	US 12,415,809 B2
	Pyrrolotriazine compounds as tam inhibitors
Yun-Long Li, Chadds Ford, PA (US); Xiaozhao Wang, Moorestown, NJ (US); Joseph Barbosa, Lambertville, NJ (US); David M. Burns, Plymouth Meeting, PA (US); Hao Feng, Glen Mills, PA (US); Joseph Glenn, Mount Royal, NJ (US); Chunhong He, Boothwyn, PA (US); Taisheng Huang, Wilmington, DE (US); Song Mei, Wilmington, DE (US); and Jincong Zhuo, Garnet Valley, PA (US)
Assigned to Incyte Corporation, Wilmington, DE (US)
Filed by Incyte Corporation, Wilmington, DE (US)
Filed on Jan. 9, 2023, as Appl. No. 18/151,688.
Application 18/151,688 is a continuation of application No. 17/073,987, filed on Oct. 19, 2020, granted, now 11,591,338.
Application 17/073,987 is a continuation of application No. 16/559,841, filed on Sep. 4, 2019, granted, now 10,844,069, issued on Nov. 24, 2020.
Application 16/559,841 is a continuation of application No. 15/971,017, filed on May 4, 2018, granted, now 10,442,810, issued on Oct. 15, 2019.
Application 15/971,017 is a continuation of application No. 15/469,975, filed on Mar. 27, 2017, granted, now 9,981,975, issued on May 29, 2018.
Claims priority of provisional application 62/438,750, filed on Dec. 23, 2016.
Claims priority of provisional application 62/362,934, filed on Jul. 15, 2016.
Claims priority of provisional application 62/314,066, filed on Mar. 28, 2016.
Prior Publication US 2024/0124463 A1, Apr. 18, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/53 (2006.01); A61P 35/00 (2006.01); C07D 403/04 (2006.01); C07D 403/14 (2006.01); C07D 487/04 (2006.01)

CPC C07D 487/04 (2013.01) [A61K 31/53 (2013.01); A61P 35/00 (2018.01); C07D 403/04 (2013.01); C07D 403/14 (2013.01)]

33 Claims

1. A method for treating a cancer in a patient, wherein the cancer is selected from lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, gastric cancer, rhabdomyosarcoma, glioblastoma, endometrial cancer, ovarian cancer, Kaposi sarcoma, esophageal cancer, pancreatic cancer, thyroid cancer, osteosarcoma, and hepatocellular cancer, said method comprising: administering to the patient a therapeutically effective amount of a compound of Formula (IIg1) or Formula (IIg2):

or a pharmaceutically acceptable salt thereof, wherein:

R¹is Cy^A3-R^A;

R^Ais H, C_1-6alkyl, C_1-6haloalkyl, halo, C_3-6cycloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1OR^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, or S(O)₂NR^c1R^d1; wherein said C_1-6alkyl or C_1-6haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹¹;

Cy^A3is piperidinyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R^A3;

each R^A3is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkyl, HO—C_1-3alkyl, H₂N—C_1-3alkyl, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino;

each R^Bis independently selected from halo, C_1-6alkyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2OR^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^e2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

R^Cis selected from OH, halo, C_1-4alkyl, and C_1-3haloalkyl;

each R¹¹is independently selected from CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3OR^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

each R¹²is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4OR^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein said C_1-6alkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

R^a1, R^c1and R^d1are each independently selected from H, C_1-6alkyl, and C_1-6haloalkyl; wherein said C_1-6alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g; or

alternatively, R^c1and R^d1attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R^g;

R^b1is selected from C_1-6alkyl and C_1-6haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

R^e1is selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl, and di(C_1-6alkyl)aminosulfonyl;

each R^a2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²; or

alternatively, any R^c2and R^d2attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R¹²;

each R^b2is independently selected from C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

each R^a3, R^c3and R^d3is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-4alkylene, phenyl-C_1-4alkylene, 5-6 membered heteroaryl-C_1-4alkylene, and 4-7 membered heterocycloalkyl-C_1-4alkylene; wherein said C_1-6alkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-4alkylene, phenyl-C_1-4alkylene, 5-6 membered heteroaryl-C_1-4alkylene, and 4-7 membered heterocycloalkyl-C_1-4alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g; or

alternatively, any R^c3and R^d3attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R^g;

each R^b3is independently selected from C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-4alkylene, phenyl-C_1-4alkylene, 5-6 membered heteroaryl-C_1-4alkylene, and 4-7 membered heterocycloalkyl-C_1-4alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a4, R^c4and R^d4, is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl; wherein said C_1-6alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g; or

alternatively, any R^c4and R^d4attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R^g;

each R^b4is independently selected from C_1-6alkyl and C_1-6haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkyl, HO—C_1-3alkyl, H₂N—C_1-3alkyl, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.