Claims for Patent: 10,189,797

Summary for Patent: 10,189,797

Title:	Chemical modulators of immune checkpoints and therapeutic use
Abstract:	Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods are useful for treating cancer and viral infection in a subject.
Inventor(s):	Chen; Wei (Chapel Hill, NC), Lyerly; Herbert Kim (Chapel Hill, NC), Ren; Xiu-rong (Durham, NC), Wang; Jiangbo (Durham, NC), Guo; Hongtao (Durham, NC), Hobeika; Amy (Durham, NC), Mook; Robert A. (Chapel Hill, NC)
Assignee:	Duke University (Durham, NC)
Application Number:	15/395,464
Patent Claims:	1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, ##STR00035## wherein, R.sup.1a is OR.sup.4 or NR.sup.8--SO.sub.2--R.sup.9; R.sup.1b, R.sup.1c and R.sup.1e are hydrogen; R.sup.1d is halogen; A is heteroaryl selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, thiazolyl, and quinolinyl; D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, and quinolinyl with 0-5 substituents independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, OR.sup.4, SR.sup.5, NR.sup.6R.sup.7, and NR.sup.8--SO.sub.2--R.sup.9; R.sup.4 is selected from the group consisting of hydrogen, --C(O)-alkyl, --C(O)-alkenyl, --C(O)-alkoxyalkyl, --C(O)-heteroalkyl, --C(O)-heteroaryl, --C(O)--O-heteroalkyl, --C(O)--O-heteroaryl, --C(O)--O-alkyl, --C(O)--O-alkenyl, --C(O)--O-alkoxyalkyl, --C(O)--NH-alkyl, and --C(O)-heterocycle; R.sup.5, R.sup.6 and R.sup.7 are each independently selected from the group consisting of hydrogen, alkyl, --C(O)-alkyl, --C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl; R.sup.8 is selected from the group consisting of hydrogen and alkyl; and R.sup.9 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl; and wherein the cancer is breast cancer. 2. The method of claim 1, wherein D is a 6 membered aryl. 3. The method of claim 1, wherein D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl. 4. The method of claim 1, wherein R.sup.1a is OR.sup.4. 5. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: 4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; 4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and 4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol, or a pharmaceutically acceptable salt thereof. 6. A method of downregulating an immune checkpoint in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) pharmaceutically acceptable salt thereof, ##STR00036## Wherein, R.sup.1a is OR.sup.4 or NR.sup.8--SO.sub.2--R.sup.9; R.sup.1b, R.sup.1c and R.sup.1e are hydrogen; R.sup.1d is halogen; A is heteroaryl selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, thiazolyl, and quinolinyl; D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, with 0-5 substituents independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, OR.sup.4, SR.sup.5, NR.sup.6R.sup.7, and NR.sup.8--SO.sub.2--R.sub.9; R.sup.4 is selected from the group consisting of hydrogen, --C(O)-alkyl, --C(O)-alkenyl, --C(O)-alkoxyalkyl, --C(O)-heteroalky, --C(O)-heteroaryl, --C(O)--O-heteroalkyl, --C(O)--O-heteroaryl, --C(O)--O-alkyl, --C(O)--O-alkenyl, C(O)--O-alkoxyalkyl, --C(O)--NH-alkyl and --C(O)-heterocycle; R.sup.5, R.sup.6 and R.sup.7 are each in selected from the group consisting of hydrogen, alkyl, --C(O)-alkyl, --C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl; R.sup.8 is selected from the group consisting of hydrogen and alkyl; and R.sup.9 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl; and wherein the immune checkpoint is selected from the group consisting of programmed cell death protein 1 (PD-1), programmed death-ligand 1(PD-L1) and cytoxic T-lymphocyte-associated protein 4(CTLA-4), or a combination thereof. 7. The method of claim 6, wherein D is a 6 membered aryl. 8. The method of claim 6, wherein D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl. 9. The method of claim 6, wherein R.sup.1a is OR.sup.4. 10. The method of claim 6, wherein the compound of formula (I) is selected from the group consisting of: 4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; 4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and 4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol; or a pharmaceutically acceptable salt thereof. 11. The method of claim 6, wherein the downregulating an immune checkpoint results in activating the immune system. 12. A compound selected from the group consisting of: 4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; 4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and 4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol. 13. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 12. 14. The method of claim 1, further comprising administering at least one of cisplatin, oxaliplatin, a kinase inhibitor, pembrolizumab, ipilimumab, trastuzumab, cetuximab, panitumumab, lambrolizumab and nivolumab. 15. The method of claim 6, further comprising administering at least one of cisplatin, oxaliplatin, a kinase inhibitor, pembrolizumab, ipilimumab, trastuzumab, cetuximab, panitumumab, lambrolizumab and nivolumab. 16. The method of claim 1, wherein the compound is ##STR00037## or a pharmaceutically acceptable salt thereof. 17. The method of claim 16, wherein R.sup.1a is OR.sup.4. 18. The method of claim 16, wherein D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl. 19. The method of claim 17, wherein R.sup.4 is hydrogen and D is nitro.

Details for Patent 10,189,797

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-12-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-12-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2035-12-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2035-12-30
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2035-12-30
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2035-12-30