WO2025162358A1

WO2025162358A1 - Fto inhibitors of bicyclic structures

Info

Publication number: WO2025162358A1
Application number: PCT/CN2025/075110
Authority: WO
Inventors: Wei Li; Niu Huang; Leilei Chen
Original assignee: Rpxds Co Ltd
Current assignee: Rpxds Co Ltd
Priority date: 2024-01-30
Filing date: 2025-01-26
Publication date: 2025-08-07
Anticipated expiration: 2026-07-30

Abstract

Disclosed herein is a compound of Formulas (I) and (II) as an FTO inhibitor with novel structures. Also disclosed herein is a pharmaceutical composition comprising the same, and a method of inhibiting weight gain, promoting weight loss, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity-related disease (esp. obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) or Alzheimer's disease by inhibiting FTO by using the compound disclosed herein.

Description

FTO INHIBITORS OF BICYCLIC STRUCTURES

FILED OF THE INVENTION

Disclosed herein is a compound of Formulas (I) and (II) as an FTO inhibitor with novel structures. Also disclosed herein is a pharmaceutical composition comprising the same, and a method of inhibiting weight gain, promoting weight loss, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity-related disease (esp. obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) or Alzheimer’s disease by inhibiting FTO by using the compound disclosed herein.

BACKGROUND OF THE INVENTION

Obesity is a severe health problem worldwide and many factors contribute to this chronic disease, including environmental factors and genetic factors. Genome-wide association studies to investigate patients with obesity revealed a gene for FTO (fat mass and obesity) to strongly associate with obesity. FTO’s functional role in obesity was confirmed in transgenic animal models, such as FTO knockout mouse, FTO-overexpression mouse and FTO-I367F mutation mouse. More specifically, FTO global-knockout and neuron-specific knockout induce body weight loss, while FTO gene overexpression results in obesity. One mis-sense mutation was observed to inhibit FTO enzymatic function and protect mouse from obesity. Nevertheless, FTO is expressed in many tissues, especially in hypothalamic nuclei controlling energy expenditure, which is consistent with the suggestion that FTO affects energy homeostasis. FTO protein is an α-ketoglutarate and iron (II) dependent nucleic acid demethylase. Its preferred substrate is N6-meA in message RNA, which locates near the stop codon and influences gene translation.

WO2016206573A1 discloses entacapone analogs showing FTO inhibition. However, inhibition of COMT for an FTO inhibitor is not desirable as the inhibition of COMT may affect the metabolism of important neurotransmitters in the body, including dopamine, epinephrine, and norepinephrine, which further results in effects unrelated to FTO inhibition and results in potential side effects. In addition, inhibition of COMT may also affect the metabolism of drugs or small molecules having catechol groups, resulting in adverse drug-drug interactions.

There is a need for novel FTO inhibitors with improved properties.

SUMMARY OF THE INVENTION

Disclosed herein are compounds used as FTO inhibitors comprising a bicyclic moiety, pharmaceutical compositions comprising the same, and methods of using the same. In particular, the compounds disclosed herein show comparable or improved FTO inhibition and improved selectivity of FTO inhibition over COMT inhibition or even without COMT inhibition by structural modifications by combing the bicyclic moiety, the hydroxy group in Formula (I) and R¹ group.

In one aspect, provided herewith is a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a deuterated analog thereof,

wherein

X¹, X², and X³, are each independently -O-, -S-, -NH-, -N=, -CH=, or -CH₂-, provided that no two -O-and/or -S-are adjacent,

X⁴, X⁵, X⁶ are each independently -CH= or -N=,

X⁷ and X⁸ are each independently nitrogen and carbon;

m and n are each a number of 0 to 3, provided that the valency theory has been met;

R² and R³ are each independently halogen, deuterium, cyano, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1- ₆alkoxy, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1- ₆alkoxyC_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl-S-, C_2-6alkenyl, C_2-6alkynyl, -SO₂R^2a, -COOR^2a, or -NR^2aR^2b,

wherein R^2a and R^2b are each independently hydrogen, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, or C_1-6alkoxyC_1-6alkyl;

R¹ is -C (O) NR^a1R^a2, -C (O) R^a3, or R^a4,

wherein

R^a1 is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, or C_1-6alkoxy;

R^a2 is

a) C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl, wherein each of said C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, -OR^b1, halogen, C_1-6alkyl-S-, cyano, -NR^b2R^b3, -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, -NR^b2C (O) R^b3, phenyl, naphthalenyl, heteroaryl or heterocyclyl, wherein each of said phenyl or naphthalenyl is unsubstituted or substituted with one or more substituents R^c3;

b) C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, each of C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

wherein

R^b1 is

1) hydrogen;

2) C_1-6alkyl, C_1-6alkoxy, or C_1-6alkoxyC_1-6alkyl-;

3) phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl, -C_1-6alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl; or

4) heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with C_1- ₆alkyl, oxo, or heteroaryl;

R^c1, and R^c2 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^b2 and R^b3 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1-6alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) ;

- C_2-6alkenyl or C_2-6alkynyl;

- C_1-6alkyl-S-

- C_1-6alkoxy or phenoxy, wherein each of said C_1-6alkoxy or phenoxy is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclyl;

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- Heterocyclyl, which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, C_1-6alkyl substituted heterocyclyl,

- Heteroaryl, which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl;

- C_3-8cylcoalkyl;

- phenyl; and

R^e1, R^e2, and R^e3 are each independently hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl-substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) ;

alternatively, R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl,

R^b4 is hydroxy; halogen; oxo; cyano; C_1-6alkyl; haloC_1-6alkyl; C_1-6alkoxy; C_1-6alkoxyC_1-6alkyl; haloC_1-6alkoxy; NR^c4R^c5, wherein R^c4 and R^c5 are each independently hydrogen, alkyl, or phenyl; phenyl, heterocyclyl, or heteroaryl, wherein each of said phenyl, heterocyclyl or heteroaryl is unsubstituted or substituted with one or more halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, -NR^e4R^e5, or -COOR^e4, wherein R^e4 and R^e5 are hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl, or C_1- ₆alkyl-substituted heteroaryl;

R^a3 is C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein each of said C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, or haloC_1-6alkoxy;

R^a4 is heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, phenoxy, -NR^c6R^c7, -C (O) NR^c6R^c7, -OC (O) NR^c6R^c7, -C (O) R^c6, or -NR^c6C (O) R^c7,

R^c6 and R^c7 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy,provided that the bicyclic moietyis aromatic.

The bicylic moiety

In some embodiments, X⁴, X⁵, and X⁶ are each -CH=; and X⁷ and X⁸ are carbon.

In some embodiments, X¹ is O, S or -NH-, X² is -N= and X³ is -CH=. In some embodiments, X¹ is -N=, X² is -CH=, and X³ is O, S or -NH-. In some embodiments, X¹ is O or S, X² is -N= and X³ is -CH=. In some embodiments, X¹ is -N=, X² is -CH=, and X³ is O or S. In some embodiments, X¹ is -N=, X² is -N=, and X³ is -NH-; or X¹ is -N=, X² is -NH-, and X³ is -N=; or X¹ is -NH-, X² is -N=, and X³ is -N=.

In some embodiments, n is 0. In some embodiments, n is 0 and m is 1 to 3, e.g., 1 or 2 or 3.

In some embodiments, the bicyclic moiety is benzofuranyl, benzo [b] thiophenyl, benzo [d] isoxazolyl, benzo [d] isothiazolyl, benzo [c] isoxazolyl, benzo [c] isothiazolyl, benzo [d] oxazolyl, 1H-benzo [d] imidazolyl, benzo [d] thiazolyl, pyrazolo [1, 5-a] pyridinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 3] triazolo [1, 5-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a] pyridinyl, [1, 2, 4] triazolo [1, 5-a] pyridinyl, benzo [d] [1, 2, 3] oxadiazolyl, benzo [c] [1, 2, 5] oxadiazolyl, benzo [d] [1, 2, 3] thiadiazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, 2H-benzo [d] [1, 2, 3] triazolyl, tetrazolo [1, 5-a] pyridinyl, isoindolinyl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridinyl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridinyl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridinyl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazinyl, or 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidinyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, deuterium, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C_1-6alkylSO₂-, NR^2aR^2b, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, hydroxyC_1-6alkyl, C_1- ₆alkoxyC_1-6alkyl, cyano, COOR^2a, or cycloalkyl.

In some embodiments, the bicyclic moiety is benzofuran-5-yl, benzo [b] thiophen-5-yl, benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [d] isothiazol-5-yl, benzo [c] isoxazol-5-yl, benzo [c] isothiazol-5-yl, benzo [d] oxazol-5-yl, benzo [d] oxazol-6-yl, 1H-benzo [d] imidazol-6-yl, benzo [d] thiazol-6-yl, pyrazolo [1, 5-a] pyridin-5-yl, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 3] triazolo [1, 5-a] pyridin-5-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-7-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-6-yl, benzo [d] [1, 2, 3] oxadiazol-5-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl , benzo [d] [1, 2, 3] oxadiazol-6-yl, benzo [d] [1, 2, 3] thiadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, tetrazolo [1, 5-a] pyridin-7-yl, tetrazolo [1, 5-a] pyridin-6-yl, isoindolin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazin-6-yl, or 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidin-5-yl, each of which is unsubstituted or substituted as defined above. In some embodiments, the substituents are oxo, fluoro, chloro, bromo, nitro, methoxy, hydroxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfonyl, amino, methylamino, methyl, trifluoromethyl-d3, hydroxymethyl, cyano, methoxycarbonyl, carboxy, or cyclopropyl.

In some embodiments, the bicyclic moiety is benzofuran-5-yl, benzo [b] thiophen-5-yl, benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [d] isothiazol-5-yl, benzo [c] isoxazol-5-yl, benzo [c] isothiazol-5-yl, benzo [d] oxazol-5-yl, benzo [d] oxazol-6-yl, 1H-benzo [d] imidazol-6-yl, benzo [d] thiazol-6-yl, pyrazolo [1, 5-a] pyridin-5-yl, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 3] triazolo [1, 5-a] pyridin-5-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-7-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-6-yl, benzo [d] [1, 2, 3] oxadiazol-5-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, benzo [d] [1, 2, 3] thiadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, tetrazolo [1, 5-a] pyridin-7-yl, tetrazolo [1, 5-a] pyridin-6-yl, 2-oxo-2, 3-dihydrobenzo [d] oxazol-5-yl, 2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl, 1, 3-dioxoisoindolin-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7-chloro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4- (trifluoromethyl) -1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7- (trifluoromethyl) -3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-cyano-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4-cyano-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidin-5-yl, 7-nitro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-methyl-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-methoxy-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-hydroxy-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 6-fluoro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4-methyl-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 4-methoxy-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 4-hydroxy-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7-fluoro-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 5-methoxy-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 5-hydroxy-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 7-methyl-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, 1-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 3-methylbenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl.

In some embodiments, the bicyclic moiety is benzo [d] isoxazolyl, benzo [c] [1, 2, 5] oxadiazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, or 2H-benzo [d] [1, 2, 3] triazolyl, each of which is unsubstituted or substituted as defined above.

In some embodiments, the bicyclic moiety is benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-, benzo [d] [1, 2, 3] triazol-5-yl, or 2H-benzo [d] [1, 2, 3] triazol-5-yl, each of which is unsubstituted or substituted as defined above.

In some embodiments, the bicyclic moiety is benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 2- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl.

R¹ as -C (O) NR^a1R^a2

In some embodiments, R¹ is -C (O) NR^a1R^a2,

wherein

R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, or C_1-6alkoxy;

R^a2 is

b) C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C_3-8cycloalkyl, phenyl, Heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

Wherein

R^b1 is

1) hydrogen;

2) C_1-6alkyl, C_1-6alkoxy, or C_1-6alkoxyC_1-6alkyl-;

3) phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl (e.g., azetidinyl) , -C_1- ₆alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl (e.g., pyridinyl, pyrazolyl, pyrazinyl) ; or

4) heteroaryl (e.g., pyrimidinyl, pyridinyl, 1H-benzo [d] imidazolyl, 1H-indazolyl) or heterocyclyl (e.g., azetidinyl, pyrrolidinyl) , which is unsubstituted or substituted with C_1-6alkyl, oxo, or pyridinyl;

R^c1 and R^c2 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^b2 and R^b3 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy;

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_2-6alkenyl or C_2-6alkynyl;

- C_1-6alkyl-S-

- C_1-6alkoxy or phenoxy, wherein each of said C_1-6alkoxy or phenoxy is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl (pyrazolyl) , or alkyl-substituted heterocyclyl (piperidinyl) ;

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- Heterocyclyl (e.g., azetidin-1-yl, piperidin-4-yl, morpholino, piperazinyl, morpholino) , which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, C_1-6alkyl substituted heterocyclyl,

- Heteroaryl (e.g., pyrazinyl, pyridinyl, pyrimidinyl) , which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl (e.g., pyridinyl)

- C_3-8cylcoalkyl;

- phenyl,

R^e1, R^e2, and R^e3 are each independently hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl-substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) .

In some embodiments, R^a1 is C_1-6alkyl, or deuterated C_1-6alkyl. In some embodiments, R^a1 is C_1-6alkyl. In some embodiments, wherein R^a1 is hydrogen, methyl, ethyl, CH₃-d₃, CF₃, CHF₂, methoxy. In some embodiments, R^a1 is methyl or ethyl.

In some embodiments, R^a2 is C_1-6alkyl. In some embodiments, R^a2 is methyl, ethyl, isopropyl, propyl, isobutyl, or butyl. In some embodiments, R^a2 is CH₃-d₃, methoxyethyl, CF₃CH₂, methylthiolethyl, cyanomethyl, trifluoromethyl.

In some embodiments, R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is substituted with -OR^b1, wherein R^b1 is hydrogen, methoxy, phenyl which is unsubstituted or substituted with 1, 2, or 3 substituents selected from the groups consisting of fluoro, bromo, chloro, methyl, hydroxymethyl, trifluoromethyl, azetidin-1-yl, 2-amino-2-oxoethyl, acetamido, pyridin-2-yl, 1H-pyrazol-1-yl, pyrazin-2-yl, N, N-dimethylamino, 2- (dimethylamino) -2-oxoethyl, 2-hydroxypropyl, or methylamino; pyrimidinyl, pyridinyl, 1H-benzo [d] imidazolyl, or 1H-indazolyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, oxo, or pyridinyl.

In some embodiments, R^a2 is 2- (o-tolyloxy) ethyl, 2- (2- (hydroxymethyl) phenoxy) ethyl, 2- (2- (trifluoromethyl) phenoxy) ethyl, 2- (2- (hydroxymethyl) -3-methylphenoxy) ethyl, 2-phenoxyethyl, 2- (3- (azetidin-1-yl) phenoxy) ethyl, 2- (4- (azetidin-1-yl) phenoxy) ethyl, 2- (2- (2-amino-2-oxoethyl) phenoxy) ethyl, 2- (3-acetamidophenoxy) ethyl, 2- (4- (pyridin-2-yl) phenoxy) ethyl, 2- (4-methyl-3- (1H-pyrazol-1-yl) phenoxy) ethyl, 2- (3- (pyrazin-2-yl) phenoxy) ethyl, N, N-dimethylaminophenoxyethyl, 2- (3- (2- (dimethylamino) -2-oxoethyl) phenoxy) ethyl, 2- (3- (2-hydroxypropyl) phenoxy) ethyl, 2- (4-methyl-3-methylaminophenoxy) ethyl, 2- (2-chlorophenoxy) ethyl, 2-fluoro-5-methylphenoxy, 2- (pyrimidin-2-yloxy) ethyl, 2- (pyridin-2-yloxy) ethyl, 2- (pyridin-3-yloxy) ethyl, 2- ( (2-oxo-2H- [1, 2'-bipyridin] -4'-yl) oxy) ethyl, 2- ( (1-methyl-1H-benzo [d] imidazol-4-yl) oxy) ethyl, 2- ( (1-methyl-1H-indazol-4-yl) oxy) ethyl, or 2- ( (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) oxy) ethyl.

In some embodiments, R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is substituted with -NR^b2R^b3, wherein R^b2 is hydrogen, or C_1-6alkyl (e.g., methyl, ethyl, etc) and R^b3 is C_1-6alkyl, phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, oxo, or halogen. In some embodiments, R^a2 is 2- ( (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) ethyl, N-methyl-N- (2-fluoro-5-methylphenyl) amino, N- (2-fluoro-5-methylphenyl) amino, or dimethylamino.

In some embodiments, R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a phenyl group which is unsubstituted or substituted with one or more substituents R^c3. In some embodiments, R^c3 is halogen; hydroxy; cyano; oxo; C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1- ₆alkoxy, phenyl, or alkyl-substituted heteroaryl (e.g., pyrazolyl) ; C_1-6alkoxy; phenoxy, C_2-6alkenyl; C_2- ₆alkynyl; hydroxy; C_1-6alkoxy which is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl (pyrazolyl) , or alkyl-substituted heterocyclyl (piperidinyl) ; -C_1- ₆alkylC (O) NR^e2R^e3; -C (O) NR^e1R^e2; -NR^e1R^e2; -NR^e1C (O) R^e2; -NR^e1-C (O) -NR^e2R^e3; -NR^e1R^e2; R^e1, R^e2, R^e3 are each independently hydrogen, C_1-6alkyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) ; heterocyclyl (e.g., azetidin-1-yl, piperidin-4-yl, morpholino, piperazinyl, morpholino) , which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, or C_1- ₆alkyl substituted heterocyclyl; heteroaryl (pyrazinyl, pyridinyl, pyrimidinyl) , which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl (e.g., pyridinyl) ; C_3- ₈cylcoalkyl; phenyl; or C_1-6alkyl-S-. In some embodiments, R^c3 is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, ethynyl, vinyl trifluoromethyl, methoxymethyl, (1-methyl-1H-pyrazol-4-yl) methyl, hydroxy, methoxy, (1-methylpiperidin-4-yl) methoxy, trifluoromethoxy, difluoromethoxy, 2, 2, 2-trifluoroethoxy, cyano, oxo, hydroxymethyl, 3-methylureido, thiazol-2-ylamino, (1-methyl-1H-pyrazol-4-yl) amino, azetidin-1-yl, 1-methylpiperidin-4-yl, piperidin-4-yl, 4-methylpiperazin-1-yl, morpholino, pyrazin-2-yl, 3- (hydroxymethyl) pyridin-2-yl, pyridin-3-yl, phenyl, pyrimidin-4-yl, 1, 2, 3, 6-tetrahydropyridin-4-yl, 4'-methyl- [1, 1'-bipiperazin] -4-yl, amino, acetamido, dimethylamino, methylthio, cyclopropyl, 2-amino-2-oxoethyl, or 2- (methylamino) -2-oxoethyl. In some embodiments, R^a2 is 5-chloro-2-fluorobenzyl, 2-fluoro-5-methylbenzyl, 2-hydroxybenzyl, 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-hydroxy-3-methylbenzyl, 5-cyano-2-fluorobenzyl, 2-fluoro-5- (trifluoromethyl) benzyl, 2-chlorobenzyl, 2, 6-difluorobenzyl, 3-chloro-2-fluorobenzyl, 2, 5-difluorobenzyl, 2-fluoro-4-methoxybenzyl, 1- (5-chloro-2-fluorophenyl) ethyl, 2-fluoro-5-methoxybenzyl, 2, 4, 5-trifluorobenzyl, 2, 4-difluorobenzyl, 2, 4-difluoro-5-methylbenzyl, 2-fluoro-5- (methoxymethyl) benzyl, 2-fluoro-3, 5-dimethylbenzyl, benzyl, 4-chloro-2-fluorobenzyl, 2- (5-chloro-2-fluorophenyl) propan-2-yl, (5-chloro-2-fluorophenyl) fluoromethyl, (5-chloro-2-fluorophenyl) difluoromethyl, 1- (3-chlorophenyl) -2-hydroxyethyl, 1- (5-chloro-2-fluorophenyl) cyclopropyl, 2-fluorobenzyl, 2-fluoro-3-hydroxybenzyl, 2-fluoro-3- (hydroxymethyl) benzyl, 2-fluoro-3- (3-methylureido) benzyl, 2-fluoro-3- (thiazol-2-ylamino) benzyl, 2-fluoro-3- ( (1-methyl-1H-pyrazol-4-yl) amino) benzyl, 4-ethyl-2-fluorobenzyl, 4- (azetidin-1-yl) -2-fluorobenzyl, 5-chloro-2-fluoro-4- (pyrazin-2-yl) benzyl, 2-fluoro-4- (3- (hydroxymethyl) pyridin-2-yl) benzyl, 2-fluoro-4- (1-methylpiperidin-4-yl) benzyl, 2-fluoro-4- (piperidin-4-yl) benzyl, 2-fluoro-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzyl, 2-fluoro-4- (4-methylpiperazin-1-yl) benzyl, 2-fluoro-4- (4'-methyl- [1, 1'-bipiperazin] -4-yl) benzyl, 5-chloro-2-fluoro-4- ( (1-methylpiperidin-4-yl) methoxy) benzyl, 2-fluoro-4- ( (1-methylpiperidin-4-yl) methoxy) benzyl, 2-cyano-N- (4-cyano-2-fluorobenzyl, 3-chloro-2, 6-difluorobenzyl, 5-chloro-2, 4-difluorobenzyl, 3-amino-5-chloro-2-fluorobenzyl, 3-acetamido-5-chloro-2-fluorobenzyl, 5-chloro-2-hydroxybenzyl, 5-cyano-2-hydroxybenzyl, 2-cyano-5-methylbenzyl, 2-fluoro-5- (trifluoromethoxy) benzyl, 5- (difluoromethoxy) -2-fluorobenzyl, 2-fluoro-5- (2, 2, 2-trifluoroethoxy) benzyl, 5- (dimethylamino) -2-fluorobenzyl, 2-fluoro-5- (methylthio) benzyl, 5-ethynyl-2-fluorobenzyl, 2-fluoro-5-vinylbenzyl, 2-fluoro-5- ( (trifluoromethoxy) methyl) benzyl, 2-fluoro-5- (hydroxymethyl) benzyl, 5- (azetidin-1-yl) -2-fluorobenzyl, 5-cyclopropyl-2-fluorobenzyl, 2-fluoro-5-morpholinobenzyl, 2-amino-2-oxoethyl) -2-fluorobenzyl, 2-fluoro-5- (2- (methylamino) -2-oxoethyl) benzyl, 2-fluoro-5- ( (1-methyl-1H-pyrazol-4-yl) methyl) benzyl, 2-fluoro-4- (2- (methylamino) -2-oxoethyl) benzyl, 2-cyanobenzyl, (3-fluoronaphthalen-2-yl) methyl, 2-fluoro-4- (pyridin-3-yl) benzyl, (3-fluoro- [1, 1'-biphenyl] -4-yl) methyl, (4-fluoro- [1, 1'-biphenyl] -3-yl) methyl, 2-fluoro-5- (pyrimidin-4-yl) benzyl, 3-phenylpropyl, 3- (2-cyanophenyl) propyl, 3- (2-chlorophenyl) propyl, 3- (2-methoxyphenyl) propyl, 3- (2-fluorophenyl) propyl, or 3-oxo-3-phenylpropyl.

