IP Library › Granted Patent US 12673046
Granted Patent B2
US 12673046 · App. 17/906,600 · Granted Jul 7, 2026

Substituted tetrazoles as ACSS2 inhibitors

Inventors: Thomas Fuchss (Darmstadt, DE); Lisa Koetzner (Darmstadt, DE); Christina Schindler (Darmstadt, DE); Daniel Kuhn (Darmstadt, DE)
Assignees: MERCK PATENT GMBH; RYVU THERAPEUTICS S.A.
A61K31/437A61K9/02A61K9/06A61K9/08A61K9/19A61K9/2013A61K9/2059A61K9/2813A61K9/2826A61K9/286A61K9/4825A61K31/444A61K31/501A61K31/506A61K41/17A61K47/02A61K47/44C07D471/04C07B2200/05
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Quick Facts
Patent No.
US 12673046
App. No.
17/906,600
Granted
Jul 7, 2026
Kind
B2
Abstract

Substituted tetrazoles of formula I-a, I-b, or I-c: or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer or tautomer thereof; useful as ACSS2 inhibitors are provided.

Claims (245)

1 . A compound of formula (I-a), formula (I-b), or formula (I-c):

or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof,

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic, wherein the C 1-6 aliphatic or OC 1-6 aliphatic is optionally substituted with one or more substituents independently selected from the group consisting of NH 2 and OH;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic.

2 . The compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein R 1 and R 2 are identical.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein R 1 and R 2 are different.

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein:

Ar A is phenyl, wherein the phenyl is optionally substituted with one or two substituents independently selected from the group consisting of R A1 and R A2 ;

Hetar A is a monocyclic heteroaryl;

wherein the monocyclic heteroaryl contains 5 or 6 ring atoms;

wherein the monocyclic heteroaryl contains ring carbon atoms and 1 or 2 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 and R A2 ;

Ar B is phenyl, wherein the phenyl is optionally substituted with one or two substituents independently selected from the group consisting of R B1 and R B2 ; and

Hetar B is a monocyclic heteroaryl;

wherein the monocyclic heteroaryl contains 5 or 6 ring atoms;

wherein the monocyclic heteroaryl contains ring carbon atoms and 1 or 2 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 and R B2 .

5 . The compound according to claim 4 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein:

each R A1 is independently H, F, Cl, C 1-4 aliphatic, or OC 1-4 aliphatic;

each R A2 is independently H, F, Cl, C 1-4 aliphatic, or OC 1-4 aliphatic;

each R B1 is independently H, F, Cl, C 1-4 aliphatic, or OC 1-4 aliphatic; and

each R B2 is independently H, F, Cl, C 1-4 aliphatic, or OC 1-4 aliphatic.

6 . The compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein:

R 3 is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of NH 2 and OH;

R 4 is H; and

R 5 is H, F, Cl, C 1-4 alkyl, or OC 1-4 alkyl.

7 . The compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein:

Ar A is phenyl, deuterophenyl, fluorophenyl, or methylphenyl;

Hetar A is thiophen-2-yl, thiophen-3-yl, methylthiophenyl, methylpyrazolyl, thiazolyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazinyl, or pyrimidinyl;

Ar B is phenyl, deuterophenyl, fluorophenyl, or methylphenyl;

Hetar B is thiophen-2-yl, thiophen-3-yl, methylthiophenyl, methylpyrazolyl, thiazolyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazinyl, or pyrimidinyl;

R 3 is CH 3 , CH 2 CH 3 , CH 2 CH 2 NH 2 , or CH 2 CH 2 OH;

R 4 is H; and

R 5 is H, F, Cl, CH 3 , CH 2 CH 3 , or OCH 3 .

8 . The compound according to claim 7 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof, wherein:

Ar A is 2,3,4,5,6-pentadeuterophenyl, 2-fluorophenyl, or 2-methylphenyl;

Hetar A is thiophen-2-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1,3-thiazol-2-yl, pyridazin-3-yl, pyrimidin-2-yl, or pyrimidin-4-yl;

Ar B is 2,3,4,5,6-pentadeuterophenyl, 2-fluorophenyl, or 2-methylphenyl; and

Hetar B is is thiophen-2-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1,3-thiazol-2-yl, pyridazin-3-yl, pyrimidin-2-yl, or pyrimidin-4-yl.

