US 12,466,822 B2
Heterocyclic compounds as immunomodulators
Liangxing Wu, Wilmington, DE (US); Neil Lajkiewicz, Bedford, MA (US); Chunhong He, Boothwyn, PA (US); Kaijiong Xiao, Clark, NJ (US); Wenyu Zhu, Media, PA (US); Zhenwu Li, Wilmington, DE (US); Chao Qi, Newark, DE (US); Leah C. Konkol, Newark, DE (US); and Wenqing Yao, Chadds Ford, PA (US)
Assigned to Incyte Corporation, Wilmington, DE (US)
Filed by Incyte Corporation, Wilmington, DE (US)
Filed on Sep. 24, 2021, as Appl. No. 17/483,959.
Application 17/483,959 is a continuation of application No. 17/170,662, filed on Feb. 8, 2021, abandoned.
Application 17/170,662 is a continuation of application No. 16/913,616, filed on Jun. 26, 2020, abandoned.
Application 16/913,616 is a continuation of application No. 16/678,117, filed on Nov. 8, 2019, abandoned.
Application 16/678,117 is a continuation of application No. 16/365,234, filed on Mar. 26, 2019, abandoned.
Application 16/365,234 is a continuation of application No. 16/058,149, filed on Aug. 8, 2018, abandoned.
Application 16/058,149 is a continuation of application No. 15/850,985, filed on Dec. 21, 2017, abandoned.
Claims priority of provisional application 62/551,011, filed on Aug. 28, 2017.
Claims priority of provisional application 62/487,362, filed on Apr. 19, 2017.
Claims priority of provisional application 62/438,038, filed on Dec. 22, 2016.
Prior Publication US 2022/0213090 A1, Jul. 7, 2022
Int. Cl. C07D 471/04 (2006.01); A61K 31/4375 (2006.01); A61P 37/00 (2006.01); A61P 37/02 (2006.01); C07D 401/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61P 37/00 (2018.01); A61P 37/02 (2018.01); C07D 401/04 (2013.01); C07D 519/00 (2013.01)] 28 Claims
 
1. A compound of Formula (IIa):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
ring A is selected from:

OG Complex Work Unit Chemistry
wherein each subscript r is an integer of 1, 2, or 3;
L is —C(O)NR13—, wherein the carbonyl group is attached to ring A;
X is N or CR17;
R2 is H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl or —N(C1-4 alkyl)2, wherein the C1-4 alkyl and C1-4 alkoxy of R2 is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, —C(O)NH2, NH2, —NHC1-4 alkyl, and —N(C1-4 alkyl)2;
R3 is methyl, halo, CN or C1-4 haloalkyl;
R4 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl or —N(C1-4 alkyl)2;
R5 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl or —N(C1-4 alkyl)2;
R6 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R6 is optionally substituted with 1, 2, 3, 4 or 5 Rb substituents;
R7 is H, halo, CN, C1-4 alkyl, C1-4 alkoxy or C1-4 haloalkoxy, wherein the C1-4 alkyl and C1-4 alkoxy of R7 are each optionally substituted with CN;
or two R6 substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents;
R8 and R9 are each independently selected from H, halo, CN, OH, —COOH, C1-4 alkyl, C1-4 alkoxy, —NHC1-4 alkyl, —N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R8 or R9 are each optionally substituted with 1, 2 or 3 independently selected R9 substituents;
or R8 and R9 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or 7-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 Rq substituents;
or R8 and R10 taken together with the atoms to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to one additional heteroatoms as ring members selected from O, N or S, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R8 and R10 are each optionally substituted with 1 or 2 Rq substituents;
R10 and R11 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-6 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, —C(O)Rg, —C(O)ORg, —C(O)NRgRg, —SO2Rg and —SO2NRgRg, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-6 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R10 or R11 are each optionally substituted with 1, 2, or 3 independently selected Rd substituents;
or R10 and R11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is each optionally substituted with 1, 2 or 3 Rf substituents;
R12 is H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl or —N(C1-4 alkyl)2;
each R13 is independently H, C1-6 haloalkyl or C1-6 alkyl optionally substituted with a substituent selected from C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl and —N(C1-4 alkyl)2;
R14 and R15 are each independently selected from H, halo, CN, OH, —COOH, C1-4 alkyl, C1-4 alkoxy, —NHC1-4 alkyl, —N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R14 or R15 are each optionally substituted with 1, 2, or 3 independently selected Rq substituents;
or R14 and R15 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 Rq substituents;
R17 is H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, —COOH, NH2, —NHC1-4 alkyl or —N(C1-4 alkyl)2, wherein the C1-4 alkyl and C1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo and —C(O)NH2;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rd are each optionally substituted with 1, 2, or 3 independently selected Rf substituents;
each Re is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Re are each optionally substituted with 1, 2 or 3 independently selected Rf substituents;
each Rb substituent is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents;
each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents;
each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NRo)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rn are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;
each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 Rp substituents;
each Rp is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O) Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rp is optionally substituted with 1, 2 or 3 Rq substituents;
or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents;
each Rh is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Ri substituents;
each Rj is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 haloalkoxy of Ri are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;
or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rr substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
each Ri, Rk, Ro or Rr is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, and C2-4 alkynyl of Ri, Rk, Ro or Rr are each optionally substituted with 1, 2 or 3 Rq substituents;
each Rq is independently selected from halo, OH, CN, —COOH, NH2, —NH—C1-6 alkyl, —N(C1-6 alky)2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with 1, 2, or 3 substituents selected from halo, OH, CN, —COOH, NH2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
the subscript m is an integer of 0, 1, 2 or 3;
the subscript n is an integer of 0, 1, 2 or 3;
each subscript q is independently an integer of 1, 2, 3 or 4; and
the subscript p is an integer of 1, 2, 3 or 4.