In some embodiments, R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a heteroaryl or heterocyclyl group which is unsubstituted or substituted with one or more substituents R^c3. In some embodiments, the heteroaryl or heterocyclyl group is selected from the group consisting of triazolyl, isoquinolinyl, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, drobenzofuranyl, 2, 3-dihydrodrobenzofuranyl, drobenzofuranyl, 2, 3-dihydrodrobenzofuranyl, benzo [b] [1, 4] dioxinyl, 2, 3-dihydrobenzo [b] [1, 4] dioxinyl, benzo [b] [1, 4] oxazinyl, 2, 3-dihydrobenzo [b] [1, 4] oxazinyl, benzo [b] [1, 4] thiazinyl or 3, 4-dihydro-2H-benzo [b] [1, 4] thiazinyl, 1, 2, 3, 4-tetrahydroquinoxalinyl or 1, 2, 3, 4-tetrahydroquinoxalinl, isochromanyl, or indazolyl. In some embodiments, the heteroaryl or heterocyclyl group is selected from the group consisting of 1H-1, 2, 3-triazol-4-yl, isoquinolin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1H-1, 2, 3-triazol-4-yl, 1H-1, 2, 4-triazol-3-yl, 2H-1, 2, 3-triazol-4-yl, 1H-imidazol-4-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, drobenzofuran-6-yl or 2, 3-dihydrodrobenzofuran-6-yl, drobenzofuran-5-yl or 2, 3-dihydrodrobenzofuran-5-yl, benzo [b] [1, 4] dioxin-6-yl or 2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl, benzo [b] [1, 4] oxazin-7-yl or 2, 3-dihydrobenzo [b] [1, 4] oxazin-7-yl, 2H-benzo [b] [1, 4] thiazin-7-yl or 3, 4-dihydro-2H-benzo [b] [1, 4] thiazin-7-yl, 1, 2, 3, 4-tetrahydroquinoxalin-6-yl or 1, 2, 3, 4-tetrahydroquinoxalin-6-yl, isochroman-7-yl, or 1H-indazol-6-yl. In some embodiments, R^c3 is selected from the group consisting of halogen, C_1-6alkyl, C_1-6alkoxy; hydroxy, cyano, heterocyclyl, NR^e1R^e2, oxo, heterocyclyl or phenyl. In some embodiments, R^c3 is selected from the group consisting of fluoro, bromo, chloro, methyl, ethyl, methoxy, ethoxy, hydroxy, cyano, morpholino, (1-methyl-1H-1, 2, 3-triazol-4-yl) amino, oxo, pyridinyl or phenyl. In some embodiments, R^a2 is (1- (pyridin-4-yl) -1H-1, 2, 3-triazol-4-yl) methyl, (7-fluoroisoquinolin-6-yl) methyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrazin-2-ylmethyl, (4-methylpyridin-2-yl) methyl, (4-methoxypyridin-2-yl) methyl, (2-chloro-5-methylpyridin-3-yl) methyl, (2-chloro-5-fluoropyridin-4-yl) methyl, (2-chloro-5-hydroxypyridin-4-yl) methyl, (5-fluoro-2-methylpyridin-4-yl) methyl, (5-fluoro-2-methoxypyridin-4-yl) methyl, (2-cyano-5-fluoropyridin-4-yl) methyl, (2-cyano-5-hydroxypyridin-4-yl) methyl, (5-fluoro-2-morpholinopyridin-4-yl) methyl, (5-fluoro-2- ( (1-methyl-1H-1, 2, 3-triazol-4-yl) amino) pyridin-4-yl) methyl, 5-chloro-2-oxo-1, 2-dihydropyridin-3-yl) methyl, (1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl, (1-phenyl-1H-1, 2, 4-triazol-3-yl) methyl, (2-phenyl-2H-1, 2, 3-triazol-4-yl) methyl, (1-phenyl-1H-imidazol-4-yl) methyl, 1-phenyl-1H-pyrazol-4-yl) methyl, (1-phenyl-1H-pyrazol-3-yl) methyl, (5-fluoro-2, 3-dihydrobenzofuran-6-yl) methyl, (6-fluoro-2, 3-dihydrobenzofuran-5-yl) methyl, (2, 3-dihydrobenzofuran-6-yl) methyl, (7-fluoro-2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) methyl, (6-fluoro-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) methyl, (6-fluoro-4-methyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) methyl, (6-fluoro-4-methyl-3, 4-dihydro-2H-benzo [b] [1, 4] thiazin-7-yl) methyl, (7-fluoro-1, 2, 3, 4-tetrahydroquinoxalin-6-yl) methyl, (6-fluoroisochroman-7-yl) methyl, or (7-fluoro-1H-indazol-6-yl) methyl.

In some embodiments, R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is substituted with -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, -NR^b2C (O) R^b3, or -NR^b2R^b3, wherein R^b1 and R^b2 are defined as in Formula (I) . In some embodiments, R^a2 is 2- (methylamino) -2-oxoethyl, 2- (methoxyamino) -2-oxoethyl, 2- (dimethylamino) -2-oxoethyl, 2-oxo-2- (phenylamino) ethyl, 2-oxo-2- (pyridin-4-ylamino) ethyl, 2- ( (2-methoxyethyl) amino) -2-oxoethyl, dimethylaminocarbonyloxyethyl, carboxymethyl, mMethoxycarbonylmethyl, methylcarbonylaminoethyl, 3- (azetidin-1-yl) -3-oxopropyl, 2- (methylamino) ethyl, or carbamoyl.

In some embodiments, R^a2 is C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen; C_1- ₆alkyl which is unsubstituted or substituted with R^c3. In some embodiments, R^a2 is pyridin-2-yl, pyridin-3-yl, isoquinolin-4-yl, pyrimidin-5-yl, isoxazol-5-yl, isoxazol-3-yl, triazol-3-yl, benzo [c] isoxazol-3-yl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridinyl, triazolo [4, 3-a] pyridinyl, 5, 6-dihydro-8H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazinyl, triazolo [3, 4-c] [1, 4] oxazinyl, 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazinyl, triazolo [5, 1-c] [1, 4] oxazinyl, or phenyl, each of which is unsubstituted or substituted with R^c3. In some embodiments, R^c3 is phenyl; C_1-6alkoxy; cyano; oxo; -NR^e1R^e2; -NR^e1-C (O) -NR^e2R^e3; phenoxy, phenyl, or heteroaryl. In some embodiments, R^c3 is fluoro, bromo, chloro, methyl, methoxy, amino, cyano, oxo, acetamido, 3-methylureido, benzyl, phenoxy, pyridin-2-yl, or phenyl. In some embodiments, R^a2 is cyclopropyl, pyridin-3-yl, 4-methylpyridin-3-yl, 4, 6-dimethylpyridin-3-yl, 4-methoxypyridin-3-yl, 6-amino-4-cyanopyridin-3-yl, isoquinolin-4-yl, 5-methyl-2-oxo-1, 2-dihydropyridin-4-yl, 4-methylpyrimidin-5-yl, 5-fluoro-4-methylpyridin-3-yl, 6-amino-4-methylpyridin-3-yl, 6-acetamido-4-methylpyridin-3-yl, 4-methyl-6- (3-methylureido) pyridin-3-yl, 5-methoxypyridin-3-yl, 4-benzylpyridin-3-yl, 5-phenoxypyridin-3-yl, isoxazol-5-yl, 4-methylisoxazol-5-yl, 3, 4-dimethylisoxazol-5-yl, 4-methyl-3-phenylisoxazol-5-yl, 4-methyl-3- (pyridin-2-yl) isoxazol-5-yl, isoxazol-3-yl, 4-methyl-4H-1, 2, 4-triazol-3-yl, 4-phenylisoxazol-5-yl, 3-methyl-4-phenylisoxazol-5-yl, benzo [c] isoxazol-3-yl, 1-methyl-2-oxo-1, 2-dihydropyridin-3-yl, 3-fluoro-6-methylpyridin-2-yl, 5-methyl-2-oxo-1, 2-dihydropyridin-3-yl, 4-fluoro-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl, 1-phenyl-1H-1, 2, 3-triazol-4-yl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl, 5, 6-dihydro-8H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazin-3-yl, 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazin-3-yl, 5-fluoro-2-methylphenyl, 2-chloro-5-fluorophenyl, or 2-cyano-5-fluorophenyl.

In some embodiments, R^a2 is alkenyl or alkynyl, each of which is further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more R^c3. In some embodiments, R^a2 is but-2-yn-1-yl, 3- (1-methyl-1H-pyrazol-4-yl) prop-2-yn-1-yl, 4, 4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N, N-dimethylaminobut-2-yn-yl, N, N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5, 6-dihydroxyhex-2-yn-1-yl, 5-hydroxy-4-methylpent-2-yn-1-yl, 3- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) prop-2-yn-1-yl, 3- (1-methyl-2-oxopiperidin-3-yl) prop-2-yn-1-yl, 4- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) but-3-yn-2-yl, 4- (1-methyl-2-oxopiperidin-3-yl) but-3-yn-2-yl, 3-phenylprop-2-yn-1-yl, 3- (o-tolyl) prop-2-yn-1-yl, 3- (2-fluorophenyl) prop-2-yn-1-yl, 3- (2-chlorophenyl) prop-2-yn-1-yl, 3- (3-fluorophenyl) prop-2-yn-1-yl, 3- (4-fluorophenyl) prop-2-yn-1-yl, 3- (2-hydroxyphenyl) prop-2-yn-1-yl, 3- (pyridin-3-yl) prop-2-yn-1-yl, 4- (pyridin-3-yl) but-3-yn-2-yl, 3- (pyridin-4-yl) prop-2-yn-1-yl, 3- (2-cyanophenyl) prop-2-yn-1-yl, 4- (pyridin-2-yl) but-2-yn-1-yl, 4- (pyrazin-2-yl) but-2-yn-1-yl, or 4- (pyridin-2-yl) pent-2-yn-1-yl.

R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2 form a ring

In some embodiments, R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl.

In some embodiments, R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of piperidinyl, 6-azaspiro [2.5] octane-6-yl, 5-azaspiro [2.5] octane-5-yl, piperidinyl, piperazinyl, 1, 2, 3, 6-tetrahydropyridinyl, thiomorpholine, morpholine, azetidine, azepane, azocane, 3-azabicyclo [3.1.0] hexane, and octahydrocyclopenta [c] pyrrole, wherein each of said ring is unsubstituted or substituted as define above.

In some embodiments, R^b4 is hydroxy; halogen; oxo; cyano; C_1-6alkyl; haloC_1-6alkyl; C_1-6alkoxy; C_1- ₆alkoxyC_1-6alkyl; haloC_1-6alkoxy; NR^c4R^c5 (R^c4 and R^c5 are each independently hydrogen, alkyl, or phenyl) ; phenyl, heterocyclyl (e.g., pyrrolidine, azetidine) , or heteroaryl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenoxy, cyclohexyl, 1H-pyrazol-4-yl, or 1-methyl-1H-pyrazol-4-yl) , wherein each of said phenyl, heterocyclyl or heteroaryl is unsubstituted or substituted with one or more halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, -NR^e4R^e5, or -COOR^e4, wherein R^e4 and R^e5 are hydrogen, C_1-6alkyl, phenyl, C_1- ₆alkyl-substituted phenyl, heteroaryl, or C_1-6alkyl-substituted heteroaryl.

In some embodiments, R^b4 is 3-chlorophenyl, methoxymethyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, m-tolyl, 3- (trifluoromethyl) phenyl, 3- (N, N-dimethylamino) phenyl, 3- (methylamino) phenyl, 3- (methoxycarbonyl, 3- (carboxy) phenyl) , methoxyphenyl) , phenoxy, cyclohexyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, fluoro, bromo, chloro, azetidine, oxo, pyrrolidine, hydroxy, amino, trifluoromethyl, or phenylamino.

In some embodiments, R¹ is 4- (3-chlorophenyl) piperidine-1-carbonyl, 6-azaspiro [2.5] octane-6-carbonyl, 5-azaspiro [2.5] octane-5-carbonyl, piperidine-1-carbonyl, 4- (methoxymethyl) piperidine-1-carbonyl, 4-phenylpiperidine-1-carbonyl, 4-phenylpiperazine-1-carbonyl, 4-phenyl-1, 2, 3, 6-tetrahydropyridine-1-carbonyl, 4- (pyridin-2-yl) piperidine-1-carbonyl, 4- (pyridin-3-yl) piperidine-1-carbonyl, 4- (pyridin-4-yl) piperidine-1-carbonyl, 4- (m-tolyl) piperidine-1-carbonyl, 4- (3- (trifluoromethyl) phenyl) piperidine-1-carbonyl, 4- (3- (N, N-dimethylamino) phenyl) piperidin-1-ylcarbonyl, 4- (3- (methylamino) phenyl) piperidin-1-ylcarbonyl, 4- (3- (methoxycarbonyl) phenyl) piperidin-1-ylcarbonyl, 4- (3- (carboxy) phenyl) piperidin-1-ylcarbonyl, 4- (4-methoxyphenyl) piperidine-1-carbonyl, 4-phenoxypiperidine-1-carbonyl, 4-cyclohexylpiperidine-1-carbonyl, 3-phenylpiperidine-1-carbonyl, 3- (1H-pyrazol-4-yl) piperidine-1-carbonyl, 3- (1-methyl-1H-pyrazol-4-yl) piperidine-1-carbonyl, 3- (methoxymethyl) piperidine-1-carbonyl, 4, 4-difluoropiperidine-1-carbonyl, 3, 3-difluoropiperidine-1-carbonyl, 1, 1-dioxidothiomorpholine-4-carbonyl, morpholine-4-carbonyl, azetidine-1-carbonyl, pyrrolidine-1-carbonyl, 3-fluoroazetidine-1-carbonyl, 3, 3-difluoroazetidine-1-carbonyl, 3-hydroxyazetidine-1-carbonyl, 3-aminoazetidine-1-carbonyl, 3- (trifluoromethyl) azetidine-1-carbonyl, azepane-1-carbonyl, azocane-1-carbonyl, 3-azabicyclo [3.1.0] hexane-3-carbonyl, octahydrocyclopenta [c] pyrrole-2-carbonyl, or 4- (phenylamino) piperidine-1-carbonyl.

In some embodiments, R¹ is -C (O) R^a3, wherein R^a3 is C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein each of said C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, or haloC_1- ₆alkoxy. In some embodiments, R^a3 is methyl, ethyl, isopropyl, propyl, ethynyl, vinyl, methoxy, ethoxy, ethylthiol, 1-methylcyclopropane, 1-fluorocyclopropane, 2, 2-difluorocyclopropane, 1- (trifluoromethyl) cyclopropane, cyclopropyl, cyclobutyl, thiazole-4-carbonyl or 1H-imidazole-1-carbonyl.

R¹ as R^a4

In some embodiments, R¹ is heteroaryl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, phenoxy, -NR^b2R^b3, -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, or -NR^b2C (O) R^b3. In some embodiments, R¹ is thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, oxidized pyrazinyl, pyrimidinyl, oxidized pyrimidinyl, pyridazinyl, pyrdinyl, or benzo [d] thiazolyl, each of which is unsubstituted or substituted with as defined above. In some embodiments, R¹ is thiazol-2-yl, thiazol-4-yl, 1, 2, 4-thiadiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, oxidized pyrazinyl, pyrimidin-2-yl, pyrimidin-4-yl, oxidized pyrimidinyl, pyridazin-3-yl, pyrimidine-5-yl, pyrdin-2-yl, pyrazine-2-yl, pyridazine-3-yl, or benzo [d] thiazol-2-yl.

In some embodiments, R¹ is thiazol-2-yl, thiazol-4-yl, 1, 2, 4-thiadiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazine 1-oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine 1-oxide, pyridazin-3-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 3- (trifluoromethyl) pyridin-2-yl, 5-bromopyrimidin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5-methylpyrimidin-4-yl, 5- (trifluoromethyl) pyrimidin-4-yl, 3-methylpyrazin-2-yl, 5-fluoropyridin-2-yl, 3, 5-difluoropyridin-2-yl, 5-methylthiazol-4-yl, 1-methyl-1H-imidazol-2-yl, N, N-dimethylaminocarbonylpyrimidine-5-yl, N, N-dimethylaminocarbonylpyrdin-2-yl, N, N-dimethylaminocarbonylpyrazine-2-yl, N, N-dimethylaminocarbonylpyridazine-3-yl, 5-phenoxypyridin-2-yl, 5-phenoxypyrazin-2-yl, or benzo [d] thiazol-2-yl.

In one aspect, provided herewith is a compound of Formula (II)

wherein

X¹ and X³, are each independently -O-, -S-, -NH-, -N=, or -CH=;

R¹ is

1) -C (O) NR^a1R^a2, wherein R^a1 and R^a2 are each independently C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

2) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_1- ₆alkyl which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more substituents R^c3;

3) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_1- ₆alkyl which is unsubstituted or substituted with one or more halogen or hydroxy, and which is further substituted with -OR^b1, wherein R^b1 is phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl, -C_1- ₆alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl; or

4) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_2- ₆alkenyl or C_2-6alkynyl, each of which is further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more substituents R^c3;

5) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_3- ₈cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

6) -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl,

7) heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, phenoxy, -NR^c6R^c7, -C (O) NR^c6R^c7, -OC (O) NR^c6R^c7, -C (O) R^c6, or -NR^c6C (O) R^c7,

wherein

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_2-6alkenyl or C_2-6alkynyl;

- hydroxy;

- C_1-6alkyl-S-

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- C_3-8cylcoalkyl;

- phenyl; and

R^c6 and R^c7 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy,

provided that the bicyclic moietyis aromatic.

The bicylic moiety

In some embodiments, the bicyclic moietyiseach of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, deuterium, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C_1-6alkylSO₂-, NR^2aR^2b, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl, cyano, COOR^2a, or cycloalkyl.

In some embodiments, n is 0. In some embodiments, R² is selected from the group consisting of fluoro, chloro, bromo, nitro, methoxy, hydroxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfonyl, amino, methylamino, methyl, trifluoromethyl-d3, hydroxymethyl, cyano, methoxycarbonyl, carboxy, or cyclopropyl.

In some embodiments, the bicyclic moiety is benzo [d] isoxazol-5-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, 1-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 3-methylbenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl. In some embodiments, the bicyclic moiety is benzo [d] isoxazolyl, benzo [c] [1, 2, 5] oxadiazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, or 2H-benzo [d] [1, 2, 3] triazolyl, each of which is unsubstituted or substituted as defined above.

In some embodiments, the bicyclic moiety is benzo [d] isoxazol-5-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-, benzo [d] [1, 2, 3] triazol-5-yl, or 2H-benzo [d] [1, 2, 3] triazol-5-yl, each of which is unsubstituted or substituted as defined above.

In some embodiments, the bicyclic moiety is benzo [d] isoxazol-5-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 2- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl.

1) to 5) , wherein -C (O) NR^a1R^a2

In some embodiments, R^a2 is alkenyl or alkynyl, which is unsubstituted or substituted with one or more R^c3. In some embodiments, R^a2 is but-2-yn-1-yl, 3- (1-methyl-1H-pyrazol-4-yl) prop-2-yn-1-yl, 4, 4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N, N-dimethylaminobut-2-yn-yl, N, N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5, 6-dihydroxyhex-2-yn-1-yl, 5-hydroxy-4-methylpent-2-yn-1-yl, 3- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) prop-2-yn-1-yl, 3- (1-methyl-2-oxopiperidin-3-yl) prop-2-yn-1-yl, 4- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) but-3-yn-2-yl, 4- (1-methyl-2-oxopiperidin-3-yl) but-3-yn-2-yl, 3-phenylprop-2-yn-1-yl, 3- (o-tolyl) prop-2-yn-1-yl, 3- (2-fluorophenyl) prop-2-yn-1-yl, 3- (2-chlorophenyl) prop-2-yn-1-yl, 3- (3-fluorophenyl) prop-2-yn-1-yl, 3- (4-fluorophenyl) prop-2-yn-1-yl, 3- (2-hydroxyphenyl) prop-2-yn-1-yl, 3- (pyridin-3-yl) prop-2-yn-1-yl, 4- (pyridin-3-yl) but-3-yn-2-yl, 3- (pyridin-4-yl) prop-2-yn-1-yl, 3- (2-cyanophenyl) prop-2-yn-1-yl, 4- (pyridin-2-yl) but-2-yn-1-yl, 4- (pyrazin-2-yl) but-2-yn-1-yl, or 4- (pyridin-2-yl) pent-2-yn-1-yl.

6) R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2 form a ring

R¹ as heteroaryl, or heterocyclyl

In some embodiments, disclosed here are the compounds exemplified in the instant application.

