US 12,054,484 B2
Substituted tetrahydropyrans as CCR2 modulators
Junfa Fan, Palo Alto, CA (US); Jaroslaw Kalisiak, Mountain View, CA (US); Rebecca M. Lui, Mountain View, CA (US); Venkat Reddy Mali, Cupertino, CA (US); Jeffrey P. McMahon, San Francisco, CA (US); Jay P. Powers, Pacifica, CA (US); Hiroko Tanaka, Mountain View, CA (US); Yibin Zeng, Foster City, CA (US); and Penglie Zhang, Foster City, CA (US)
Assigned to CHEMOCENTRYX, INC., Thousand Oaks, CA (US)
Filed by CHEMOCENTRYX, INC., San Carlos, CA (US)
Filed on Jun. 24, 2021, as Appl. No. 17/357,427.
Application 17/357,427 is a continuation of application No. 16/579,488, filed on Sep. 23, 2019, abandoned.
Application 16/579,488 is a continuation of application No. 15/692,811, filed on Aug. 31, 2017, granted, now 10,464,934, issued on Nov. 5, 2019.
Application 15/692,811 is a continuation of application No. 15/158,713, filed on May 19, 2016, granted, now 9,783,540, issued on Oct. 10, 2017.
Claims priority of provisional application 62/164,957, filed on May 21, 2015.
Prior Publication US 2022/0153733 A1, May 19, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/35 (2006.01); A61K 31/453 (2006.01); A61K 31/4545 (2006.01); A61K 31/4725 (2006.01); A61K 31/496 (2006.01); A61K 31/536 (2006.01); A61K 31/538 (2006.01); A61K 31/551 (2006.01); A61K 31/553 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); A61P 37/00 (2006.01); C07D 309/24 (2006.01); C07D 405/04 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 471/04 (2006.01)
CPC C07D 471/04 (2013.01) [A61K 31/453 (2013.01); A61K 31/4545 (2013.01); A61K 31/4725 (2013.01); A61K 31/496 (2013.01); A61K 31/536 (2013.01); A61K 31/538 (2013.01); A61K 31/551 (2013.01); A61K 31/553 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); A61P 37/00 (2018.01); C07D 405/04 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01)] 8 Claims
 
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound having the formula (Ia1′):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is aryl-C1-4 alkylene, heteroaryl-C1-4 alkylene, aryl, or heteroaryl;
wherein the heteroaryl or heteroaryl portion of heteroaryl-C1-4 alkylene has 1, 2, or 3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein the aryl portion of aryl-C1-4 alkylene, heteroaryl portion of heteroaryl-C1-4 alkylene, aryl, or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected RX substituents;
R2 is H, C1-8 alkyl, C3-8 cycloalkyl-C1-4 alkylene, aryl-C1-4 alkylene, heteroaryl-C1-4 alkylene, C3-8 cycloalkyl, aryl, or heteroaryl;
wherein the heteroaryl or heteroaryl portion of heteroaryl-C1-4 alkylene has 1, 2, or 3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein the aryl portion of aryl-C1-4 alkylene, heteroaryl portion of heteroaryl-C1-4 alkylene, aryl, or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected RX substituents; or
R1 and R2 together with the nitrogen atom to which they are attached, form a monocyclic 6- to 11-membered heterocyclyl, a fused bicyclic 6- to 11-membered heterocyclyl, a monocyclic 6- to 11-membered heteroaryl, or a fused bicyclic 6- to 11-membered heteroaryl;
wherein the monocyclic 6- to 11-membered heterocyclyl, fused bicyclic 6- to 11-membered heterocyclyl, monocyclic 6- to 11-membered heteroaryl, or fused bicyclic 6- to 11-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected RX substituents;
each Rx is independently halogen, —CN, —Rc, —X1C(O)NRaRb, —X1C(O)ORa, —X1NRaRb, —X1ORa, —C(O)Ra, —C(O)NRaRb, —C(O)ORa, —NRaRb, —NRbC(O)Ra, —NRaC(O)NRaRb, —NRbC(O)ORe, —ORa, —OX1C(O)NRaRb, —OX1C(O)ORa, —OX1NRaRb, —OX1ORa, —OC(O)NRaRb, —SF5, —S(O)2NRaRb, phenyl, or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, OH, C1-4 alkoxy, and C1-4 haloalkoxy; or
two vicinal Rx, together with the carbon atoms to which they are attached, form a fused 5- or 6-membered carbocyclyl;
each Ra is independently H, C1-8 alkyl, or C1-8 haloalkyl;
each Rb is independently H, C1-8 alkyl, or C1-8 haloalkyl; or
each Ra and Rb, together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein each 5- or 6-membered heterocyclyl is optionally and independently substituted with 1 oxo substituent;
each Rc is independently C1-8 alkyl, C1-8 haloalkyl, or C3-6 cycloalkyl;
R3 is H, C1-8 alkyl, C3-8 cycloalkyl-C1-4 alkylene, or C3-8 cycloalkyl, wherein the C1-8 alkyl, C3-8 cycloalkyl portion of C3-8 cycloalkyl-C1-4 alkylene, or C3-8 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected Ry substituents;
R4 is H, C1-8 alkyl, or C(O)OH, wherein the C1-8 alkyl is optionally substituted with 1 or 2 independently selected Ry substituents;
each Ry is independently halogen, —CN, —Rf, —C(O)Rd, —C(O)NRdRe, —C(O)ORd, —NRdRe, —NReC(O)Rd, —NRdC(O)NRdRe, —NReC(O)ORf, —ORd, —OC(O)NRdRe, or —S(O)2NRdRe;
each Rd is independently H, C1-8 alkyl, or C1-8 haloalkyl;
each Re is independently H, C1-8 alkyl, or C1-8 haloalkyl; or
each Rd and Re, together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each Rf is independently C1-8 alkyl, C1-8 haloalkyl, or C3-6 cycloalkyl;
each Rz is independently halogen, —CN, —Ri, —X1C(O)NRgRh, —X1NRgRh, —X1NRhC(O)Rg, —C(O)Rg, —C(O)NRgRh, —C(O)ORg, —NRgRh, —NHCH2Rj, —NRhC(O)Rg, —NRgC(O)NRgRh, —NRhC(O)ORi, —NH(pyrrolinyl), —NH(tetrahydrofuranyl), —NH(piperidinyl), —NH(tetrahydropyranyl), —NH(morpholinyl), —ORg, —OC(O)NRgRh, —S(O)2NRgRh, or tetrazolyl;
each Rg is independently H, C1-8 alkyl, Cis haloalkyl, or C3-6 cycloalkyl;
each Rh is independently H, C1-8 alkyl, Cis haloalkyl, or C3-6 cycloalkyl; or
each Rg and Rh, together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein each 5- or 6-membered heterocyclyl is optionally and independently substituted with 1 or 2 oxo substituents;
each Ri is independently C1-8 alkyl, C1-8 haloalkyl, or C3-6 cycloalkyl;
each Rj is independently C3-6 cycloalkyl, pyrrolinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, or morpholinyl;
each X1 is independently C1-4 alkylene;
m is 1;
n is 1; and
q is 1, 2, 3, 4, or 5.