O)Ra, —NRbC(O)2Rc, —NRa—C(O)NRaRb, —NRaC(O)NRaRb, —NRaRb, —ORa, and —S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 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 Rc is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, —CN, —Rf, —CO2Rd, —CONRdRe, —C(O)Rd, —OC(O)NRdRe, —NReC(O)Rd, —NReC(O)2Rf, —NRdC(O)NRdRe, —NRdC(O)NRdRe, —NRdRe, —ORd, and —S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 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 Rf is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R3 is independently selected from the group consisting of halogen, —CN, —Ri, —CO2Rg, —CONRgRh, —C(O)Rg, —OC(O)NRgRh, —NRhC(O)Rg, —NRhC(O)2Ri, —NRgC(O)NRgRh, —NRgRh, —ORg, —S(O)2NRgRh, —X4—Rj, —X4—NRgRh, —X4—CONRgRh, —X4—NRhC(O)Rg, —NHRj and —NHCH2Rj, wherein X4 is a C1-4 alkylene; each Rg and Rh is independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl and C1-8 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 Ri is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, Ri and Rj are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3.