In one aspect, provided herein is a method for inhibiting FTO or a method for treating a disease associated with excess FTO activity, including obesity, obesity-related diseases, and Alzheimer’s disease. Specifically, disclosed herein is a method of inhibiting weight gain; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or an obesity-related disease (especially, obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) , macular degeneration or Alzheimer’s disease; or treating injury or promoting wound healing or tissue regeneration in a subject, comprising administering the subject in need thereof an effective amount of the compounds disclosed herein.

In one aspect, provided herein is the use of the compounds disclosed herein in the manufacture of a medicament for inhibiting weight gain; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or an obesity-related disease (especially, obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) , macular degeneration or Alzheimer’s disease; or treating injury or promoting wound healing or tissue regeneration.

In one aspect, provided herein is any one of the compounds disclosed herein for use in inhibiting weight gain; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or an obesity-related disease (especially, obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) , macular degeneration or Alzheimer’s disease; or treating injury or promoting wound healing or tissue regeneration.

In some embodiments concerning the above method or use, the above method or use is characterized by FTO inhibition.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following terms have the indicated meanings throughout the specification:

As used herein, including the appended claims, the singular forms of words such as “a, ” “an, ” and “the, ” include their corresponding plural references unless the context clearly dictates otherwise.

The term “or” is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.

The term “alkyl” refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C_1-6alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or s-butyl ( “s-Bu” ) , 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups. The alkyl group can be optionally substituted or enriched in deuterium, e.g., -CD₃ (methyl-d3) , -CD₂CD₃ (ethyl-d5) and the like.

The term “alkylene” refers to a divalent alkyl group as defined herein. For example, methylene refers to -CH₂-.

The term “halogen” refers to fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .

The term “haloalkyl” refers to an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC_1-8alkyl, haloC_1-6alkyl or halo C_1-4alkyl, but not limited to -CF₃, -CH₂Cl, -CH₂CF₃, -CCl₂, CF₃, and the like.

The term “alkyloxy” or “alkoxy” refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of an alkyloxy, e.g., C_1-6alkyloxy or C_1-4 alkyloxy include, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.

The term “alkoxy-alkyl-” refers to an alkyl group as defined above further substituted with an alkoxy as defined above. Examples of an alkoxy-alkyl-, e.g., C_1-6alkoxy-C_1-6alkyl-include, but not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl and the like.

The term “amino” refers to –NH₂. The term “alkylamino” refers to -NH (alkyl) . The term “dialkylamino” refers to -N (alkyl) ₂.

The term “alkenyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C = C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C_2-6alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups.

The term “alkenylene” refers to a divalent alkenyl group as defined herein.

The term “alkynyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C_2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl) , 1-butynyl, 2-butynyl, and 3-butynyl groups.

The term “alkynylene” refers to a divalent alkynyl group as defined herein.

The term “cycloalkyl” refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.

For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, Examples of the saturated monocyclic cycloalkyl group, e.g., C_3- ₈cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C_3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems. In some embodiments, a cycloalkyl group also comprises at least one double bond or at least one triple bond.

The term “deuterated” in a deuterated analog is used herein to modify a chemical structure or an organic group or radical, wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s) , e.g., “deuterated-alkyl” , “deuterated-cycloalkyl” , “deuterated-heterocycloalkyl” , “deuterated-aryl” , “deuterated-heteroaryl” , “deuterated-heterocyclyl” , and the like. For example, the term “deuterated-alkyl” defined above refers to an alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. In a deuterated alkyl group, at least one carbon atom is bound to a deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. For example, -CD₃ and methyl-d3 are exchanable, and refer to a methyl group in which all the three hydrogen atoms are replaced by deuterium. The other deuterated groups, such as deuterated alkyl is interpreted accordingly.

The term “aryl” used alone or in combination with other terms refers to a group selected from:

- 5-and 6-membered carbocyclic aromatic rings, e.g., phenyl;

- bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and,

- tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeable throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl) . Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term “heteroaryl” herein refers to a group selected from:

- 5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;

- 8-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

- 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.

The term “optionally oxidized sulfur” used herein refers to S, SO or SO₂.

The terms “aromatic heterocyclic ring” and “heteroaryl” are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9-or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) and the remaining ring members being carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) . In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5-to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) . In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 8-to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

Examples of the heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, or 1, 3, 4-oxadiazolyl) , phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, or 1, 3, 4-triazolyl) , quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [2, 3-b] pyridin-5-yl) , pyrazolopyridinyl (such as 1H-pyrazolo [3, 4-b] pyridin-5-yl) , benzoxazolyl (such as benzo [d] oxazol-6-yl) , pteridinyl, purinyl, 1-oxa-2, 3-diazolyl, 1-oxa-2, 4-diazolyl, 1-oxa-2, 5-diazolyl, 1-oxa-3, 4-diazolyl, 1-thia-2, 3-diazolyl, 1-thia-2, 4-diazolyl, 1-thia-2, 5-diazolyl, 1-thia-3, 4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl) , benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo [d] thiazol-6-yl) , indazolyl (such as 1H-indazol-5-yl) and 5, 6, 7, 8-tetrahydroisoquinoline.

“Heterocyclyl, ” “heterocycle” or “heterocyclic” are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

Exemplary monocyclic 4 to 9-membered heterocyclyl groups include, but not limited to, (as numbered from the linkage position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl , pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1, 4-oxathianyl, 1, 4-dioxepanyl, 1, 4-oxathiepanyl, 1, 4-oxaazepanyl, 1, 4-dithiepanyl, 1, 4-thiazepanyl and 1, 4-diazepanyl, 1, 4-dithianyl, 1, 4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1, 1-dioxo-thiomorpholinyl.

Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and /or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

When compounds disclosed herein contain a di-substituted cyclohexyl or cyclobutyl group, substituents found on cyclohexyl or cyclobutyl ring may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.

It may be advantageous to separate reaction products from one another and /or from starting materials. The desired products of each step or series of steps is separated and /or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ( “SMB” ) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

“Diastereomers” refers to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and /or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley &Sons, Inc., 1994; Lochmuller, C. H., et al. “Chromatographic resolution of enantiomers: Selective review. ” J. Chromatogr., 113 (3) (1975) : pp. 283-302] . Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

“tautomer” is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) . For example, a trizolyl group may have following tautomeric forms,

“Pharmaceutically acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.

In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

As defined herein, “apharmaceutically acceptable salt thereof” includes salts of at least one compound of Formula (I) , and salts of the stereoisomers of the compound of Formula (I) , such as salts of enantiomers, and /or salts of diastereomers.

The terms “administration” , “administering” , “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as the contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

The term “effective amount” or “therapeutically effective amount” refers to an amount of the active ingredient, such as a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined above, a disease or disorder in a subject. In the case of combination therapy, the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise, ” and variations such as “comprises” and “comprising” are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term “comprising” can be substituted with the term “containing” , “including” or sometimes “having” .

Throughout this specification and the claims which follow, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-8, C_1-6, and the like.

The expression “unsubstituted or substituted with” , e.g., “unsubstituted or substituted with R_d” refers to that such a group is unsubstituted or substituted with at least one substituents, e.g., R_d. With reference to “substituted with... ” , e.g., “substituted with R_d” , if without designating the number of substituents, it usually refers to a group substituted with at least one substituents, e.g., selected from R_d, for example, 1 to 4, 1 to 3, 1 or 2, or 1 substituent, provided that the valency theory is met.

The term “at least one” or “one or more” are exchangeable and refer to one, two, three or more of the subject in reference to which the term is used. In particular, the term “at least one substituent” refers to one, two, three or more substituent, for example 1 to 5, 1 to 4, 1 to 3, 1 or 2, or one substituents, as long as the valence theory has been met.

EXAMPLES

Reagents and solvents were obtained from commercial sources such as Sigma-Aldrich, Alfa, Sinopharm Chemical Reagent Co. (SCRC) or other, unless explicitly indicated otherwise.

As used herein, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

Specifically, but without limitation, the following abbreviations may be used in the Examples and throughout the specification:

The following example, either for intermediates or for the final compounds, are for illustration only. However, the invention shall not be construed thereto.

Intermediate Aa1

Step 1: Synthesis of 6-bromo-4-chloro-1H-benzo [d] [1, 2, 3] triazole (2)

To a solution of 5-bromo-3-chlorobenzene-1, 2-diamine (5 g, 22.6 mmol) in AcOH (30 mL) and H₂O (15 mL) was added NaNO₂ (1.6 g, 23.3 mmol) . After stirring at rt for 6 h. The reaction mixture was filtration to obtain the product (5 g, 95%) . MS [M+H] ⁺ calcd for C₆H₃BrClN₃ 234.2, found 234.2.

Step 2: Synthesis of methyl 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (3)

A solution of 6-bromo-4-chloro-1H-benzo [d] [1, 2, 3] triazole (5 g, 21.6 mmol) , TEA (6.5 g, 64.7 mmol) and Pd (dppf) Cl₂·DCM (1.2 g, 1.1 mmol) in MeOH (40 mL) was stirred under CO at 80 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (4 g, 88%) . MS [M+H] ⁺ calcd for C₈H₆ClN₃O₂ 212.2, found 212.2.

Step 3: Synthesis of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (4)

To a solution of methyl 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (500 mg, 2.4 mmol) in THF/H₂O (5/5 mL) was added LiOH (198 mg, 4.7 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (300 mg, 64%) . MS [M+H] ⁺calcd for C₇H₄ClN₃O₂ 198.2, found 198.2.

Intermediate Aa2

Step 1: Synthesis of methyl 4-bromo-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (2)

To a solution of methyl 3, 4-diamino-5-bromobenzoate (5 g, 20.49 mmol) in H₂O (80 mL) was added AcOH (3.1 g, 51.23 mmol) , NaNO₂ (2.8 g, 40.98 mmol) . After stirring at 25 ℃ for 1 h. The resulting solid was filtered, washed with water and dried to obtain the product (5.1 g, crude) . MS [M+2] ⁺ calcd for C₈H₆BrN₃O₂ 258.0, found 258.0.

Step 2: Synthesis of 4-bromo-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (3)

To a solution of methyl 7-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (500 mg, 1.96 mmol) in THF/H₂O (3/3 mL) was added LiOH (247 mg, 5.88 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (400 mg, 85%) . MS [M+2] ⁺calcd for C₇H₄ClN₃O₂ 244, found 244.

Intermediate Aa3

Step 1: Synthesis 4-nitro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (2)

To a solution 3 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (1.8 g, 11.04 mmol) in H₂SO₄ (40 mL) was added HNO₃ (40 mL) dropwise at 0℃ . After addition the mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was quenched by ice. It was filtered and collected solids. The solids washed with water until neutral to obtain the product (600 mg, 26%) . MS [M+H] ⁺ calcd for C₇H₄N₄O₄ 209.0, found 209.0.

Intermediate Aa4 (method 1)

Step 1: Synthesis of 6-bromo-4-methyl-1H-benzo [d] [1, 2, 3] triazole (2)

To a solution of 5-bromo-3-methylbenzene-1, 2-diamine (2 g, 9.95 mmol) and NaNO₂ (1.37 g, 19.9 mmol) in H₂O (20 mL) was added AcOH (1.42 mL, 24.88mmol) . The mixture is stirred for 2 h at RT. Concentrated in vacuo to dryness to afford the desired product (1.5 g, 71%) . MS [M+H] ⁺ calcd for C₇H₆BrN₃ 211.97, found 211.97.

Step 2: Synthesis of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (3)

A solution of 6-bromo-4-methyl-1H-benzo [d] [1, 2, 3] triazole (800 mg, 3.77 mmol) , TEA (1.57 mL, 11.32 mmol) and Pd (dppf) Cl₂ (310.1 mg, 0.38 mmol) in MeOH (10 mL) was stirred under CO at 80℃ for 5 h. The mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, PE /EA = 1/5) afforded the desired product (350 mg, 48%) . MS [M+H] ⁺ calcd for C₉H₉N₃O₂ 192.07, found 192.07.

Step 3: Synthesis of 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (4)

To a solution of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (300 mg, 1.57 mmol) in THF/H₂O (4/1 mL) was added LiOH (131.94 mg, 3.14 mmol) at 0℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (30 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (200 mg, 72%) . MS [M+H] ⁺ calcd for C₈H₇N₃O₂ 178.05, found 178.05.

Intermediate Aa4 (method 2)

Step 1: Synthesis of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (2)

To a solution of methyl 4-bromo-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (300 mg, 1.18 mmol) in dioxane (5 mL) and H₂O (1 mL) was added Pd (dppf) Cl₂ (86 g, 0.12 mmol) , K₂CO₃ (407 g, 2.95 mmol) and 2,4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (1.78 g, 3.54 mmol) . After stirring at 100 ℃ under N₂ atmosphere for 18 h. The mixture was neutralized with hydrochloric acid, extracted by EA (20 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (120 mg, 53%) . MS [M+H] ⁺ calcd for C₉H₉N₃O₂ 192.1, found 192.1.

Step 2: Synthesis of 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (3)

To a solution of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (120 mg, 0.63 mmol) in THF/H₂O (3/3 mL) was added LiOH (79 mg, 1.88 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (10 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (90 mg, 81%) . MS [M+H] ⁺calcd for C₈H₇N₃O₂ 178.1, found 178.1.

Intermediate Aa5

Step 1: Synthesis of 5-bromo-3- (trifluoromethyl) benzene-1, 2-diamine (2)

To a solution of 4-bromo-2-nitro-6- (trifluoromethyl) aniline (1 g, 3.51 mmol) , Zn (2.3 g, 35.09 mmol) and Ammonium formate (2.2 g, 35.09 mmol) in MeOH (20 mL) . The mixture was stirred at 60℃ for 1 h. Filter reaction solution and the mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄. Concentrated in vacuo to dryness to afford the desired product (890 mg, 99%) . MS [MH] ⁺ calcd for C₇H₆BrF₃N₂ 254.97, found 254.97.

Step 2: Synthesis of 6-bromo-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole (3)

To a solution of 5-bromo-3- (trifluoromethyl) benzene-1, 2-diamine (870 mg, 3.41 mmol) and NaNO₂ (470 mg, 6.82 mmol) in H₂O (8 mL) was added AcOH (0.49 mL, 8.53 mmol) . The mixture is stirred for 2 h at RT. Concentrated in vacuo to dryness to afford the desired product (850 mg, 93%) . MS [MH] ⁺ calcd for C₇H₃BrF₃N₃ 265.95, found 265.95.

Step 3: Synthesis of methyl 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

A solution of 6-bromo-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole (200 mg, 0.75 mmol) , TEA (228 mg, 2.26 mmol) and Pd (dppf) Cl₂·DCM (62 mg, 0.075 mmol) in MeOH (8 mL) was stirred under CO at 100℃ for 8 h. The mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, PE /EA = 4/1) afforded the desired product (97 mg, 52.8%) . MS [M-H] ^-calcd for C₉H₆F₃N₃O₂ 246.04, found 246.04.

Step 4: Synthesis of 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (5)

To a solution of methyl 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (97 mg, 0.40 mmol) in THF/H₂O (4/2 mL) was added LiOH (83 mg, 1.98 mmol) . After addition, the reaction was stirred at r. t. for 8 h. The mixture was neutralized with hydrochloric acid, extracted by EA (30 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (67 mg, 72.5%) . MS [MH] ⁺ calcd for C₈H₄F₃N₃O₂ 232.03, found 232.03.

Intermediate Aa6

Step 1: Synthesis of methyl 4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (2)

To a solution of methyl 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (1 g, 4.72 mmol) in DMF (10 mL) was added DIEA (1.6 g, 9.43 mmol) and SEMCl (0.9 g, 5.19 mmol) at 0 ℃ and stirring at rt for overnight. Cool the reaction mixture to 0 ℃ and add saturated aqueous NaCl (30 mL) to the reaction mixture. Extracted by EA (100 mL*3) , dried by Na₂SO₄, further purification by column chromatography (silica gel, PE/EA=1/1) afforded the desired product (1 g, 62%) . MS [M+H] ⁺ calcd for C₁₄H₂₀ClN₃O₃Si 342.2, found 342.2.

Step 2: Synthesis of methyl 1- ( (2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (3)

To a solution of methyl 4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (1 g, 2.92 mmol) in dry toluene (40 mL) was added LiCl (368 mg, 8.76 mmol) , CuI (55 mg, 0.29 mmol) and Pd (PPh₃) ₄ (335 mg, 0.29 mmol) was stirred at same temperature and stirring in the microwave at 130 ℃ for 2 h. The reaction mixture was extracted with EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/1) to obtain the product (660 mg, 68%) . MS [M+H] ⁺ calcd for C₁₆H₂₃N₃O₃Si 334.2, found 334.2.

Step 3: Synthesis of methyl 4-vinyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

To a solution of methyl 1- ( (2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (660 mg, 1.98 mmol) in DCM (10 mL) was added TFA (5 mL) at 0 ℃ for 4 h. After concentrate the mixture and purification by column chromatography (silica gel, PE/EA=1/3) afforded the desired product (350 mg, 87%) . MS [M+H] ⁺ calcd for C₁₀H₉N₃O₂ 204.2, found 204.2.

Step 4: Synthesis of methyl 4-ethyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (5)

A solution of methyl 4-vinyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (350 mg, 1.72 mmol) and Pd/C (150 mg) in MeOH (10 mL) was stirred under H₂ at rt for 2 h. The reaction solution is removed Pd/C by filtration and removed in vacuo to afford the desired product (200 mg, 57%) . MS [M+H] ⁺ calcd for C₁₀H₁₁N₃O₂ 206.2, found 206.2.

Step 5: Synthesis of 4-ethyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (6)

To a solution of methyl 4-ethyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (200 mg, 0.98 mmol) in THF/H₂O (5/5 mL) was added LiOH (123 mg, 2.93 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the product (150 mg, 80%) . MS [M+H] ⁺ calcd for C₉H₉N₃O₂ 192.2, found 192.2

Intermediate Aa7

Step 1: Synthesis of 3-amino-5-bromo-2-nitrobenzonitrile (2)

To a solution of 5-bromo-3-fluoro-2-nitroaniline (3 g, 12.77 mmol) in DMF (30 mL) was added NaCN (751 mg, 15.32 mmol) . After stirring at 130 ℃ for overnight. Cool the reaction mixture to 25 ℃ and add water (60 mL) to the reaction mixture. Extracted by EA (200 mL*3) , dried by Na₂SO₄, further purification by column chromatography (silica gel, DCM/MeOH=25/1) afforded the desired product (3 g, 97%) . MS [M+H] ⁺ calcd for C₇H₄BrN₃O₂ 242.2, found 242.2.

Step 2: Synthesis of 2, 3-diamino-5-bromobenzonitrile (3)

To a solution of 3-amino-5-bromo-2-nitrobenzonitrile (3 g, 12.40 mmol) in MeOH (30 mL) was added Fe (3.5 g, 61.98 mmol) and NH₄Cl (3.3 g, 61.98 mmol) . After stirring at 50 ℃ for 4 h. The reaction mixture was filtration to obtain the product (1.6 g, 61%) . MS [M+H] ⁺ calcd for C₇H₆BrN₃ 212.2, found 212.2.

Step 3: Synthesis of 6-bromo-1H-benzo [d] [1, 2, 3] triazole-4-carbonitrile (4)

To a solution of 2, 3-diamino-5-bromobenzonitrile (1.6 g, 7.55 mmol) in AcOH (8 mL) and H₂O (8 mL) was added NaNO₂ (547 mg, 7.92 mmol) . After stirring at rt for 3 h. The reaction mixture was filtration to obtain the product (1.5 g, 89%) . MS [M+H] ⁺ calcd for C₇H₃BrN₄ 223.2, found 223.2.

Step 4: Synthesis of methyl 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (5)

A solution of 6-bromo-1H-benzo [d] [1, 2, 3] triazole-4-carbonitrile (1.5 g, 6.73 mmol) , TEA (2038 mg, 20.18 mmol) and Pd (dppf) Cl₂·DCM (393 mg, 0.34 mmol) in MeOH (20 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, DCM /MeOH = 20/1) afforded the desired product (1.2 g, 88%) . MS [M+H] ⁺ calcd for C₉H₆N₄O₂ 203.2, found 203.2.

Step 5: Synthesis of 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (6)

To a solution of methyl 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (1.2 g, 5.94 mmol) in THF/H₂O (5/5 mL) was added LiOH (499 mg, 11.88 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (800 mg, 72%) . MS [M+H] ⁺calcd for C₈H₄N₄O₂ 189.2, found 189.2.

Intermediate Aa8

Step 1: Synthesis of 2- (difluoromethoxy) -6-nitroaniline (2)

To a solution of 2-amino-3-nitrophenol (2 g, 12.98 mmol) , sodium (I) 2-chloro-2, 2-difluoroacetate (4.9 g, 32.44 mmol) and K₂CO₃ (2.1 g, 15.57 mmol) in DMF (15 mL) and H₂O (1.5 mL) . The mixture was stirred under N₂ at 100℃ for 2.5 h. The mixture was extracted by EA (50 mL*3) , the organic phase was washed by 1M NaOH (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, PE /DCM = 3/1) afforded the desired product (500 mg, 18%) . MS [MH] ⁺ calcd for C₇H₆F₂N₂O₃ 205.03, found 205.03.

Step 2: Synthesis of 4-bromo-2- (difluoromethoxy) -6-nitroaniline (3)

To a solution of 2- (difluoromethoxy) -6-nitroaniline (403 mg, 1.98 mmol) in AcOH (5 mL) was added sodium acetate (259.3 mg, 3.16 mmol) , bromine (0.014 mL, 2.17mmol) . The mixture was stirred at RT for 0.2 h. Add 5 mL H₂O to the reaction solution. Filter reaction solution to afford the desired product (500 mg, 89%) . MS [MH] ⁺ calcd for C₇H₅BrF₂N₂O₃ 282.95, found 282.95.