9 . A medicament comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof.

10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof.

11 . The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition further comprises a second active ingredient.

12 . A kit comprising separate packs of (a) an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof; and (b) a second active ingredient.

13 . A method for inhibiting acetyl Co-A synthetase 2 (ACSS2) activity in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof.

14 . The method according to claim 13 , wherein the subject has a medical disease or disorder selected from the group consisting of an addiction, an anxiety disorder, bipolar disorder, cancer, depression, an inflammatory disease, an impulse control disorder, a lipid metabolism disorder, a neurogenerative disease, a phobia, post-traumatic stress disorder (PTSD), schizophrenia, and a viral infection.

15 . The method according to claim 14 , wherein the addiction is a behavioral addiction.

16 . The method according to claim 14 , wherein the anxiety disorder is panic disorder.

17 . The method according to claim 14 , wherein the impulse control disorder is obsessive-compulsive disorder or Tourette's syndrome.

18 . The method according to claim 14 , wherein the inflammatory disease is selected from the group consisting of idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, systemic sclerosis, and ulcerative colitis.

19 . The method according to claim 14 , wherein the lipid metabolism disorder is fatty liver disease.

20 . The method according to claim 19 , wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).

21 . The method according to claim 13 , wherein the subject has a medical disease or disorder selected from the group consisting of an addiction, Crohn's disease, Huntington's disease, non-alcoholic steatohepatitis, a tumor, and a viral infection caused by cytomegalovirus (CMV).

22 . The method according to claim 21 , wherein the addiction is selected from the group consisting of an addiction to alcohol, an addiction to an amphetamine, an addiction to an anxiolytic, an addiction to cannabis, an addiction to cocaine, an addiction to a hallucinogen, an addiction to a hypnotic, an addiction to an inhalant, an addiction to an opioid, an addiction to a sedative, and an addiction to tobacco.

23 . The method according to claim 22 , wherein the addiction to a hallucinogen is an addiction to phencyclidine (PCP).

24 . A process for manufacturing a compound of formula (I-a), formula (I-b), or formula (I-c) according to claim 1 :

or a deuteroisotope or tautomer thereof,

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic, wherein the C 1-6 aliphatic or OC 1-6 aliphatic is optionally substituted with one or more substituents independently selected from the group consisting of NH 2 and OH;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

wherein the process comprises the following step:

(a) cyclizing a carbonitrile of formula (II-a):

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

with sodium azide, optionally in the presence of zinc chloride, to yield the compound of formula (I-a) above; or

(b) cyclizing a carbonitrile of formula (II-b):

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R 42 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

with sodium azide, optionally in the presence of zinc chloride, to yield the compound of formula (I-b) above; or

(c) cyclizing a carbonitrile of formula (II-c):

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

with sodium azide, optionally in the presence of zinc chloride, to yield the compound of formula (I-c) above.

25 . A compound of formula (II-a), formula (II-b), or formula (II-c):

or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof,

wherein:

R 1 is Ar A or Hetar A ;

Ar A is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

Hetar A is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R A1 , R A2 , R A3 , R A4 , and R A5 ;

R 2 is Ar B or Hetar B ;

Ar B is a monocyclic or bicyclic aryl;

wherein the monocyclic or bicyclic aryl contains 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms; and

wherein the monocyclic or bicyclic aryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

Hetar B is a monocyclic or bicyclic heteroaryl;

wherein the monocyclic or bicyclic heteroaryl contains 5, 6, 7, 8, 9, 10, or 11 ring atoms;

wherein the monocyclic or bicyclic heteroaryl contains ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the monocyclic or bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R B1 , R B2 , R B3 , R B4 , and R B5 ;

each R A1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R A5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B1 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B2 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B3 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B4 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

each R B5 is independently H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic;

R 3 is C 1-6 aliphatic or OC 1-6 aliphatic, wherein the C 1-6 aliphatic or OC 1-6 aliphatic is optionally substituted with one or more substituents independently selected from the group consisting of NH 2 and OH;

R 4 is H, D, C 1-6 aliphatic, or OC 1-6 aliphatic; and

R 5 is H, D, F, Cl, Br, I, C 1-6 aliphatic, or OC 1-6 aliphatic.

26 . A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, deuteroisotope, stereoisomer, or tautomer thereof.