Step 3: Synthesis of 5-bromo-3- (difluoromethoxy) benzene-1, 2-diamine (4)

To a solution of 4-bromo-2- (difluoromethoxy) -6-nitroaniline (492 mg, 1.74 mmol) , Zn (1.14 g, 17.39 mmol) and Ammonium formate (1.1 g, 17.39 mmol) in MeOH (8 mL) . The mixture was stirred at 60℃ for 1 h.Filter reaction solution and the mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄. Concentrated in vacuo to dryness to afford the desired product (420 mg, 95%) . MS [MH] ⁺ calcd for C₇H₇BrF₂N₂O 252.97, found 252.97.

Step 4: Synthesis of 6-bromo-4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazole (5)

To a solution of 5-bromo-3- (difluoromethoxy) benzene-1, 2-diamine (400 mg, 1.58 mmol) and NaNO₂ (218 mg, 3.16 mmol) in H₂O (8 mL) was added AcOH (0.23 mL, 3.95 mmol) . The mixture is stirred for 2 h at RT. Concentrated in vacuo to dryness to afford the desired product (390 mg, 93%) . MS [MH] ⁺ calcd for C₇H₄BrF₂N₃O 263.95, found 263.95.

Step 5: Synthesis of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (6)

A solution of 6-bromo-4-methyl-1H-benzo [d] [1, 2, 3] triazole (390 mg, 1.48 mmol) , TEA (450 mg, 4.45 mmol) and Pd (dppf) Cl₂·DCM (121 mg, 0.15 mmol) in MeOH (16 mL) was stirred under CO at 80℃ for 8 h. The mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, DCM /MeOH = 9/1) afforded the desired product (270 mg, 75%) . MS [M-H] ^-calcd for C₉H₇F₂N₃O₃ 244.05, found 244.05.

Step 6: Synthesis of 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (7)

To a solution of methyl 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (250 mg, 1.03 mmol) in THF/H₂O (8/4 mL) was added LiOH (216 mg, 5.14 mmol) . After addition, the reaction was stirred at 60℃ for 8 h. The mixture was neutralized with hydrochloric acid, extracted by EA (30 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (220 mg, 93%) . MS [MH] ⁺ calcd for C₈H₅F₂N₃O₃ 230.03, found 230.03.

Intermediate Aa9

Step 1: Synthesis of 5-bromo-3-methoxybenzene-1, 2-diamine (2)

To a solution of 4-bromo-2-methoxy-6-nitroaniline (1.00 g, 4.06 mmol) in MeOH (15 mL) was added Zn (2.34 g, 36.5 mmol) and HCOONH₄ (2.55 g, 40.6 mmol) . The mixture was stirred for 2 h at 60℃. The mixture was filtered and concentrated in vacuo to dryness. Added water (10 mL) , extracted with DCM (10 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness to afford the desired product (800 mg, 91.2%) . MS [M+H] ⁺ calcd for C₇H₉BrN₂O 217.1, found 217.1.

Step 2: Synthesis of 6-bromo-4-methoxy-1H-benzo [d] [1, 2, 3] triazole (3)

To a solution of 5-bromo-3-methoxybenzene-1, 2-diamine (800 mg, 3.70 mmol) and NaNO₂ (511 mg, 7.40 mmol) in H₂O (20 mL) was added AcOH (555 mg, 9.25 mmol) . The mixture was stirred for 2 h at RT. The mixture was concentrated in vacuo to dryness to afford the desired product (700 mg, 83.3%) . MS [M+H] ⁺ calcd for C₇H₆BrN₃O 228.2, found 228.2.

Step 3: Synthesis of methyl 4-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

To a solution of 6-bromo-4-methoxy-1H-benzo [d] [1, 2, 3] triazole (700 mg, 3.08 mmol) in MeOH (10 mL) was added TEA (934 mg, 9.25 mmol) and Pd (dppf) Cl₂ (219 mg, 0.30 mmol) . The mixture was stirred for 5 h at 80℃ under CO. The reaction mixture was quenched by water (10 mL) , extracted with EA (10 mL x 3) , dried over Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (PE /EA = 3/2) to afford the desired product (600 mg, 94.1%) . MS [M+H] ⁺ calcd for C₉H₉N₃O₃ 208.2, found 208.2.

Step 4: 4-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (5)

To a solution of methyl 4-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (600 mg, 2.89 mmol) in THF/H₂O (4/1 mL) was added LiOH (345 mg, 14.4 mmol) . The mixture was stirred overnight at RT. The mixture was adjusted PH=5 with hydrochloric acid (1 N) , filtered and collected the cake to afford the desired product (400 mg, 71.4%) . MS [M+H] ⁺ calcd for C₈H₇N₃O₃ 194.1, found 194.1.

Intermediate Aa10

Step 1: Synthesis of 5-bromo-3-fluorobenzene-1, 2-diamine (2)

To a solution of 4-bromo-2-fluoro-6-nitroaniline (1.00 g, 4.27 mmol) in MeOH (15 mL) was added Zn (2.46 g, 38.4 mmol) and HCOONH₄ (2.69 g, 42.7 mmol) . The mixture was stirred for 2 h at 60℃. The mixture was filtered and concentrated in vacuo to dryness. Added water (10 mL) , extracted with DCM (15 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness to afford the desired product (810 mg, 92.9%) . MS [M+H] ⁺ calcd for C₆H₆BrFN₂ 205.1, found 205.1.

Step 2: Synthesis of 6-bromo-4-fluoro-1H-benzo [d] [1, 2, 3] triazole (3)

To a solution of 5-bromo-3-fluorobenzene-1, 2-diamine (810 mg, 3.97 mmol) and NaNO₂ (547 mg, 7.94 mmol) in H₂O (20 mL) was added AcOH (595 mg, 9.92 mmol) . The mixture was stirred for 2 h at RT. The mixture was concentrated in vacuo to dryness to afford the desired product (700 mg, 82.0%) . MS [M+H] ⁺calcd for C₆H₃BrFN₃ 216.1, found 216.1.

Step 3: Synthesis of methyl 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

To a solution of 6-bromo-4-fluoro-1H-benzo [d] [1, 2, 3] triazole (700 mg, 3.25 mmol) in MeOH (10 mL) was added TEA (986 mg, 9.76 mmol) and Pd (dppf) Cl₂ (234 mg, 0.32 mmol) . The mixture was stirred for 16 h at 80℃ under CO. The reaction mixture was quenched by water (10 mL) , extracted with EA (10 mL x 3) , dried over Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (PE /EA = 3/2) to afford the desired product (590 mg, 93.0%) . MS [M+H] ⁺ calcd for C₈H₆FN₃O₂ 196.1, found 196.1.

Step 4: 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (5)

To a solution of methyl 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (590 mg, 3.02 mmol) in THF/H₂O (4/1 mL) was added LiOH (363 mg, 15.1 mmol) . The mixture was stirred overnight at RT. The mixture was adjusted PH=5 with hydrochloric acid (1 N) , filtered and collected the cake to afford the desired product (450 mg, 82.3%) . MS [M+H] ⁺ calcd for C₇H₄FN₃O₂ 182.1, found 182.1.

Intermediate Aa11

Step 1: Synthesis of (6-bromo-1H-benzo [d] [1, 2, 3] triazol-4-yl) methanol (2)

To a solution of methyl 6-bromo-1H-benzo [d] [1, 2, 3] triazole-4-carboxylate (5 g, 19.53 mmol) in MeOH (50 mL) was added NaBH4 (3.0 g, 78.13 mmol) at 0 ℃ and stirring at 60 ℃ for 4 h. Cool the reaction mixture to 0 ℃ and add saturated aqueous NH₄Cl (50 mL) to the reaction mixture. Extracted by EA (150 mL*3) , dried by Na₂SO₄, further purification by column chromatography (silica gel, PE/EA=1/2) afforded the desired product (2 g, 45%) . MS [M+H] ⁺ calcd for C₇H₆BrN₃O 228.2, found 228.2.

Step 2: Synthesis of methyl 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (3)

A solution of (6-bromo-1H-benzo [d] [1, 2, 3] triazol-4-yl) methanol (2 g, 8.77 mmol) , TEA (2658 mg, 26.32 mmol) and Pd (dppf) Cl₂·DCM (711 mg, 0.88 mmol) in MeOH (20 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA=1/2) afforded the desired product (1.5 g, 83%) . MS [M+H] ⁺calcd for C₉H₉N₃O₃ 208.2, found 208.2.

Step 3: Synthesis of methyl 4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

To a solution of methyl 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (1.5 g, 7.25 mmol) in DMF (10 mL) was added DIEA (1.9 g, 14.49 mmol) and SEMCl (2.5 g, 14.49 mmol) at 0 ℃ and stirring at rt for overnight. Cool the reaction mixture to 0 ℃ and add saturated aqueous NaCl (30 mL) to the reaction mixture. Extracted by EA (100 mL*3) , dried by Na₂SO₄, further purification by column chromatography (silica gel, PE/EA=2/1) afforded the desired product (2.6 g, 77%) . MS [M+H] ⁺ calcd for C₂₁H₃₇N₃O₅Si₂ 468.2, found 468.2.

Step 4: Synthesis of 4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (5)

To a solution of methyl 4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (2.6 g, 5.56 mmol) in THF/H₂O (15/15 mL) was added LiOH (700 mg, 16.67 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/2) to obtain the product (2 g, 79%) . MS [M+H] ⁺ calcd for C₂₀H₃₅N₃O₅Si₂ 454.2, found 454.2

Intermediate Aa12

Step 1: Synthesis of 6-bromo-7-chloro-1H-benzo [d] [1, 2, 3] triazole (2)

To a solution of 4-bromo-3-chlorobenzene-1, 2-diamine (1.9 g, 8.64 mmol) in H₂O (30 mL) was added AcOH (1.3 g, 21.6 mmol) , NaNO₂ (1.2 g, 17.28 mmol) . After stirring at 25 ℃ for 1 h. The resulting solid was filtered, washed with water and dried to obtain the product (2.1 g, crude) . MS [M+H] ⁺ calcd for C₆H₃BrClN₃ 231.9, found 231.9.

Step 2: Synthesis of methyl 7-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (3)

A solution of 6-bromo-7-chloro-1H-benzo [d] [1, 2, 3] triazole (1.5 g, 6.49 mmol) , TEA (1.98 mg, 19.48 mmol) and Pd (dppf) Cl₂ (475 mg, 0.65 mmol) in MeOH (15 mL) was stirred under CO at 90 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 5/1) afforded the desired product (400 mg, 29%) . MS [M+H] ⁺ calcd for C₈H₆ClN₃O₂ 212.0, found 212.0.

Step 3: Synthesis of 7-chlorobenzo [d] isoxazole-5-carboxylic acid (4)

To a solution of methyl 7-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (100 mg, 0.47 mmol) in THF/H₂O (3/3 mL) was added LiOH (60 mg, 1.42 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (65 mg, 70%) . MS [M+H] ⁺calcd for C₇H₄ClN₃O₂ 198.0, found 198.0.

Intermediate Aa13

Step 1: Synthesis of 4-bromo-3-fluorobenzene-1, 2-diamine (2)

To a solution of 4-bromo-3-fluoro-2-nitroaniline (1 g, 4.27 mmol) in MeOH (30 mL) was added Zn (2.5 g, 38.46 mmol) , HCOONH₄ (2.68 g, 42.74 mmol) . After stirring at 60 ℃ for 2 h. The resulting solid was filtered, washed with DCM and dried to obtain the product (900 mg, crude) . MS [M+H] ⁺ calcd for C₆H₆BrFN₂ 205.0, found 205.0.

Step 2: Synthesis of 6-bromo-7-fluoro-1H-benzo [d] [1, 2, 3] triazole (3)

To a solution of 4-bromo-3-fluorobenzene-1, 2-diamine (900 mg, 4.41 mmol) in H₂O (20 mL) was added AcOH (602 mg, 11.03 mmol) , NaNO₂ (610 mg, 8.82 mmol) . After stirring at 25 ℃ for 1 h. The resulting solid was filtered, washed with water and dried to obtain the product (700 mg, crude) . MS [M+H] ⁺calcd for C₆H₃BrFN₃ 215.9, found 215.9.

Step 3: Synthesis of methyl 7-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (4)

A solution of 6-bromo-7-fluoro-1H-benzo [d] [1, 2, 3] triazole (700 mg, 3.26 mmol) , TEA (987 mg, 9.77 mmol) and Pd (dppf) Cl₂ (241 mg, 0.33 mmol) in MeOH (10 mL) was stirred under CO at 90 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 5/1) afforded the desired product (320 mg, 51%) . MS [M+H] ⁺ calcd for C₈H₆FN₃O₂ 196.0, found 196.0.

Step 4: Synthesis of 7-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (5)

To a solution of methyl 7-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (320 mg, 1.64 mmol) in THF/H₂O (3/3 mL) was added LiOH (207 mg, 4.92 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (180 mg, 61%) . MS [M+H] ⁺calcd for C₇H₄FN₃O₂ 182.0, found 182.0.

Intermediate Aa14

Step 1: Synthesis of methyl 1-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (2)

A solution of 5-bromobenzo [d] isoxazole (900 mg, 4.24 mmol) , TEA (1.29 g, 12.73 mmol) and Pd (dppf) Cl₂ (155 mg, 0.21 mmol) in MeOH (20 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (700 mg, 86%) . MS [M+H] ⁺ calcd for C₉H₉N₃O₂ 191.2, found 191.2.

Step 2: Synthesis of 1-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (3)

To a solution of methyl 1-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (700 mg, 3.66 mmol) in THF/H₂O (7/7 mL) was added LiOH (176 mg, 7.32 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (300 mg, 46%) . MS [M+H] ⁺calcd for C₈H₇N₃O₂ 177.2, found 177.2.

Intermediate Aa15

Step 1: Synthesis of 4-bromo-2-chloro-5-methylaniline (2)

To a solution of 2-chloro-5-methylaniline (25 g, 176.1 mmol) in AcOH (250 mL) was added Br₂ (28.14 g, 176.1 mmol) . The reaction was stirred at 100℃ for 3 hours under N₂. The reaction mixture was quenched by H₂O (200 mL) and extracted with DCM (500 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=10/1) to obtain the product (21 g, 54.3%) . MS [M+H] ⁺ calcd for C₇H₇BrClN 219.9, found 219.9.

Step 2: Synthesis of N- (4-bromo-2-chloro-5-methylphenyl) acetamide (3)

To a solution of 4-bromo-2-chloro-5-methylaniline (21 g, 95.45 mmol) and TEA (14.46 g, 143.18 mmol) in THF (210 mL) was added acetyl chloride (8.19 g, 105 mmol) . The reaction was stirred at RT for 2 h. The mixture was quenched by ice water and extracted by DCM (300 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (17.5 g, 69.7%) . MS [M+H] ⁺calcd for C₉H₉BrClNO 262.0, found 262.0.

Step 3: Synthesis of N- (4-bromo-6-chloro-3-methyl-2-nitrophenyl) acetamide (4)

To a solution of H₂SO₄ (175 mL) and N- (4-bromo-2-chloro-5-methylphenyl) acetamide (17.5 g, 66.54 mmol) was added KNO₃ (7.39 g, 73.19 mmol) at 0℃. The reaction was stirred at R. T. for 2 h. The mixture was quenched by ice water and neutralized with NaHCO₃ at PH=6, extracted by EA (200 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (7.5 g, 36.6%) . MS [M+H] ⁺calcd for C₉H₈BrClN₂O₃ 306.9, found 306.9.

Step 4: Synthesis of 4-bromo-6-chloro-3-methyl-2-nitroaniline (5)

To a solution of N- (4-bromo-6-chloro-3-methyl-2-nitrophenyl) acetamide (7 g, 22.87 mmol) in MeOH (70 mL) was added MsOH (7 mL) , the reaction was stirred at 60℃ for 2 h. The reaction mixture was concentrated in vacuo to dryness and obtain the crude product (5.5 g, 91.7%) . MS [M+H] ⁺ calcd for C₇H₆BrClN₂O₂ 264.9, found 264.9.

Step 5: Synthesis of 4-bromo-6-chloro-3-methylbenzene-1, 2-diamine (6)

To a solution of 4-bromo-6-chloro-3-methyl-2-nitroaniline (5.5 g, 20.75 mmol) in EtOH (55 mL) was added Zn (7.07 g, 108.75 mmol) and ammonium formate (6.85 g, 108.75 mmol) , the reaction was stirred at 60℃ for 3 h. The reaction mixture was filtration to obtain the filtrate, the filtrate was concentrated in vacuo to dryness and extracted by EA (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (4.5 g, 91.8%) . MS [M+H] ⁺ calcd for C₇H₈BrClN₂ 235.0, found 235.0.

Step 6: Synthesis of 6-bromo-4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole (7)

To a solution of 4-bromo-6-chloro-3-methylbenzene-1, 2-diamine (4.5 g, 19.1 mmol) in AcOH (25 mL) and H₂O (25 mL) was added NaNO₂ (2.6 g, 38.2 mmol) . After stirring at rt for 3 h. The reaction mixture was filtration to obtain the product (3.6 g, 76.8%) . MS [M+H] ⁺ calcd for C₇H₅BrClN₃ 245.9, found 245.9.

Step 7: Synthesis of methyl 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (8)

A solution 6-bromo-4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole (200 mg, 0.81 mmol) , TEA (245 mg, 2.43 mmol) and Pd (dppf) Cl₂ (65 mg, 0.08 mmol) in MeOH (5 mL) was stirred under CO at 100 ℃ for 16 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA = 1/1) afforded the desired product (120 mg, 65.6%) . MS [M+H] ⁺ calcd for C₉H₈ClN₃O₂ 226.0, found 226.0.

Step 8: Synthesis of 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (9)

To a solution of methyl 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (120 mg, 0.53 mmol) in THF/H₂O (2/2 mL) was added LiOH (51 mg, 2.12 mmol) at 0 ℃. After addition, the reaction was for 16 h at 50℃. The mixture was neutralized with hydrochloric acid, extracted by EA (10 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (60mg, 53.6%) . MS [M+H] ⁺ calcd for C₈H₆ClN₃O₂ 212.0, found 212.0.

Intermediate Aa16

Step1: Synthesis of 4-bromo-2-chloro-5-methoxyaniline (2)

To a solution of 2-chloro-5-methoxyaniline (25 g, 158.23 mmol) in EA (250 mL) was added 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (22.47 g, 79.12 mmol) at -5℃. The reaction was stirred at RT for 1 hour under N₂. The reaction mixture was quenched by K₂CO₃ (200 mL) and extracted with DCM (500 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=10/1) to obtain the product (31 g, 83.8%) . MS [M+H] ⁺ calcd for C₇H₇BrClNO 235.9, found 235.9.

Step2: Synthesis of N- (4-bromo-2-chloro-5-methoxyphenyl) acetamide (3)

To a solution of 4-bromo-2-chloro-5-methoxyaniline (31 g, 131.4 mmol) and TEA (19.91 g, 197.1 mmol) in THF (310 mL) was added acetyl chloride (11.27 g, 144.5 mmol) . The reaction was stirred at RT for 2 h. The mixture was quenched by ice water and extracted by DCM (300 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (19.4 g, 53.0%) . MS [M+H] ⁺calcd for C₉H₉BrClNO₂ 278.0, found 278.0.

Step3: Synthesis of N- (4-bromo-6-chloro-3-methoxy-2-nitrophenyl) acetamide (4)

To a solution of H₂SO₄ (183 mL) and N- (4-bromo-2-chloro-5-methylphenyl) acetamide (18.3 g, 65.6 mmol) was added KNO₃ (7.29 g, 72.16 mmol) at 0℃. The reaction was stirred at R. T. for 2 h. The mixture was quenched by ice water and neutralized with NaHCO₃ at PH=6, extracted by EA (200 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (5.6 g, 26.7%) . MS [M+H] ⁺calcd for C₉H₈BrClN₂O₄ 322.9, found 322.9.

Step4: Synthesis of 4-bromo-6-chloro-3-methoxy-2-nitroaniline (5)

To a solution of N- (4-bromo-6-chloro-3-methoxy-2-nitrophenyl) acetamide (5.5 g, 16.98 mmol) in MeOH (55 mL) was added MsOH (5.5 mL) , the reaction was stirred at 60℃ for 2 h. The reaction mixture was concentrated in vacuo to dryness and obtain the crude product (4.7 g, 98.5%) . MS [M+H] ⁺ calcd for C₇H₆BrClN₂O₃ 280.9, found 280.9.

Step5: Synthesis of 4-bromo-6-chloro-3-methoxybenzene-1, 2-diamine (6)

To a solution of 4-bromo-6-chloro-3-methoxy-2-nitroaniline (4.7 g, 16.73 mmol) in EtOH (47 mL) was added Zn (5.44 g, 83.65 mmol) and ammonium formate (5.27 g, 83.65 mmol) , the reaction was stirred at 60℃ for 3 h. The reaction mixture was filtration to obtain the filtrate, the filtrate was concentrated in vacuo to dryness and extracted by EA (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (4.0 g, 95.2%) . MS [M+H] ⁺ calcd for C₇H₈BrClN₂O 251.0, found 251.0.

Step6: Synthesis of 6-bromo-4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole (7)

To a solution of 4-bromo-6-chloro-3-methoxybenzene-1, 2-diamine (4 g, 15.94 mmol) in AcOH (40 mL) and H₂O (40 mL) was added NaNO₂ (2.2 g, 31.88 mmol) . After stirring at rt for 3 h. The reaction mixture was filtration to obtain the product (2.3 g, 55.2%) . MS [M+H] ⁺ calcd for C₇H₅BrClN₃O 261.9, found 261.9.

Step7: Synthesis of methyl 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (8)

A solution 6-bromo-4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole (800 mg, 3.05 mmol) , TEA (924 mg, 9.15 mmol) and Pd (dppf) Cl₂ (253 mg, 0.31 mmol) in MeOH (15 mL) was stirred under CO at 110 ℃ for 24 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA = 1/1) afforded the desired product (200 mg, 27.1%) . MS [M+H] ⁺ calcd for C₉H₈ClN₃O₃ 242.0, found 242.0.

Step8: Synthesis of 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (9)

To a solution of methyl 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (200 mg, 0.83 mmol) in THF/H₂O (2/2 mL) was added LiOH (80 mg, 3.32 mmol) at 0 ℃. After addition, the reaction was for 16 h at 50℃. The mixture was neutralized with hydrochloric acid, extracted by EA (10 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (70mg, 37.2%) . MS [M+H] ⁺ calcd for C₈H₆ClN₃O₃ 228.0, found 228.0.

Intermediate Ab1

Step 1: Synthesis of methyl benzo [d] isoxazole-5-carboxylate (2)

A solution of 6-bromo-4-chloro-1H-benzo [d] [1, 2, 3] triazole (2 g, 10.1 mmol) , TEA (3.1 g, 30.3 mmol) and Pd (dppf) Cl₂·DCM (584 mg, 0.5 mmol) in MeOH (20 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (1.2 g, 67%) . MS [M+H] ⁺ calcd for C₉H₇NO₃ 178.2, found 178.2.

Step 2: Synthesis of benzo [d] isoxazole-5-carboxylic acid (3)

To a solution of methyl benzo [d] isoxazole-5-carboxylate (1.2 g, 6.8 mmol) in THF/H₂O (5/5 mL) was added LiOH (569 mg, 13.6 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (1.05g, 95%) . MS [M+H] ⁺ calcd for C₈H₅NO₃ 164.2, found 164.2.

Intermediate Ab2

Step 1: Synthesis of 5-bromo-3-chloro-2-hydroxybenzaldehyde (2)

To a solution of 4-bromo-2-chlorophenol (1 g, 4.83 mmol) in TFA (10 mL) was added hexamethylenetetramine (1.4 g, 9.66 mmol) in portions over 1.5 hours. After stirring at 90 ℃ for 15 h. Cool the reaction mixture to room temperature and pour into water (20 mL) (exothermic) . Allow the mixture to cool to room temperature and add 50%aqueous H₂SO₄ (5 mL) . Allow the mixture to cool to room temperature and collect the precipitate by vacuum filtration to obtain the product (1.045 g, 92%) . MS [M+H] ⁺ calcd for C₇H₄BrClO₂ 237.2, found 237.2.

Step 2: Synthesis of 5-bromo-7-chlorobenzo [d] isoxazole (3)

To a solution of 5-bromo-3-chloro-2-hydroxybenzaldehyde (1 g, 4.26 mmol) in EtOH (15 mL) was added hydroxylamine hydrochloride (352 mg, 5.11 mmol) DDQ (1160 mg, 5.11 mmol) , PPh₃ (1339 mg, 5.11 mmol) and TEA (517 mg, 5.11 mmol) . After stirring at 80 ℃ for 1 h. Add water (20 mL) to the reaction mixture. The reaction mixture was filtration to obtain the product (479 mg, 49%) . MS [M+H] ⁺ calcd for C₇H₃BrClNO 234.2, found 234.2.

Step 3: Synthesis of methyl 7-chlorobenzo [d] isoxazole-5-carboxylate (4)

A solution of 5-bromo-7-chlorobenzo [d] isoxazole (479 mg, 2.06 mmol) , TEA (626 mg, 6.19 mmol) and Pd (dppf) Cl₂·DCM (82 mg, 0.10 mmol) in MeOH (10 mL) was stirred under CO at 80 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (361 mg, 82%) . MS [M+H] ⁺ calcd for C₉H₆ClNO₃ 212.2, found 212.2.

Step 4: Synthesis of 7-chlorobenzo [d] isoxazole-5-carboxylic acid (5)

To a solution of methyl 7-chlorobenzo [d] isoxazole-5-carboxylate (361 mg, 1.70 mmol) in THF/H₂O (3/3 mL) was added LiOH (143 mg, 3.41 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (156 mg, 46%) . MS [M+H] ⁺ calcd for C₈H₄ClNO₃ 198.2, found 198.2.

Intermediate Ab3

Step 1: Synthesis of 5-bromo-2-hydroxy-3-methylbenzaldehyde (2)

To a solution of 2-hydroxy-3-methylbenzaldehyde (1 g, 7.35 mmol) in AcOH (10 mL) was added Br₂ (0.45 mL, 8.82 mmol) at rt under N₂ atmosphere. After stirring at rt for overnight. Cool the reaction mixture to 0 ℃ and add saturated aqueous Na₂S₂O₃ (30 mL) to the reaction mixture. Extracted by EA (100 mL*3) , dried by Na₂SO₄, further purification by column chromatography (silica gel, PE/EA=1/2) afforded the desired product (1.4 g, 89%) . MS [M+H] ⁺ calcd for C₈H₇BrO₂ 215.2, found 215.2.

Step 2: Synthesis of 5-bromo-7-methylbenzo [d] isoxazole (3)

To a solution of 5-bromo-2-hydroxy-3-methylbenzaldehyde (1.4 g, 6.51 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (539 mg, 7.81 mmol) DDQ (1774 mg, 7.81 mmol) , PPh₃ (2048 mg, 7.81 mmol) and TEA (790 mg, 7.81 mmol) . After stirring at 80 ℃ for 1 h. Add water (20 mL) to the reaction mixture. The reaction mixture was filtration to obtain the product (741 mg, 54%) . MS [M+H] ⁺ calcd for C₈H₆BrNO 212.2, found 212.2.

Step 3: Synthesis of methyl 7-methylbenzo [d] isoxazole-5-carboxylate (4)

A solution of 5-bromo-7-methylbenzo [d] isoxazole (741 mg, 3.50 mmol) , TEA (1059 mg, 10.49 mmol) and Pd (dppf) Cl₂·DCM (142 mg, 0.17 mmol) in MeOH (10 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (356 mg, 53%) . MS [M+H] ⁺ calcd for C₁₀H₉NO₃ 192.2, found 192.2.

Step 4: Synthesis of 7-methylbenzo [d] isoxazole-5-carboxylic acid (5)

To a solution of methyl 7-methylbenzo [d] isoxazole-5-carboxylate (356 mg, 1.86 mmol) in THF/H₂O (3/3 mL) was added LiOH (157 mg, 3.73 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (207 mg, 63%) . MS [M+H] ⁺ calcd for C₉H₇NO₃ 178.2, found 178.2.

Intermediate Ab4

Step 1: Synthesis of 5-bromo-7-methoxybenzo [d] isoxazole (2)

A solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1 g, 4.33 mmol) , TEA (0.66 mL, 4.76 mmol) and NH₂OH·HCl (358.5 mg, 5.20 mmol) in EtOH (20 mL) was stirred under N₂ at 95 ℃ for 5 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of above compounds in THF (10 mL) was added DDQ (982.9 mg, 4.33 mmol) and PPh₃ (1.1 g, 4.33 mmol) dropwise at 0 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, PE /EA = 1/5) afforded the desired product (500 mg, 51%) . MS [M+H] ⁺ calcd for C₈H₆BrNO₂ 227.96, found 227.96.

Step 2: Synthesis of methyl 7-methoxybenzo [d] isoxazole-5-carboxylate (3)

A solution of 5-bromo-7-methoxybenzo [d] isoxazole (500 mg, 2.19 mmol) , TEA (0.91 mL, 6.58 mmol) and Pd (dppf) Cl₂ (179.5 mg, 0.22 mmol) in MeOH (10 mL) was stirred under CO at 80℃ for 5 h. The mixture was extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by column chromatography (silica gel, PE /EA = 1/5) afforded the desired product (350 mg, 77%) . MS [M-H] ^-calcd for C₁₀H₉NO₄ 208.05, found 208.05.

Step 3: Synthesis of 7-methoxybenzo [d] isoxazole-5-carboxylic acid (4)

To a solution of 7-methoxybenzo [d] isoxazole-5-carboxylic acid (350 mg, 1.69 mmol) in THF/H₂O (4/1 mL) was added NaOH (169 mg, 4.23 mmol) at 0℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (20 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (270 mg, 83%) . MS [M+H] ⁺ calcd for C₉H₇NO₄ 194.04, found 194.04.

Intermediate Ab5

Step 1: Synthesis of 3-methylbenzo [d] isoxazole-5-carboxylic acid (2)

To a solution of 5-bromo-3-methylbenzo [d] isoxazole (100 mg, 0.47 mmol) in THF (5 mL) was added n-BuLi (0.21 mL, 0.52 mmol) dropwise at -78 ℃ under CO₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, allow the mixture to warm to ambient temperature stirred overnight. The reaction mixture was quenched by H₂O and acidify the mixture to pH = 1 with 1M HCl. After then, extracted with EA (30 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/3) to obtain the product (50 mg, 60%) . MS [MH] ⁺ C₉H₇NO₃ 178.04, found 178.04.

Intermediate Ac1

Step1: Synthesis of methyl [1, 2, 3] triazolo [1, 5-a] pyridine-5-carboxylate (2)

A solution of 5-bromo- [1, 2, 3] triazolo [1, 5-a] pyridine (1 g, 5.05 mmol) , TEA (1.5 g, 15.15 mmol) and Pd (dppf) Cl₂·DCM (205 mg, 0.25 mmol) in MeOH (20 mL) was stirred under CO at 120 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (390 mg, 44%) . MS [MH] ⁺ calcd for C₉H₇NO₃ 178.2, found 178.2.

Step2: Synthesis of [1, 2, 3] triazolo [1, 5-a] pyridine-5-carboxylic acid (3)

To a solution of methyl [1, 2, 3] triazolo [1, 5-a] pyridine-5-carboxylate (510 mg, 2.88 mmol) in THF/H₂O (4/4 mL) was added LiOH (354 mg, 8.64 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (400 mg, 85%) . MS [MH] ⁺ calcd for C₇H₅N₃O₂ 164.0, found 164.0.

Intermediate B1

Step 1: Synthesis of 1- (5-chloro-2-fluorophenyl) -N-methylethan-1-amine (2)

To a solution of compound 1 (600 mg, 3.47 mmol) and methylamine hydrochloride (259 mg, 3.82 mmol) in MeOH (10 mL) was added NaBH₃CN (437 mg, 6.94 mmol) and ZnCl₂ (566 mg, 4.16 mmol) . The mixture was stirred at 50℃ for 6 hours. The reaction mixture was quenched by ice water (20 mL) , acidified to pH about 7-8 by Na₂CO₃, and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (300 mg, 46%) . MS [MH] ⁺ calcd for C₉H₁₁ClFN 188.1, found 188.1.

Step 2: Synthesis of N- (1- (5-chloro-2-fluorophenyl) ethyl) -2-cyano-N-methylacetamide (3)

To a solution of 1- (5-chloro-2-fluorophenyl) -N-methylethan-1-amine (300 mg, 1.60 mmol) and 2-cyanoacetic acid (136 mg, 1.60 mmol) in DCM (10 mL) was added T₃P (761 mg, 2.39 mmol) and DIEA (618 mg, 4.79 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/2) to obtain the product (150 mg, 37%) . MS [MH] ⁺ calcd for C₁₂H₁₂ClFN₂O 254.9, found 254.9

Intermediate B2

Step 1: Synthesis of 1- (2-fluoro-5- (trifluoromethyl) phenyl) -N-methylmethanamine (2)

To a solution of compound 1 (700 mg, 3.65 mmol) and methylamine hydrochloride (297 mg, 4.37 mmol) in MeOH (10 mL) was added NaBH₃CN (459 mg, 7.29 mmol) and ZnCl₂ (594 mg, 4.37 mmol) . The mixture was stirred at 50℃ for 6 hours. The reaction mixture was quenched by ice water (20 mL) , acidified to pH about 7-8 by Na₂CO₃, and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (300 mg, 46%) . MS [M+H] ⁺ calcd for C₉H₉F₄N 208.1, found 208.1.

Step 2: Synthesis of 2-cyano-N- (2-fluoro-5- (trifluoromethyl) benzyl) -N-methylacetamide (3)

To a solution of 1- (2-fluoro-5- (trifluoromethyl) phenyl) -N-methylmethanamine (300 mg, 1.45 mmol) and 2-cyanoacetic acid (123 mg, 1.45 mmol) in DCM (10 mL) was added T₃P (691 mg, 2.17 mmol) and DIEA (561 mg, 4.35 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/2) to obtain the product (220 mg, 55%) . MS [M+H] ⁺ calcd for C₁₂H₁₀F₄N₂O 274.9, found 274.9.

Intermediate B3

Step 1: Synthesis of 1- (2-bromoethoxy) -2-chlorobenzene (2)

To a solution of compound 1 (1 g, 7.75 mmol) and 1, 2-dibromoethane (2.9 g, 15.50 mmol) in NaOH (10 mL, 1.6 N) . The mixture was stirred at 100℃ for 12 hours. The reaction mixture was quenched by ice water (20 mL) and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=5/1) to obtain the product (1 g, 55%) . MS [M+H] ⁺ calcd for C₈H₈BrClO 237.1, found 237.1.

Step 2: Synthesis of 2- (2-chlorophenoxy) -N-methylethan-1-amine (3)

To a solution of compound 2 (1 g, 4.24 mmol) and methylamine hydrochloride (346 mg, 5.08 mmol) in MeOH (10 mL) was added NaBH₃CN (320 mg, 5.08 mmol) and ZnCl₂ (1153 mg, 8.47 mmol) . The mixture was stirred at 50℃ for 6 hours. The reaction mixture was quenched by ice water (30 mL) , acidified to pH about 7-8 by Na₂CO₃, and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (600 mg, 76%) . MS [M+H] ⁺ calcd for C₉H₁₂ClNO 186.1, found 186.1.

Step 3: Synthesis of N- (2- (2-chlorophenoxy) ethyl) -2-cyano-N-methylacetamide (4)

To a solution of 2- (2-chlorophenoxy) -N-methylethan-1-amine (600 mg, 3.23 mmol) and 2-cyanoacetic acid (277 mg, 3.23 mmol) in DCM (10 mL) was added T₃P (1539 mg, 4.84 mmol) and DIEA (1248 mg, 9.68 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (500 mg, 61%) . MS [M+H] ⁺ calcd for C₁₂H₁₃ClN₂O₂ 252.9, found 252.9.

Intermediate B4

Step 1: Synthesis of 4-fluoro-3- ( (methylamino) methyl) benzonitrile (2)

To a solution of compound 1 (700 mg, 4.70 mmol) and methylamine hydrochloride (383 mg, 5.64 mmol) in MeOH (20 mL) was added NaBH₃CN (592 mg, 9.40 mmol) and ZnCl₂ (767 mg, 5.64 mmol) . The mixture was stirred at 50℃ for 6 hours. The reaction mixture was quenched by ice water (20 mL) , acidified to pH about 7-8 by Na₂CO₃, and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (500 mg, 65%) . MS [M+H] ⁺ calcd for C₉H₉FN₂ 165.1, found 165.1.

Step 2: Synthesis of 2-cyano-N- (5-cyano-2-fluorobenzyl) -N-methylacetamide (3)

To a solution of 4-fluoro-3- ( (methylamino) methyl) benzonitrile (500 mg, 3.05 mmol) and 2-cyanoacetic acid (259 mg, 3.05 mmol) in DCM (10 mL) was added T₃P (1454 mg, 4.57 mmol) and DIEA (1180 mg, 9.15 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/2) to obtain the product (350 mg, 50%) . MS [M+H] ⁺ calcd for C₁₂H₁₀FN₃O 231.9, found 231.9.

Intermediate B5

Step 1: Synthesis of 1-phenyl-1H-1, 2, 3-triazole-4-carbaldehyde (2)

A mixture of (1-phenyl-1H-1, 2, 3-triazol-4-yl) methanol (1 g, 5.7 mmol) and MnO₂ (7.4 g, 85.7 mmol) in EA (20 mL) was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled to RT and diluted with H₂O (30 mL) . Extracted with ethyl acetate (100 mL x 3) . The combined organic phases were washed with brine, dried by anhydrous Na₂SO₄. Purify the product by column chromatography (dichloromethane/methanol (10: 1) ) to give the product (900 mg, 91%) . MS [M+H] ⁺ calcd for C₉H₇N₃O 174.1, found 174.1.

Step 2: Synthesis of N-methyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) methanamine (3)

To a solution of compound 2 (900 mg, 5.2 mmol) and methylamine hydrochloride (354 mg, 5.2 mmol) in MeOH (20 mL) was added NaBH₃CN (393 mg, 6.2 mmol) and ZnCl₂ (1415 mg, 10.4 mmol) . The mixture was stirred at 50℃ for 6 hours. The reaction mixture was quenched by ice water (20 mL) , acidified to pH about 7-8 by Na₂CO₃, and extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (780 mg, 80%) . MS [M+H] ⁺ calcd for C₁₀H₁₂N₄ 189.1, found 189.1.

Step 3: Synthesis of 2-cyano-N-methyl-N- ( (1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) acetamide (4)

To a solution of N-methyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) methanamine (780 mg, 4.1 mmol) and 2-cyanoacetic acid (353 mg, 4.1 mmol) in DCM (20 mL) was added T₃P (1979 mg, 6.2 mmol) and DIEA (1606 mg, 12.4 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (180 mg, 17%) . MS [M+H] ⁺ calcd for C₁₃H₁₃N₅O 255.9, found 255.9.

Intermediate B6

Step 1: Synthesis of 2-cyano-N-methyl-N- (2-phenoxyethyl) acetamide (2)

To a solution of N-methyl-2-phenoxyethan-1-amine (120 mg, 0.79 mmol) and 2-cyanoacetic acid (67.5 mg, 0.79 mmol) in DCM (6 mL) was added T₃P (376.8 mg, 1.2 mmol) and DIEA (203.8 mg, 1.58 mmol) . The mixture is stirred for 8 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (15 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/3) to obtain the product (80 mg, 46%) . MS [M+H] ⁺ C₁₂H₁₄N₂O₂ 219.11, found 219.11.

Intermediate B7

Step 1: Synthesis of 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile (2)

To a solution of 4- (3-chlorophenyl) piperidine (500 mg, 2.55 mmol) and 2-cyanoacetic acid (217 mg, 2.55 mmol) in DCM (10 mL) was added T₃P (1217 mg, 3.83 mmol) and DIEA (987 mg, 7.66 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/2) to obtain the product (400 mg, 60%) . MS [M+H] ⁺ calcd for C₁₄H₁₄ClN₂O 262.9, found 262.9.

Intermediate B8

Step 1: Synthesis of N-phenylpiperidin-4-amine (2)

A mixture of tert-butyl 4- (phenylamino) piperidine-1-carboxylate (1 g, 3.6 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at rt for 2 hours. The reaction mixture concentrated in vacuo to dryness to give the product (600 mg, 94%) . MS [M+H] ⁺ calcd for C₁₁H₁₆N₂ 177.1, found 177.1.

Step 2: Synthesis of 3-oxo-3- (4- (phenylamino) piperidin-1-yl) propanenitrile (3)

To a solution of N-methyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) methanamine (600 mg, 3.4 mmol) and 2-cyanoacetic acid (290 mg, 4.1 mmol) in DCM (10 mL) was added T₃P (1611 mg, 5.1 mmol) and DIEA (1319 mg, 10.2 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/3) to obtain the product (180 mg, 22%) . MS [M+H] ⁺ calcd for C₁₄H₁₇N₃O 243.9, found 243.9.

Step 3: Synthesis of tert-butyl (1- (2-cyanoacetyl) piperidin-4-yl) (phenyl) carbamate (4)

To a solution of compound 2 (180 mg, 0.7 mmol) and (Boc) ₂O (807 mg, 3.7 mmol) in DCM (20 mL) was added DMAP (271 mg, 2.2 mmol) . The mixture was stirred at rt for 6 hours. The reaction mixture was quenched by ice water (20 mL) , extracted by EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/1) to obtain the product (130 mg, 51%) . MS [M+H] ⁺ calcd for C₁₉H₂₅N₃O₃ 344.1, found 344.1.

Intermediate B9

Step1: Synthesis of 3- (3-azabicyclo [3.1.0] hexan-3-yl) -3-oxopropanenitrile (3)

A solution of 3-azabicyclo [3.1.0] hexane hydrochloride (2 g, 16.81 mmol) , 2-cyanoacetic acid (2.13 g, 25.21 mmol) in DCM was added T₄P (9 g, 25.21 mmol) and DIEA (6.47 g, 50.43 mmol) was stirred under N₂ at 25 ℃ for 16 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (1.5 g, 60%) . MS [M+H] ⁺calcd for C₈H₁₀N₂O 151.1, found 151.1.

Intermediate B10

Step1: Synthesis of 3- (2-chlorophenyl) -N-methylprop-2-yn-1-amine (2)

A solution of N-methylprop-2-yn-1-amine (400 mg, 5.8 mmol) , 1-chloro-2-iodobenzene (1380 mg, 5.8 mmol) , PdCl₂ (PPh₃) ₂ (81 mg, 0.1 mmol) and copper iodide (11 mg, 0.1 mmol) in anhydrous diethylamine solution (10 mL) was stirred under N₂ at rt for 22 h. The solvent was removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/2) afforded the desired product (250 mg, 24%) . MS [M+H] ⁺ calcd for C₁₀H₁₀ClN 180.1, found 180.1.

Step2: Synthesis of N- (3- (2-chlorophenyl) prop-2-yn-1-yl) -2-cyano-N-methylacetamide (3)

To a solution of 3- (2-chlorophenyl) -N-methylprop-2-yn-1-amine (250 mg, 1.4 mmol) and 2-cyanoacetic acid (118 mg, 1.4 mmol) in DCM (10 mL) was added T₃P (662 mg, 2.1 mmol) and DIEA (537 mg, 4.2 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/2) to obtain the product (150 mg, 44%) . MS [M+H] ⁺ calcd for C₁₃H₁₁ClN₂O 246.9, found 246.9.

Intermediate B11

Step 1: Synthesis of 1- (5-chloro-2-fluorophenyl) -N-methylmethanamine (2)

The mixture of 5-chloro-2-fluorobenzaldehyde (50.0 g, 316.45 mmol) in MeOH (200 mL) was added Methylamine hydrochloride (42.7 g, 632.59 mmol) and stirred at 0℃ for 30 mins. NaBH₃CN (29.8 g, 474.52 mmol) , ZnCl₂ (86.1 g, 633.09 mmol) was added to the above mixture, then the mixture was warmed to 50℃, stirred for 16 hours. The reaction was quenched by ice water (200 ML) , acidified to pH about 7-8 by Na₂CO₃, extracted by EA (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=90/10, 0.1%TFA) to obtain the product (23.0 g, 41.8%) . MS [M+H] ⁺calcd for C₈H₉ClFN 174.1, found 174.1.

Step 2: Synthesis of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide (3)

The mixture of (1- (5-chloro-2-fluorophenyl) -N-methylmethanamine (23.0 g, 132.95 mmol) in DCM (200 mL) was added 2-cyanoacetic acid (12.43 g, 146.24 mmol) , T₃P (126.83 g, 199.42 mmol) and DIEA (51.45 g, 398.84 mmol) . The reaction was stirred at rt for 16 h. The reaction was quenched by ice water (200 ML) , extracted by EA (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/1) to obtain the product (18.0 g, 56.6%) . MS [M+H] ⁺ calcd for C₁₁H₁₀ClFN₂O 241.1, found 241.1.

Intermediate B12

Step1: Synthesis of 1- (2-fluoro-5-methylphenyl) -N-methylmethanamine (2)

NaBH₄ (OAc) ₃ (2.3 g, 10.86 mmol) was added to a solution of 2-fluoro-5-methylbenzaldehyde (1 g, 7.24 mmol) and Methylamine (7.2 mL, 14.48 mmol) in DCE (20 mL) was stirred at room temperature for 5 h, then the solution was quenched by 1N NaOH (20 mL) . The mixture was extracted by DCM (20 mL X 3) and dried by Na₂SO₄, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE /EA = 6/1) afforded the desired product (1.048 g, 94%) . MS [M+H] ⁺calcd for C9H12FN 154.1, found 154.1.

Step2: Synthesis of 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide (3)

A solution of 1- (2-fluoro-5-methylphenyl) -N-methylmethanamine (1.048 g, 6.84 mmol) , 2-cyanoacetic acid (582 mg, 6.84 mmol) , HATU (3.12 g, 8.21 mmol) and DIPEA (1.33 g, 10.26 mmol) in DCM (20 mL) was stirred at room temperature for 5 h, then the solution was quenched by water (25 mL) . The mixture was extracted by ethyl acetate (20 mL X 3) and dried by Na₂SO₄, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE /EA = 4/1) afforded the desired product (980 mg, 65%) . MS [M+H] ⁺ calcd for C12H13FN2O 221.2, found 221.2.

Intermediate B13

Step1: Synthesis of N- (5-chloro-2-fluorobenzyl) ethanamine (2)

The mixture of 5-chloro-2-fluorobenzaldehyde (900 mg, 5.7 mmol) in MeOH (500 mL) was added Methylamine hydrochloride (775 mg, 11.4 mmol) , NaBH₃CN (428 mg, 6.8 mmol) and ZnCl₂ (1.5 g, 11.4 mmol) , then the mixture was warmed to 50℃, stirred for 6 hours. The reaction was quenched by ice water (50 mL) , acidified to pH about 7-8 by Na₂CO₃, extracted by EA (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (750 mg, 70%) . MS [M+H] ⁺ calcd for C₉H₁₁ClFN 188.1, found 188.1.

Step2: Synthesis of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-ethylacetamide (3)

The solution of 4-fluoro-3- ( (methylamino) methyl) benzonitrile (650 mg, 3.5 mmol) and 2-cyanoacetic acid (294 mg, 3.5 mmol) in DCM (50 mL) at 25℃. The flask is equipped with a magnetic stirring bar and a three-way stopcock attached to a balloon filled with nitrogen. To the stirred solution is added T₃P (1.7 g, 5.2 mmol) and DIEA (1.3 g, 10.4 mmol) . The flask is evacuated and purged with nitrogen. The mixture is stirred for 8 h at 25℃. The reaction was quenched by water (50 mL) , extracted by DCM (200 mL*3) , dried by Na₂SO₄. The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (420 mg, 48%) . MS [M-H] ⁺ calcd for C₁₂H₁₂ClFN₂O 254.9, found 254.9.

Intermediate B14

To a solution of 4- (piperidin-4-yl) pyridine (300 mg, 1.85 mmol) and 2-cyanoacetic acid (157 mg, 1.85 mmol) in DCM (6 mL) was added T₃P (884.5 mg, 2.78 mmol) and DIEA (477 mg, 3.7 mmol) . The mixture is stirred for 8 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (15 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/3) to obtain the product (250 mg, 58.9%) . MS [MH] ⁺ C₁₃H₁₅N₃O 230.12, found 230.12.

Intermediate B15

To a solution of 4-phenylpiperidine (500 mg, 3.11 mmol) and 2-cyanoacetic acid (264 mg, 3.11 mmol) in DCM (10 mL) was added T₃P (1.48 g, 4.67 mmol) and DIEA (942 mg, 9.33 mmol) . The mixture is stirred for 4 h at 25 ℃. The reaction mixture was quenched by water (20 mL) , extracted by DCM (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/2) to obtain the product (160 mg, 23%) . MS [M+H] ⁺ calcd for C₁₄H₁₆N₂O 229.1, found 229.1.

Intermediate B16

Step1: Synthesis of tert-butyl (2- (2-chlorophenoxy) ethyl) carbamate (2)

A solution of 2-chlorophenol (1.0 g, 7.8 mmol) and NaH (187.5 mg, 7.8 mmol) in anhydrous THF (25 mL) was stirred at 0 ℃ for 30 min. tert-butyl (2-bromoethyl) carbamate (1.7 g, 7.8 mmol) was added dropwise and the reaction mixture was stirred at 0 ℃ for 15 min then allowed to warm to RT and stirred overnight. The reaction was quenched by water (30 mL) and was extracted with EtOAc (200 mL X 3) , and then dried over Na₂SO₄, and filtered. The solvent was removed in vacuo to tert-butyl (2- (2-chlorophenoxy) ethyl) carbamate (1.1 g, 52%) . MS [MH] ⁺ calcd for C₁₃H₁₈ClNO₃ 272.1, found 272.1.

Step2: Synthesis of tert-butyl (2- (2-chlorophenoxy) ethyl) (ethyl) carbamate (3)

The mixture of tert-butyl (2- (2-chlorophenoxy) ethyl) carbamate (1.1 g, 4.1 mmol) and NaH (0.2 g, 8.1 mmol) in THF (50 mL) was at -20℃ for 30 min under N₂ atmosphere. After iodoethane (0.6 g, 4.1 mmol) was added, stirred for overnight. The above compound was added the reaction mixture, warmed to RT, and stirred for overnight. After the completion of the reaction, the mixture was acidified to pH about 5-6 by HCl, extracted with DCM (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to obtain the product (1.0 g, 83%) . MS [M-H] ⁺ calcd for C₁₅H₂₂ClNO₃ 299.9, found 299.9.

Step3: Synthesis of 2- (2-chlorophenoxy) -N-ethylethan-1-amine (4)

A mixture of tert-butyl (2- (2-chlorophenoxy) ethyl) (ethyl) carbamate (900 mg, 3.0 mmol) , TFA (0.5 mL) in DCM (20 mL) was stirred for overnight at 25 ℃. The reaction was dried to obtain the product (500 mg, 83%) . MS [M-H] ^-calcd for C₁₀H₁₄ClNO 199.9, found 199.9.

Step4: Synthesis of N- (2- (2-chlorophenoxy) ethyl) -2-cyano-N-ethylacetamide (5)

The solution of 2- (2-chlorophenoxy) -N-ethylethan-1-amine (500 mg, 2.5 mmol) and 2-cyanoacetic acid (213 mg, 2.5 mmol) in DCM (50 mL) at 25℃. The flask is equipped with a magnetic stirring bar and a three-way stopcock attached to a balloon filled with nitrogen. To the stirred solution is added T₃P (1.6 g, 5.0 mmol) and DIEA (1.3 g, 10.0 mmol) . The flask is evacuated and purged with nitrogen. The mixture is stirred for 8 h at 25℃. The reaction was quenched by water (20 mL) , extracted by DCM (150 mL*3) , dried by Na₂SO₄. The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (400 mg, 60%) . MS [M-H] ⁺ calcd for C₁₃H₁₅ClN₂O₂ 266.9, found 266.9.

Intermediate B17

The mixture of diethylamine (1.0 g, 13.70mmol) in DCM (20 mL) was added 2-cyanoacetic acid (1.28g, 15.07mmol) , T₃P (13.07g, 20.55mmol) and DIEA (5.3g, 41.1mmol) . The reaction was stirred at rt for 16 h. The reaction mixture was washed with ice water (50 ML) , extracted with EA (50 mL*3) . The combined extraction was dried over anhydrous Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/1) to obtain the product (900 mg, 46.9%) . MS [M+H] ⁺calcd for C7H12N2O 141.2, found 141.2.

Compound 27

(Z) -3- (1H-benzo [d] [1, 2, 3] triazol-6-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methylacrylamide (27)

A solution of 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (200 mg, 1.2 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide (296 mg, 1.2 mmol) in THF (10 mL) was added LiHMDS (3.1 mL, 3.1 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=7/3, 0.1%TFA, 2 times) to obtain the product (27.3 mg, HPLC: 95.563%) . MS [M-H] ^-calcd for C₁₈H₁₃ClFN₅O₂ 384.0, found 383.6. ¹HNMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H) , 7.58 (s, 2H) , 7.38 –7.34 (m, 1H) , 7.23-7.20 (m, 1H) , 7.11 (s, 1H) , 4.57 (s, 2H) , 2.95 (s, 3H) .

Compound 490

(Z) -3- (1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-2- (thiazol-2-yl) acrylonitrile (490)

A solution of 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (150 mg, 0.92 mmol) in SOCl₂ (20 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 2- (thiazol-2-yl) acetonitrile (114 mg, 0.92 mmol) in THF (10 mL) was added LiHMDS (2.3 mL, 2.3 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (0.05%TFA; ACN-H₂O) to the product (1.2 mg, 0.5%) . MS [M-H] ^-calcd for C₁₂H₇N₅OS 268.0, found 268.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H) , 7.95 –7.79 (m, 2H) , 7.54 (d, J = 2.9 Hz, 1H) , 7.14 (s, 1H) .

Compound A1

(Z) -3- (1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N-methylacrylamide (A1)

A solution of 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (150 mg, 0.92 mmol) in SOCl₂ (20 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 2-cyano-N-methylacetamide (90 mg, 0.92 mmol) in THF (10 mL) was added LiHMDS (2.3 mL, 2.3 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (0.05%TFA; ACN-H₂O) to the product (20 mg, 8.9%) . MS [MH] ⁺ calcd for C₁₁H₉N₅O₂ 244.1, found 243.9. ¹HNMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H) , 8.49 (s, 1H) , 8.04 (d, J = 8.2 Hz, 1H) , 7.86 (d, J = 8.5 Hz, 1H) , 2.81 (s, 3H) .

Compound 439

(Z) -6- (2-cyano-3-cyclopropyl-1-hydroxy-3-oxoprop-1-en-1-yl) -1H-benzo [d] [1, 2, 3] triazole-4-carbonitrile (439)

Step 1: Synthesis of 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carbonyl fluoride

A solution of 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (410 mg, 2.18 mmol) in DCM (10 mL) was add DAST (702 mg, 4.36 mmol) . After stirring at 40 ℃ for 3 h. The mixture was extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (320 mg, 77%) . MS [M+H] ⁺ calcd for C₈H₃FN₄O 191.2, found 191.2.

Step 2: Synthesis of (Z) -6- (2-cyano-3-cyclopropyl-1-hydroxy-3-oxoprop-1-en-1-yl) -1H-benzo [d] [1, 2, 3] triazole-4-carbonitrile (439)

To a solution of 3-cyclopropyl-3-oxopropanenitrile (166 mg, 1.53 mmol) in THF (10 mL) was added LiHMDS (1.3 mL, 1.33 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the 5 (290 mg, 1.53 mmol) was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=7/3, 0.1%TFA, 2 times) to obtain the product (1.01 mg, HPLC: 93.759%) . MS [M-H] ^-calcd for C₁₄H₉N₄O₂ 278.1 found 278.2. ¹HNMR (400 MHz, DMSO-d₆) δ 7.23 (s, 1H) , 7.10 (s, 1H) , 6.98 (s, 1H) , 2.54 (s, 1H) , 0.76-0.71 (m, 4H) .

Compound 153

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl) -N-methylacrylamide (153)

Step 1: Synthesis of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide

A solution of 4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (600 mg, 1.32 mmol) in DCM (10 mL) was added (COCl) ₂ (502 mg, 3.96 mmol) and DMF (10 mg, 0.08 mmol) stirred at 0 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide (317 mg, 1.32 mmol) in THF (10 mL) was added LiHMDS (3.3 mL, 3.31 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by AcOH and extracted with EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=25/1) to obtain the product (150 mg, 17%) . MS [M+H] ⁺ calcd for C₃₁H₄₃ClFN₅O₅Si₂ 675.9, found 675.9.

Step 2: Synthesis of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl) -N-methylacrylamide (153)

To a solution of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (4- ( ( (2- (trimethylsilyl) ethoxy) methoxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (150 mg, 0.22 mmol) in DCM (10 mL) was added TFA (3 mL) at 0 ℃ for 4 h. After concentrate the mixture and purification by Prep-HPLC (H₂O/MeCN=7/3, 0.1%TFA, 2 times) to obtain the product (10.0 mg, HPLC: 100.00%) . MS [M-H] ^-calcd for C₁₉H₁₅ClFN₅O₃ 414.1, found 413.7. ¹HNMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H) , 7.71 (s, 1H) , 7.41 (s, 2H) , 7.29 (d, J = 8.4 Hz, 1H) , 4.92 (s, 2H) , 4.74 (s, 2H) , 3.16 (s, 3H) .

Compound 152

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (152)

Step 1: Synthesis of tert-butyl (2- (methyl-d₃) phenyl) carbamate (2)

To a solution of tert-butyl (2-iodophenyl) carbamate (4.5 g, 14.1 mmol) and iodome thane-d₃ (2.1 g, 14.1 mmol) in THF (50 mL) was added Zn (2.75 g, 42.3 mmol) , NaI (3.17 g, 21.15 mmol) and NiCl₂ (dppp) (764.22 mg, 1.41 mmol) , the reaction was stirred at room temperature for 24 hour under N₂. The reaction mixture was quenched by NH₄Cl (200 mL) and extracted with DCM (500 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=50/1) to obtain the product (2 g, 59.7%) . MS [M+H] ⁺ calcd for C₁₂H₁₄D₃NO₂ 211.2, found 211.2.

Step 2: Synthesis of 2- (methyl-d₃) aniline (3)

To a solution of tert-butyl (2- (methyl-d₃) phenyl) carbamate (2 g, 9.48 mmol) in MeOH (20 mL) was added HCl (2 mL) , the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to dryness and obtain the crude product (1.3 g) . MS [M+H] ⁺ calcd for C₇H₆D₃N 111.1, found 111.1.

Step 3: Synthesis of N- (2- (methyl-d₃) phenyl) acetamide (4)

To a solution of 2- (methyl-d₃) aniline (1.3 g, 11.71 mmol) and acetyl chloride (1 g, 12.88 mmol) in THF (10 mL) was added TEA (1.77 g, 17.57 mmol) . The reaction was stirred at RT for 2 h. The mixture was quenched by ice water and extracted by DCM (20 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (800 mg, 44.7%) . MS [M+H] ⁺calcd for C9H8D3NO 153.2, found 153.2. Step 4: Synthesis of N- (2- (methyl-d₃) -6-nitrophenyl) acetamide (5)

To a solution of N- (2- (methyl-d₃) phenyl) acetamide (800 mg, 5.23 mmol) in AcOH (5 mL) and Ac₂O (5 mL) was added HNO₃ (428.4 mg, 6.8 mmol) at 0℃. The reaction was stirred at R. T. for overnight. The mixture was quenched by ice water and neutralized with NaHCO₃ at PH=6, extracted by EA (20 mL*3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=4/1) to obtain the product (350 mg, 59.2%) . MS [M+H] ⁺calcd for C₉H₇D₃N₂O₃ 198.2, found 198.2.

Step 5: Synthesis of 2- (methyl-d₃) -6-nitroaniline (6)

To a solution of N- (2- (methyl-d₃) -6-nitrophenyl) acetamide (350 mg, 1.77 mmol) in MeOH (10 mL) was added HCl (1 mL) , the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to dryness and obtain the crude product (250 mg, 90.5%) . MS [M+H] ⁺ calcd for C₇H₅D₃N₂O₂ 156.1, found 156.1.

Step 6: Synthesis of 4-bromo-2- (methyl-d₃) -6-nitroaniline (7)

To a solution of 2- (methyl-d₃) -6-nitroaniline (250 mg, 1.6 mmol) in HOAc (5 mL) was added NBS (313.28 mg, 1.76 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The reaction mixture was quenched by water (10 mL) , extracted by DCM (10 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/1) to obtain the product (260 mg, 91.7%) . MS [M+H] ⁺ calcd for C₇H₄D₃BrN₂O₂ 235.0, found 235.0.

Step 7: Synthesis of 5-bromo-3- (methyl-d₃) benzene-1, 2-diamine (8)

To a solution of 4-bromo-2- (methyl-d₃) -6-nitroaniline (260 mg, 1.1 mmol) in EtOH (5 mL) was added Zn (357.5 mg, 5.5 mmol) and ammonium formate (346.5 mg, 5.5 mmol) , the reaction was stirred at 60℃ for 3 h. The reaction mixture was filtration to obtain the filtrate, the filtrate was concentrated in vacuo to dryness and extracted by EA (20 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (180 mg, 79.8%) . MS [M+H] ⁺ calcd for C₇H₆D₃BrN₂ 205.0, found 205.0.

Step 8: Synthesis of 6-bromo-4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole (9)

To a solution of 5-bromo-3- (methyl-d₃) benzene-1, 2-diamine (180 mg, 0.88 mmol) in AcOH (2 mL) and H₂O (2 mL) was added NaNO₂ (60.72 mg, 0.88 mmol) . After stirring at rt for 3 h. The reaction mixture was filtration to obtain the product (130 mg, 68.4%) . MS [M+H] ⁺ calcd for C₇H₃D₃BrN₃ 216.0, found 216.0.

Step 9: Synthesis of methyl 4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (10)

A solution of 6-bromo-4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole (130 mg, 0.6 mmol) , TEA (181.8 mg, 1.8 mmol) and Pd (dppf) Cl₂ (43.86 mg, 0.06 mmol) in MeOH (5 mL) was stirred under CO at 80 ℃ for 6 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA = 1/1) afforded the desired product (65 mg, 55.6%) . MS [M+H] ⁺ calcd for C₉H₆D₃N₃O₂ 195.2, found 195.2.

Step 10: Synthesis of 4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (11)

To a solution of methyl 4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylate (65 mg, 0.33 mmol) in THF/H₂O (2/2 mL) was added LiOH (23.76 mg, 0.99 mmol) at 0 ℃. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (10 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness to afford the desired product (45 mg, 75.3%) . MS [M+H] ⁺ calcd for C₈H₄D₃N₃O₂ 181.1, found 181.1.

Step 11: Synthesis of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (4 - (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (152)

A solution of 4- (methyl-d₃) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (45 mg, 0.25 mmol) in SOCl₂ (3 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of N- (5-chloro-2-fluorobenzyl) -2-cyan o-N-methylacetamide (60 mg, 0.25 mmol) in THF (5 mL) was added LiHMDS (0.7 mL, 0.63 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with EA (10 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=45/55, 0.1%TFA) to obtain the product (10.2 mg, HPLC: 99.39%) . MS [M+H] ⁺ calcd for C₁₉H₁₂D₃ClFN₅O₂ 402.8, found 402.8. ¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H) , 7.58 (s, 1H) , 7.45 (s, 2H) , 7.33 (d, J = 8.7 Hz, 1H) , 4.78 (s, 2H) , 3.18 (s, 3H) .

Compound 40

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-bis (methyl-d3) acrylamide

Step 1: Synthesis of 2-cyano-N, N-bis (methyl-d3) acetamide

A solution of bis (methyl-d3) amine hydrochloride (2 g, 23.0 mmol) , 2-cyanoacetic acid (2.9 g, 34.5 mmol) in DCM was added T₄P (12.4 g, 58.8 mmol) and DIEA (6.47 g, 69.0 mmol) was stirred under N₂ at 25 ℃ for 16 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (1.1 g, 41%) . MS [M+H] ⁺calcd for C₅H₂D₆N₂O 119.1, found 119.1.

Step 2: Synthesis of (Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-bis (methyl-d3) acrylamide (40)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (300 mg, 1.52 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 12 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 32-cyano-N, N-bis (methyl-d3) acetamide (216 mg, 1.83 mmol) in THF (5 mL) was added LiHMDS (3.8 mL, 3.8 mmol) dropwise at -78 ℃ under N2 atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H₂O/MeCN=7/3, 0.1%TFA) to obtain the product (120 mg, 27%) . MS [M+H] ⁺ calcd for C₁₂H₄D₆ClN₅O₂ 298.1 , found 298.1.¹NMR (400 MHz, MeOD) δ 8.05 (s, 1H) , 7.58 (s, 1H) .

Compound 38

(Z) -3- (1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide (38)

The title compound was prepared in 48%yield from 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide according to the procedures for preparation of Compound 27, 490 and 33. MS [M+H] ⁺ calcd for C₁₂H₁₁N₅O₂ 258.1, found 257.9. ¹HNMR (400 MHz, MeOD) δ 8.41 (s, 1H) , 7.84 (s, 2H) , 3.22 –3.08 (s, 6H) .

Compound 438

(Z) -3- (1H-benzo [d] [1, 2, 3] triazol-6-yl) -2- (cyclopropanecarbonyl) -3-hydroxyacrylonitrile (438)

The title compound was prepared in 8.7%yield from 1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 3-cyclopropyl-3-oxopropanenitrile according to the procedure for preparation of Compound 27. MS [M-H] ^- calcd for C₁₃H₁₀N₄O₂ 253.1, found 253.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H) , 8.00 (d, J = 8.6 Hz, 1H) , 7.85 (d, J = 8.6 Hz, 1H) , 2.46 –2.46 (m, 1H) , 1.17 (m, 4H) .

Compound 146

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methylacrylamide (146)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (100 mg, 0.5 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide (122 mg, 0.5 mmol) in THF (20 mL) was added LiHMDS (1.3 mL, 1.3 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=6/4, 0.1%TFA, 2 times) to obtain the product 146 (61.4 mg, HPLC: 98.59%) .. MS [M+H] ⁺ calcd for C₁₈H₁₂Cl₂FN₅O₂ 420.2, found 419.8. ¹HNMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H) , 7.91 (s, 1H) , 7.38 (m, 3H) , 4.78 (s, 2H) , 3.18 (s, 3H) .

Compound 148

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (148)

The title compound was prepared in 35.9%yield from 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₅ClFN₅O₂ 400.1, found 400.1. ¹HNMR (400 MHz, DMSO-d₆) δ 16.17 (s, 1H) , 8.27 (s, 1H) , 7.58 –7.32 (m, 5H) , 4.78 (s, 2H) , 3.18 (s, 3H) , 2.68 (s, 3H) .

Compound 149

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N-methylacrylamide (149)

The title compound was prepared in 12.4%yield from 4-cyano-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₂ClFN₆O₂ 411.1, found 411.0. ¹HNMR (400 MHz, DMSO-d₆) δ8.71 (s, 1H) , 8.39 (s, 1H) , 7.40-7.28 (m, 5H) , 4.72 (s, 2H) , 3.11 (s, 3H) .

Compound 150

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N-methylacrylamide (150)

The title compound was prepared in 0.7%yield from 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₃ClF₃N₅O₃ 452.1, found 451.9. ¹HNMR (400 MHz, DMSO-d₆) δ 8.30-8.15 (m, 1H) , 7.75 –7.53 (m, 1H) , 7.44 (s, 1H) , 7.36 (dd, J = 7.9, 4.9 Hz, 2H) , 7.21 (t, J = 9.2 Hz, 1H) , 4.69 (s, 2H) , 3.12 (s, 3H) .

Compound 155

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl) -N-methylacrylamide (155)

The title compound was prepared in 5.9%yield from 4-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₅ClFN₅O₃ 416.1, found 416.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.03-8.06 (m, 1H) , 7.30-7.40 (m, 3H) , 7.13-7.18 (m, 1H) , 4.87 (s, 2H) , 4.10 (s, 3H) , 3.30 (s, 3H) .

Compound 444

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2- (4- (3-chlorophenyl) piperidine-1-carbonyl) -3-hydroxyacrylonitrile (444)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl₂ (5 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile (79 mg, 0.30 mmol) in THF (5 mL) was added LiHMDS (0.6 mL, 0.63 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H₂O/MeCN=7/3, 0.1%TFA) to obtain the product 444 (19 mg, HPLC: 95.757%) . MS [M+H] ⁺ calcd for C₂₁H₁₇Cl₂N₅O₂ 442.1, found 442.1. ¹H NMR (400 MHz, MeOD) δ 8.46 (s, 1H) , 7.96 (s, 1H) , 7.28 (d, J = 7.6 Hz, 2H) , 7.21 (d, J = 7.3 Hz, 2H) , 4.72 (d, J = 12.9 Hz, 2H) , 3.19 (t, J = 12.6 Hz, 2H) , 2.94 (t, J = 11.7 Hz, 1H) , 2.00 (d, J = 12.7 Hz, 2H) , 1.83-1.75 (m, 2H) .

Compound 445

(Z) -2- (4- (3-chlorophenyl) piperidine-1-carbonyl) -3- (4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxyacrylonitrile (445)

The title compound was prepared in 12.2%yield from 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₁H₁₇ClFN₅O₂ 426.1, found 426.0. ¹HNMR (400 MHz, DMSO-d₆) δ8.31 (s, 1H) , 7.63-7.65 (m, 1H) , 7.18-7.27 (m, 4H) , 4.68-4.71 (m, 2H) , 3.14-3.29 (m, 2H) , 2.89-2.95 (m, 1H) , 1.96-1.99 (m, 2H) , 1.72-1.81 (m, 2H) .

Compound 440

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2- (cyclopropanecarbonyl) -3-hydroxyacrylonitrile (440)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (100 mg, 0.51 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 3-cyclopropyl-3-oxopropanenitrile (55 mg, 0.51 mmol) in THF (10 mL) was added LiHMDS (1.3 mL, 1.26 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by AcOH and extracted with EA (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=6/4, 0.1%TFA) to obtain the product 440 (19.7 mg, HPLC: 98.559%) . MS [M+H] ⁺ calcd for C₁₃H₉ClN₄O₂ 289.0, found 289.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H) , 7.89 (s, 1H) , 2.54 (s, 1H) , 1.20 (s, 4H) .

Compound 491

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-2- (thiazol-2-yl) acrylonitrile (491)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (100 mg, 0.51 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 2- (thiazol-2-yl) acetonitrile (63 mg, 0.51 mmol) in THF (10 mL) was added LiHMDS (1.3 mL, 1.26 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by AcOH and extracted with EA (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H₂O/MeCN=6/4, 0.1%TFA, 2 times) to obtain the product 491 (8.6 mg, HPLC: 95.399%) .. MS [M+H] ⁺ calcd for C₁₂H₆ClN₅OS 304.0, found 304.0. ¹HNMR (400 MHz, DMSO-d₆) δ 13.58 (s, 1H) , 8.27 (s, 1H) , 7.82 (s, 1H) , 7.63 (s, 1H) , 7.33 (s, 1H) .

Compound 147

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N-methylacrylamide (147)

The title compound was prepared in 12%yield from 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₈H₁₂ClF₂N₅O₂ 404.1, found 404.1. ¹HNMR (400 MHz, DMSO-d₆) δ8.25 (s, 1H) , 7.64 (s, 1H) , 7.43-7.31 (m, 3H) , 4.76 (s, 2H) , 3.17 (s, 3H) .

Compound 166

(Z) -3- (7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methylacrylamide (166)

The title compound was prepared in 2.2%yield from 7-chlorobenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₈H₁₂Cl₂FN₅O₂ 420.0, found 420.0. ¹HNMR (400 MHz, MeOD) δ 7.91 (d, J = 8.5 Hz, 1H) , 7.62 (d, J = 8.4 Hz, 1H) , 7.42 (t, J = 7.6 Hz, 1H) , 7.37 –7.33 (m, 1H) , 7.16 (t, J = 9.2 Hz, 1H) , 3.25 (s, 2H) , 1.28 (s, 3H) .

Compound 167

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N-methylacrylamide (167)

The title compound was prepared in 1.4%yield from 7-chlorobenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ^-calcd for C₁₈H₁₂ClF₂N₅O₂ 404.1, found 404.0. ¹H NMR (400 MHz, MeOD) δ 7.69 (d, J = 8.6 Hz, 1H) , 7.65 (d, J = 8.6 Hz, 1H) , 7.38 –7.36 (m, 2H) , 7.31 (dd, J = 7.9, 3.5 Hz, 2H) , 7.11 (s, 2H) , 4.83 (s, 3H) , 1.25 (s, 3H) .

Compound 39

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide (39)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl₂ (5 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 2-cyano-N, N-dimethylacetamide (34 mg, 0.30 mmol) in THF (5 mL) was added LiHMDS (0.6 mL, 0.63 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H₂O/MeCN=7/3, 0.1%TFA) to obtain the product 39 (10.8 mg, HPLC: 96.604%) .. MS [M+H] ⁺ calcd for C₁₂H₁₀ClN₅O₂ 292.1, found 292.0. ¹HNMR (400 MHz, MeOD-d4) δ 8.43 (s, 1H) , 7.94 (s, 1H) , 3.27 (s, 6H)

Compound 36

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-N, N-diethyl-3-hydroxyacrylamide (36)

The title compound was prepared in 14.9%yield from 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-diethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₄H₁₄ClN₅O₂ 320.1, found 320.1. ¹HNMR (400 MHz, MeOD) δ 8.41 (s, 1H) , 7.89 (s, 1H) , 3.60 (d, J = 6.3 Hz, 4H) , 1.22 (t, J = 6.0 Hz, 6H) .

Compounds B-1 and B-2

(Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-N, N-diethylacrylamide (B-1) and (E) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-N, N-diethylacrylamide (B-2)

Step 1: Synthesis of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carbaldehyde (2)

To a solution of 6-bromo-4-chloro-1H-benzo [d] [1, 2, 3] triazole (500 mg, 2.16 mmol) in dry DMF (10 mL) was added n-butyl isocyanide (358 mg, 4.31 mmol) , HCOOK (362 mg, 4.31 mmol) , Johnphos (128 mg, 0.43 mmol) and Pd (OAc) ₂ (49 mg, 0.22 mmol) was stirred at same temperature and stirring at 65 ℃ for overnight. The reaction mixture was extracted with EA (50 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/2) to obtain the product (120 mg, 31%) . MS [M+H] ⁺ calcd for C₇H₄ClN₃O 182.2, found 182.2.

Step 2: Synthesis of (Z) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-N, N-diethylacrylamide (B-1) and (E) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-N, N-diethylacrylamide (B-2)

To a solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carbaldehyde (120 mg, 0.66 mol) in i-PrOH (5 mL) was added 2-cyano-N, N-diethylacetamide (77 mg, 0.55 mmol) and piperidine (6 mg, 0.07 mmol) at rt and stirring at 85 ℃ for overnight. The reaction mixture was filtration to obtain the crude product. The residue was purified by Prep-HPLC (H2O/MeCN=7/3, 0.1%TFA, 2 times) to obtain the product B-1 (4.4 mg, HPLC: 97.749%) MS [M+H] + calcd for C14H14ClN5O 304.0, found 304.0. 1HNMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H) , 7.89 (s, 1H) , 7.57 (s, 1H) , 3.44 (q, J = 7.0 Hz, 2H) , 3.26 (q, J = 7.0 Hz, 2H) , 1.14 (t, J = 7.1 Hz, 3H) , 0.98 (t, J = 7.1 Hz, 3H) , and the product B-2 (16.1 mg, HPLC: 95.551%) . MS [M+H] + calcd for C14H14ClN5O 304.0, found 304.0. 1HNMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H) , 8.05 (s, 1H) , 7.93 (s, 1H) , 3.45 (d, J = 6.9 Hz, 4H) , 1.16 (d, J = 13.6 Hz, 6H) .

Compound 41

(Z) -2-cyano-3- (4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N, N-dimethylacrylamide (41) The title compound was prepared in 3.6%yield from 4-fluoro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺calcd for C₁₂H₁₀FN₅O₂ 276.1, found 276.1. ¹HNMR (400 MHz, MeOD) δ 8.26 (s, 1H) , 7.60-7.62 (m, 1H) , 3.25 (s, 6H) .

Compound 42

(Z) -3- (4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide (42)

The title compound was prepared in 3.52%yield from 4-bromo-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS[M+2] ⁺ calcd for C₁₂H₁₀BrN₅O₂ 338.0, found 338.0. ¹HNMR (400 MHz, MeOD) δ 8.47 (s, 1H) , 8.09 (s, 1H) , 3.27 (s, 6H) .

Compound 48

(Z) -2-cyano-3-hydroxy-N, N-dimethyl-3- (4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (48)

The title compound was prepared in 3.3%yield from 4-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺calcd for C₁₃H₁₃N₅O₂ 272.1, found 272.1. ¹HNMR (400 MHz, MeOD) δ 8.28 (s, 1H) , 7.69 (s, 1H) , 3.25 (s, 6H) , 2.73 (s, 3H) .

Compound 43

(Z) -2-cyano-3-hydroxy-3- (4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl) -N, N-dimethylacrylamide (43)

The title compound was prepared in 21.5%yield from 4-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₃H₁₃N₅O₃ 288.1, found 288.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.07-8.13 (m, 1H) , 7.21 (s, 1H) , 4.06 (s, 3H) , 3.17 (s, 6H) .

Compound 154

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxy-N-methylacrylamide (154)

The title compound was prepared in 2.73%yield from 4-ethyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₀H₁₇ClFN₅O₂ 412.1, found 411.7. ¹HNMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H) , 7.49 (s, 1H) , 7.40 –7.30 (m, 2H) , 7.20 (t, J = 9.4 Hz, 1H) , 4.67 (s, 2H) , 3.09 (s, 3H) , 3.03 (d, J = 6.7 Hz, 2H) , 1.32 (t, J = 7.4 Hz, 3H) .

Compound 37

(Z) -2-cyano-N, N-diethyl-3-hydroxy-3- (4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (37)

The title compound was prepared in 0.92%yield from 4-nitro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-diethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₄H₁₄N₆O₄ 331.1 , found 331.1. ¹HNMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H) , 8.74 (s, 1H) , 3.63 (s, 4H) , 1.23 (s, 6H) .

Compound C-1 and C-2

(E) -2-cyano-N, N-diethyl-3- (4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (C-1) and (Z) -2-cyano-N, N-diethyl-3- (4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (C-2)

Step 1: Synthesis of 6-bromo-4-nitro-1H-benzo [d] [1, 2, 3] triazole (2)

A solution of 5-bromo-3-nitrobenzene-1, 2-diamine (2 g, 8.62 mmol) , NaNO₂ (595 mg, 8.62 mmol) in AcOH (20 mL) was stirred under N₂ at RT for 30 min. After addition, the reaction was warmed to 65 ℃ and stirred for 2.5 h. The reaction was extracted by EA (100 mL*3) , dried by Na₂SO₄. The combined organic phases were concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/1) to obtain the product (600 mg, 29%) . MS [M+H] ⁺ calcd for C₆H₃BrN₄O₂ 242.9, found 242.9.

Step 2: Synthesis of 4-nitro-6-vinyl-1H-benzo [d] [1, 2, 3] triazole (3)

A solution of 6-bromo-4-nitro-1H-benzo [d] [1, 2, 3] triazole (340 mg, 1.40 mmol) , trifluoro (vinyl) borate potassium (I) (399 mg, 4.20 mmol) , K₃PO₄ (594 mg, 2.80 mmol) and Pd (dppf) Cl₂·DCM (114 mg, 0.14 mmol) in dioxane (5 mL) and H₂O (1 mL) was stirred under N₂ at 100 ℃ for 3 h. The reaction solution is removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product (180 mg, 67%) . MS [M+H] ⁺ calcd for C₈H₆N₄O₂ 191.0, found 191.0.

Step 3: Synthesis of 4-nitro-1H-benzo [d] [1, 2, 3] triazole-6-carbaldehyde (5)

To a solution of 4-nitro-6-vinyl-1H-benzo [d] [1, 2, 3] triazole (180 mg, 0.95 mmol) in dioxane (2 mL) and H₂O (5 mL) was added NaIO₄ (1007 mg, 4.75 mmol) , K₂OsO₄ (69 mg, 0.19 mmol) dropwise at 0 ℃ for 10 min. After addition, the reaction was warmed to RT and stirred for 1 h. The mixture was quenched by ice, extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/8) to obtain the product (65 mg, 36%) . MS [M+H] ⁺ calcd for C₇H₄N₄O₃ 193.0, found 193.0.

Step 4: Synthesis of (E) -2-cyano-N, N-diethyl-3- (4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (C-1) and (Z) -2-cyano-N, N-diethyl-3- (4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (C-2)

A solution of 4-nitro-1H-benzo [d] [1, 2, 3] triazole-6-carbaldehyde (65 mg, 0.34 mmol) , Piperidine (3 mg, 0.03 mmol) , 2-cyano-N, N-diethylacetamide (40 mg, 0.29 mmol) in i-PrOH (4 mL) was stirred under N₂ at 85 ℃ for 16 h . The reaction solution is removed in vacuo to afford crude product. The residue was purified by Prep-HPLC (H₂O/MeCN=7/3, 0.1%FA) to obtain the product C-1 (3.02 mg, HPLC: 96.327%) . MS [M+H] ⁺ calcd for C₁₄H₁₄N₆O₃ 315.1 , found 315.1 ¹H NMR (400 MHz, DMSO-d6) δ 8.89 –8.87 (m, 2H) , 7.91 (s, 1H) , 3.56-3.52 (m, 4H) , 1.30 –1.19 (m, 6H) and the product C-2 (1.75 mg, HPLC: 96.486%) . MS [M+H] ⁺ calcd for C₁₄H₁₄N₆O₃ 315.1, found 315.1 ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H) , 8.39 (s, 1H) , 7.98 (s, 1H) , 3.46 (m, 2H) , 3.17 (m, 2H) , 1.15 (t, J = 7.1 Hz, 3H) , 1.00 (t, J = 7.1 Hz, 3H) .

Compound 47

(Z) -2-cyano-3-hydroxy-N, N-dimethyl-3- (4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (47)

The title compound was prepared in 5.06%yield from 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₃H₁₀F₃N₅O₂ 326.1, found 326.0. ¹HNMR (400 MHz, MeOD) δ 8.78 (s, 1H) , 8.24 (s, 1H) , 3.26 (s, 6H) .

Compound 485

(Z) -2- (3-azabicyclo [3.1.0] hexane-3-carbonyl) -3- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl) -3-hydroxyacrylonitrile (485)

A solution of 4-chloro-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of 3- (3-azabicyclo [3.1.0] hexan-3-yl) -3-oxopropanenitrile (46 mg, 0.30 mmol) in THF (5 mL) was added LiHMDS (0.6 mL, 0.63 mmol) dropwise at -78 ℃ under N2 atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (30 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H₂O/MeCN=7/3, 0.1%TFA) to obtain the product 485 (12.45 mg, HPLC: 96.491%) .. MS [M+H] ⁺ calcd for C₁₅H₁₂ClN₅O₂ 330.1 , found 330.1.¹NMR (400 MHz, MeOD-d4) δ 8.42 (s, 1H) , 7.93 (s, 1H) , 4.15 (d, J = 10.5 Hz, 2H) , 3.82 (s, 2H) , 1.76 (s, 2H) , 0.87 (d, J = 5.7 Hz, 1H) , 0.23 (d, J = 3.4 Hz, 1H) .

Compound 73

(Z) -3- (4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide

The title compound was prepared in 13.8%yield from 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C13H12ClN5O2 306.1 , found 330.1.¹NMR (400 MHz, MeOD-d4) δ 7.58 (s, 1H) , 3.25 (s, 6H) , 2.77 (s, 3H) .

Compound 74

(Z) -3- (4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide

The title compound was prepared in 9.2%yield from 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and 2-cyano-N, N-dimethylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C13H12ClN5O3 322.1 , found 322.1.¹NMR (400 MHz, MeOD-d4) δ 7.53 (s, 1H) , 4.63 (s, 3H) , 3.23 (s, 6H) .

Compound 298

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (1-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl) acrylamide (298)

The title compound was prepared in 48.0%yield from 1-methyl-1H-benzo [d] [1, 2, 3] triazole-6-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₅ClFN₅O₂ 400.1, found 400.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H) , 8.15 (d, J = 6.6 Hz, 1H) , 7.71 (s, 1H) , 7.41 (s, 2H) , 7.28 (s, 1H) , 4.74 (s, 2H) , 4.34 (s, 5H) , 3.14 (s, 3H) .

Compound 526

(Z) -N- (5-chloro-2-fluorobenzyl) -3- (7-chlorobenzo [d] isoxazol-5-yl) -2-cyano-3-hydroxy-N-methylacrylamide (526)

The title compound was prepared in 18.5%yield from 7-chlorobenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₁₉H₁₂Cl₂FN₃O₃ 418.0, found 418.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.10 (s, 2H) , 7.39-7.27 (m, 4H) , 4.70 (s, 2H) , 3.09 (s, 3H) .

Compound 533

(Z) -N- (1- (5-chloro-2-fluorophenyl) ethyl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (533)

The title compound was prepared in 13.3%yield from 7-methylbenzo [d] isoxazole-5-carboxylic acid and N- (1- (5-chloro-2-fluorophenyl) ethyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₁H₁₇ClFN₃O₃ 412.1, found 412.0. ¹HNMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H) , 7.98 (s, 1H) , 7.81 (s, 1H) , 7.51 (s, 1H) , 7.43 (s, 2H) , 7.26 (s, 1H) , 5.76 (m, 1H) , 2.87 (s, 3H) , 2.24 (s, 3H) , 1.55 (d, J = 5.8 Hz, 3H) .

Compound 534 and 535

(R, Z) -N- (1- (5-chloro-2-fluorophenyl) ethyl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (535) and (S, Z) -N- (1- (5-chloro-2-fluorophenyl) ethyl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (534)

Compound 533 was purified by Chiral-HPLC to obtain the product 535: MS [M-H] ^-calcd for C₂₁H₁₇ClFN₃O₃ 412.1, found 412.1. ¹H NMR ¹HNMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H) , 7.77 (s, 1H) , 7.50 (s, 1H) , 7.42 (d, J = 2.8 Hz, 2H) , 7.24 (t, J = 8.7 Hz, 1H) , 5.73 (s, 1H) , 2.85 (d, J = 4.9 Hz, 3H) , 2.22 (s, 3H) , 1.53 (s, 3H) . and the product 534: MS [M-H] ^-calcd for C₂₁H₁₇ClFN₃O₃ 412.1, found 412.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.00 –7.87 (m, 1H) , 7.78 (s, 1H) , 7.51 (s, 1H) , 7.42 (s, 2H) , 7.25 (s, 1H) , 5.75 (s, 1H) , 2.85 (s, 3H) , 2.22 (s, 3H) , 1.54 (s, 3H) .

Compound 4

(Z) -3- (benzo [d] isoxazol-5-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methylacrylamide (4)

The title compound was prepared in 18.5%yield from benzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₉H₁₃ClFN₃O₃ 384.1, found 383.6. ¹HNMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H) , 7.89-8.22 (m, 2H) , 7.05-7.48 (m, 5H) , 4.75 (s, 2H) , 3.09 (s, 3H) .

Compound 5

(Z) -3- (benzo [d] isoxazol-5-yl) -2-cyano-N- (2-fluoro-5-methylbenzyl) -3-hydroxy-N-methylacrylamide (5)

The title compound was prepared in 11.0%yield from benzo [d] isoxazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₀H₁₆FN₃O₃ 366.1, found 366.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H) , 7.94 (d, J = 7.7 Hz, 1H) , 7.19 –7.07 (m, 5H) , 4.74 (s, 2H) , 3.13 (s, 3H) , 2.28 (s, 3H) .

Compound 527

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (527)

The title compound was prepared in 10.1%yield from 7-methylbenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27.MS [M-H] ^-calcd for C₂₀H₁₅ClFN₃O₃ 397.6, found 397.6. ¹HNMR (400 MHz, DMSO-d₆) δ 7.99 (s, 1H) , 7.83 (s, 1H) , 7.43 (s, 3H) , 7.32 (d, J = 9.0 Hz, 1H) , 4.75 (s, 2H) , 3.14 (s, 3H) , 2.27 (s, 3H) .

Compound 542

(Z) -3- (benzo [d] isoxazol-5-yl) -N- (2- (2-chlorophenoxy) ethyl) -2-cyano-3-hydroxy-N-methylacrylamide (542)

The title compound was prepared in 19.1%yield from benzo [d] isoxazole-5-carboxylic acid and N- (2- (2-chlorophenoxy) ethyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^- calcd for C₂₀H₁₆ClN₃O₄ 396.1, found 396.1. ¹HNMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H) , 8.08 (s, 1H) , 7.89 (d, J = 8.2 Hz, 1H) , 7.38 (dd, J = 7.9, 1.5 Hz, 1H) , 7.31 –7.24 (m, 1H) , 7.16-7.09 (m, 3H) , 6.93 (td, J = 7.7, 1.3 Hz, 1H) , 4.28 (s, 2H) , 3.95 (s, 2H) , 3.30 (s, 3H) .

Compound 531

(Z) -3- (benzo [d] isoxazol-5-yl) -2-cyano-N- (2-fluoro-5- (trifluoromethyl) benzyl) -3-hydroxy-N-methylacrylamide (531)

The title compound was prepared in 5.2%yield from benzo [d] isoxazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5- (trifluoromethyl) benzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₀H₁₃F₄N₃O₃ 418.1, found 418.1. ¹HNMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H) , 8.14 (s, 1H) , 7.91-7.73 (m, 4H) , 7.50 (t, J = 9.0 Hz, 1H) , 7.14 (d, J = 5.7 Hz, 1H) , 4.83 (s, 2H) , 3.14 (s, 3H) .

Compound 532

(Z) -2-cyano-N- (5-cyano-2-fluorobenzyl) -3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (532)

The title compound was prepared in 34.6%yield from benzo [d] isoxazole-5-carboxylic acid and 2-cyano-N- (5-cyano-2-fluorobenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₁H₁₅FN₄O₃ 389.1, found 389.1. ¹HNMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H) , 7.96 (s, 1H) , 7.88 (dd, J = 7.1, 4.1 Hz, 2H) , 7.79 (t, J = 13.9 Hz, 2H) , 7.46 (t, J = 9.1 Hz, 1H) , 4.72 (d, J = 26.4 Hz, 2H) , 3.13 (s, 3H) , 2.24 (s, 3H) .

Compound 529

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (7-methoxybenzo [d] isoxazol-5-yl) -N-methylacrylamide (529)

The title compound was prepared in 5.3%yield from 7-methoxybenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27.MS [M-H] ^-calcd for C₂₀H₁₅ClFN₃O₄ 414.1, found 414.1. ¹HNMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H) , 7.73 –7.61 (m, 2H) , 7.43-7.29 (m, 4H) , 4.75 (s, 2H) , 3.91 (s, 3H) , 3.16 (s, 3H) .

Compound 528

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (7-hydroxybenzo [d] isoxazol-5-yl) -N-methylacrylamide (528)

To a solution of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (7-methoxybenzo [d] isoxazol-5-yl) -N-methylacrylamide (60 mg, 0.14 mmol) in DCM (10 mL) was added BBr₃ (0.80 mL, 0.72 mmol) dropwise at 0 ℃ for 15 mins. After addition, the reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by EA (50 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=7/3, 0.1%TFA, 2 times) to obtain the product (33.2 mg, HPLC: 95.176%) . MS [M-H] ^-calcd for C₁₉H₁₃ClFN₃O₄ 400.1, found 399.6. ¹H NMR (400 MHz, DMSO) δ 10.78 (s, 1H) , 7.57 (t, J = 12.1 Hz, 1H) , 7.42 (s, 3H) , 7.32 (d, J = 8.3 Hz, 2H) , 4.74 (s, 2H) , 3.14 (s, 3H) .

Compound 536

(Z) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) -N- ( (1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) acrylamide (536)

The title compound was prepared in 0.86%yield from 7-methoxybenzo [d] isoxazole-5-carboxylic acid and 2-cyano-N-methyl-N- ( (1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) acetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₁H₁₈ClN₃O₄ 413.1, found 413.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H) , 7.99 (s, 1H) , 7.88 (d, J = 7.9 Hz, 2H) , 7.82 (s, 1H) , 7.57 (dd, J = 10.7, 5.0 Hz, 3H) , 7.46 (t, J = 7.4 Hz, 1H) , 4.81 (s, 2H) , 3.23 (s, 3H) , 2.24 (s, 3H) .

Compound 545

(Z) -N- (3- (2-chlorophenyl) prop-2-yn-1-yl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (545)

The title compound was prepared in 0.86%yield from 7-methoxybenzo [d] isoxazole-5-carboxylic acid and N- (3- (2-chlorophenyl) prop-2-yn-1-yl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₁H₁₈ClN₃O₄ 414.1, found 403.9. ¹HNMR (400 MHz, DMSO-d₆) δδ7.56 (d, J = 8.1 Hz, 3H) , 7.43 (td, J = 7.8, 1.8 Hz, 2H) , 7.36 (dd, J = 8.0, 7.0 Hz, 2H) , 4.63 (s, 2H) , 3.27 (s, 3H) , 2.27 (s, 3H) .

Compound 543

(Z) -N- (2- (2-chlorophenoxy) ethyl) -2-cyano-3-hydroxy-N-methyl-3- (7-methylbenzo [d] isoxazol-5-yl) acrylamide (543)

The title compound was prepared in 1.6%yield from 7-methoxybenzo [d] isoxazole-5-carboxylic acid and N- (2- (2-chlorophenoxy) ethyl) -2-cyano -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^-calcd for C₂₁H₁₈ClN₃O₄ 412.1, found 412.1. ¹HNMR (400 MHz, DMSO-d₆) δ7.94 (s, 1H) , 7.79 (s, 1H) , 7.31-7.41 (m, 1H) , 7.20-7.29 (m, 3H) , 6.95-6.99 (m, 1H) , 4.31 (s, 2H) , 3.97 (s, 2H) , 3.33 (s, 3H) , 2.26 (s, 3H) .

Compound 538

(Z) -3- (benzo [d] isoxazol-5-yl) -2- (4- (3-chlorophenyl) piperidine-1-carbonyl) -3-hydroxyacrylonitrile (538)

The title compound was prepared in 35.9%yield from benzo [d] isoxazole-5-carboxylic acid and 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₂H₁₈ClN₃O₃ 406.1, found 406.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H) , 7.95 (s, 1H) , 7.36–7.26 (m, 5H) , 7.15 (d, J = 8.0 Hz, 1H) , 4.49 (s, 2H) , 3.11 (s, 2H) , 2.91 (s, 1H) , 1.88 (s, 2H) , 1.69 (s, 2H) .

Compound 541

(Z) -3- (benzo [d] isoxazol-5-yl) -2-cyano-3-hydroxy-N-methyl-N- (2-phenoxyethyl) acrylamide (541)

The title compound was prepared in 2.2%yield from benzo [d] isoxazole-5-carboxylic acid and 2-cyano-N-methyl-N- (2-phenoxyethyl) acetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺calcd for C₂₀H₁₇N₃O₄ 364.1, found 364.2. ¹HNMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H) , 8.07 (d, J = 91.9 Hz, 1H) , 7.31 –7.27 (m, 2H) , 7.14 –7.12 (m, 1H) , 6.97 –6.93 (m, 4H) , 4.22 (s, 2H) , 3.91 (s, 2H) , 3.25 (s, 3H) .

Compound 3

(Z) -3- (benzo [d] isoxazol-5-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-N-ethyl-3-hydroxyacrylamide (3)

The title compound was prepared in 34.6%yield from benzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-ethylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^- calcd for C₂₀H₁₅ClFN₃O₃ 398.1, found 397.6. ¹HNMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H) , 8.12 (s, 1H) , 7.90 (d, J = 7.9 Hz, 1H) , 7.40 (d, J = 9.6 Hz, 2H) , 7.30 (t, J = 9.1 Hz, 2H) , 7.14 (d, J = 8.6 Hz, 1H) , 4.75 (s, 2H) , 3.58 (s, 2H) , 1.19 (s, 3H) .

Compound 544

(Z) -3- (benzo [d] isoxazol-5-yl) -N- (2- (2-chlorophenoxy) ethyl) -2-cyano-N-ethyl-3-hydroxyacrylamide (544)

The title compound was prepared in 29.1%yield from benzo [d] isoxazole-5-carboxylic acid and N- (2- (2-chlorophenoxy) ethyl) -2-cyano-N-ethylacetamide to the procedure for preparation of Compound 27. MS [M-H] ^- calcd for C₁₂H₁₈ClN₃O₄ 410.1, found 410.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H) , 7.88 (d, J = 8.2 Hz, 1H) , 7.39 (d, J = 7.6 Hz, 1H) , 7.27 (d, J = 7.5 Hz, 1H) , 7.16-7.09 (m, 3H) , 6.95 (d, J = 7.3 Hz, 1H) , 4.28 (s, 2H) , 3.93 (s, 2H) , 3.75 (s, 2H) , 1.21 (d, J = 6.5 Hz, 3H) .

Compound 323

(Z) -3- (benzo [d] isoxazol-5-yl) -3-hydroxy-2- (4-phenylpiperidine-1-carbonyl) acrylonitrile (323)

The title compound was prepared in 1.7%yield from benzo [d] isoxazole-5-carboxylic acid and 3-oxo-3-(4-phenylpiperidin-1-yl) propanenitrile to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₂H₁₉N₃O₃ 374.1, found 374.2. ¹HNMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H) , 8.20 (s, 1H) , 7.96 (d, J = 7.5 Hz, 1H) , 7.29-6.97 (m, 7H) , 4.49 (d, J = 12.7 Hz, 2H) , 3.13 (s, 2H) , 2.88 (s, 1H) , 1.90 (d, J = 10.9 Hz, 2H) , 1.66 (d, J = 11.1 Hz, 2H) .

Compound 537

(Z) -3- (benzo [d] isoxazol-5-yl) -3-hydroxy-2- (4- (pyridin-4-yl) piperidine-1-carbonyl) acrylonitrile (537)

The title compound was prepared in 13.9%yield from benzo [d] isoxazole-5-carboxylic acid and 3-oxo-3- (4- (pyridin-4-yl) piperidin-1-yl) propanenitrile to the procedure for preparation of Compound 27. MS [M-H] ^- calcd for C₂₂H₁₉N₃O₃ 373.1, found 372.8. ¹HNMR (400 MHz, DMSO-d₆) ¹H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 2H) , 7.97-7.88 (m, 2H) , 7.26-6.97 (m, 4H) , 3.03-2.94 (m, 4H) , 2.08-1.73 (m, 4H) , 1.23 (s, 1H) .

Compound 539

(Z) -2- (4- (3-chlorophenyl) piperidine-1-carbonyl) -3-hydroxy-3- (7-methylbenzo [d] isoxazol-5-yl) acrylonitrile (539)

The title compound was prepared in 11.7%yield from 7-methylbenzo [d] isoxazole-5-carboxylic acid and 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile to the procedure for preparation of Compound 27.MS [M-H] - calcd for C₂₃H₂₀ClN₃O₃ 420.1, found 420.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H) , 7.83 (s, 1H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.28 –7.06 (m, 3H) , 4.45 (d, J = 12.3 Hz, 2H) , 3.08 (t, J = 12.0 Hz, 2H) , 2.91 –2.81 (m, 1H) , 2.25 (s, 3H) , 1.86 (d, J = 11.1 Hz, 2H) , 1.64 (d, J = 11.4 Hz, 2H) .

Compound 525

(Z) -3- (benzo [d] isoxazol-5-yl) -2-cyano-3-hydroxy-N, N-dimethylacrylamide (525)

The title compound was prepared in 3.5%yield from benzo [d] isoxazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₁₃H₁₁N₃O₃ 258.1, found 258.2. ¹HNMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H) , 8.18 (s, 1H) , 7.96 (d, J = 8.0 Hz, 1H) , 7.14 (d, J = 8.7 Hz, 2H) , 3.15 (s, 6H) .

Compound 34

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methyl-3- (3-methylbenzo [d] isoxazol-5-yl) acrylamide (34)

The title compound was prepared in 22.4%yield from 3-methylbenzo [d] isoxazole-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₀H₁₅ClFN₃O₃ 400.1, found 400.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H) , 8.03 (s, 1H) , 7.87 (s, 1H) , 7.44-7.31 (m, 3H) , 4.77 (s, 2H) , 3.17 (s, 3H) , 2.60 (s, 3H) .

Compound 32

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3- (1, 3-dioxoisoindolin-5-yl) -3-hydroxy-N-methylacrylamide (32)

The title compound was prepared in 22.4%yield from 1, 3-dioxoisoindoline-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [M+Na] ⁺ calcd for C₂₀H₁₃ClFN₃O₄ 436.1, found 436.0. ¹H NMR (400 MHz, DMSO) δ 11.56 (s, 1H) , 8.15 (s, 2H) , 7.98 (s, 1H) , 7.43 (s, 2H) , 7.31 (s, 1H) , 4.75 (s, 2H) , 3.14 (s, 3H) .

Compound 30

(Z) -2-cyano-N- (2-fluoro-5-methylbenzyl) -3-hydroxy-N-methyl-3- (2-oxo-2, 3-dihydrobenzo [d] oxazol-5-yl) acrylamide (30)

The title compound was prepared in 7.2%yield from 2-oxo-2, 3-dihydrobenzo [d] oxazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N -methylacetamide to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₀H₁₆FN₃O₄ 382.1, found 382.1. ¹HNMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H) , 7.55 (s, 1H) , 7.47 (s, 2H) , 7.16-7.08 (m, 3H) , 4.73 (s, 2H) , 3.13 (s, 3H) , 2.28 (s, 3H) .

Compound 10

(Z) -3- (benzo [d] oxazol-5-yl) -2-cyano-N- (2-fluoro-5-methylbenzyl) -3-hydroxy-N-methylacrylamide (10)

The title compound was prepared in 21.4%yield from benzo [d] oxazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H]^- calcd for C₂₀H₁₆FN₃O₃ 364.1, found 363.6. ¹HNMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H) , 8.02 (s, 1H) , 7.76 (s, 1H) , 7.22 –6.99 (m, 4H) , 4.60 (s, 2H) , 2.97 (s, 3H) , 2.28 (s, 3H) .

Compound 11

(Z) -3- (benzo [d] oxazol-6-yl) -2-cyano-N- (2-fluoro-5-methylbenzyl) -3-hydroxy-N-methylacrylamide (11)

The title compound was prepared in 9.6%yield from benzo [d] oxazole-6-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H]^- calcd for C₂₀H₁₆FN₃O₃ 364.1, found 364.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H) , 7.79 (s, 1H) , 7.24 –6.98 (m, 5H) , 4.60 (s, 2H) , 2.98 (s, 3H) , 2.27 (s, 3H) .

Compound 21

(Z) -3- (benzo [c] [1, 2, 5] oxadiazol-5-yl) -2-cyano-N- (2-fluoro-5-methylbenzyl) -3-hydroxy-N-methylacrylamide (21)

The title compound was prepared in 21.6%yield from benzo [c] [1, 2, 5] oxadiazole-5-carboxylic acid and 2-cyano-N- (2-fluoro-5-methylbenzyl) -N-methylacetamide to the procedure for preparation of Compound 27. MS [M-H] ⁺ calcd for C₁₉H₁₅FN₄O₃ 365.1, found 364.7. ¹HNMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H) , 8.25 (s, 1H) , 7.83 (s, 1H) , 7.22-7.10 (m, 3H) , 4.74 (s, 2H) , 3.12 (s, 3H) , 2.28 (s, 3H) .

Compound 16

(Z) -3- ( [1, 2, 3] triazolo [1, 5-a] pyridin-5-yl) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-N-methylacrylamide (16)

The title compound was prepared in 4.1%yield from [1, 2, 3] triazolo [1, 5-a] pyridine-5-carboxylic acid and N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide to the procedure for preparation of Compound 27. MS [MH] ⁺ calcd for C₁₈H₁₃ClFN₅O₂ 386.0, found 386.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H) , 8.42 (s, 2H) , 7.42-7.29 (m, 4H) , 4.74 (s, 2H) , 3.13 (s, 3H) .

Compound 35

(Z) -3- ( [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl) -2- (4- (3-chlorophenyl) piperidine-1-carbonyl) -3-hydroxyacrylonitrile (35)

The title compound was prepared in 15.2%yield from [1, 2, 4] triazolo [4, 3-a] pyridine-6-carboxylic acid and 3- (4- (3-chlorophenyl) piperidin-1-yl) -3-oxopropanenitrile to the procedure for preparation of Compound 27. MS [M+H] ⁺ calcd for C₂₁H₁₈ClN₅O₂ 408.1, found 408.1. ¹HNMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H) , 7.70 (s, 1H) , 7.33-6.96 (m, 7H) , 4.24 (d, J = 9.6 Hz, 2H) , 2.77 (m, 3H) , 1.74 (m, 4H)

Compound 540

(Z) -3- (benzo [d] isoxazol-5-yl) -3-hydroxy-2- (4- (phenylamino) piperidine-1-carbonyl) acrylonitrile

Step 1: Synthesis of tert-butyl (Z) - (1- (3- (benzo [d] isoxazol-5-yl) -2-cyano-3-hydroxyacryloyl) piperidin-4-yl) (phenyl) carbamate (2)

A solution of benzo [d] isoxazole-5-carboxylic acid (62 mg, 0.4 mmol) in SOCl₂ (10 mL) was stirred at 80 ℃ for 2 hours. After then it was concentrated in vacuo to give the crude intermediate. To a solution of tert-butyl (1- (2-cyanoacetyl) piperidin-4-yl) (phenyl) carbamate (130 mg, 0.4 mmol) in THF (15 mL) was added LiHMDS (0.9 mL, 0.9 mmol) dropwise at -78 ℃ under N₂ atmosphere. After addition the mixture was stirred at same temperature for another 1 hour. After then, the crude intermediate was added to above solution at -78 ℃ and stirred at RT overnight. The reaction mixture was quenched by HCl and extracted with DCM (20 mL x 3) . The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=15/1) to obtain the product (50 mg, 27%) . MS [M+H] ⁺ calcd for C₂₇H₂₈N₄O₅ 488.9, found 488.9.

Step 2: Synthesis of (Z) -3- (benzo [d] isoxazol-5-yl) -3-hydroxy-2- (4- (phenylamino) piperidine-1-carbonyl) acrylonitrile (540)

A mixture of tert-butyl 4- (phenylamino) piperidine-1-carboxylate (1 g, 3.6 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at rt for 2 hours. The reaction mixture concentrated in vacuo to dryness, then was purified by Prep-HPLC (H2O/MeCN=5/5, 0.1%TFA, 2 times) to obtain the product (5 mg, HPLC: 98.62%) . MS [M+H] ⁺ calcd for C₂₂H₂₀N₄O₃ 389.1, found 389.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H) , 7.86 (s, 1H) , 7.07 –6.99 (m, 4H) , 6.56 (d, J = 7.9 Hz, 2H) , 6.48 (d, J = 7.2 Hz, 1H) , 4.14 (s, 2H) , 3.49 (s, 1H) , 3.17 (s, 2H) , 1.94 (d, J = 7.0 Hz, 2H) , 1.34-1.31 (m, 2H) .

The following compounds were synthezied in similar manners.

Biological Assay

FTO inhibition Assay (Enzymatic Inhibition) . The inhibition assay was adapted from a publication about Maz-F coupled FTO demethylase activity assay (Chem Commun. 2017 Nov 30; 53 (96) : 12930-12933. doi: 10.1039/c7cc07699a) . FTO-catalyzed demethylation activity was measured in a 10 μl reaction system containing 20 mM HEPES buffer (pH 7.5) , 20 μM a-KG, 10 μM (NH4) 2Fe (SO4) 2, 1.5 mM L-ascorbic acid, 2 μM DRNA with m6A (5'-FAM-d (CAT) r (GG-m6A-CA) d (TATGT) -BHQ1-3') , 0.15 μM FTO protein. The reaction system was incubated at 32℃ for 45 min. Aliquot MazF into each well above (40 ul 1×Maz-F+ 10 ul the reaction /well) , the final concentration is 50 nM, and the reaction system was incubated at 37℃ for 25 min. MazF cleaves only nonmethylated DRNA (-ACA-) , permitting specific detection of the methylation states of DRNA. Maz-F readily cleaves the DRNA and eventually liberates 5’-FAM, which gives a strong fluorescence signal around 535 nm (485 nm excitation-535 emission) .

COMT Inhibition Assay. The inhibition of the compounds against COMT was measured in the reaction kinetic model. The test compound was diluted with assay buffer to desired concentration. The COMT enzyme was also diluted with assay buffer. Then 5 μL diluted test article, 5 μL diluted COMT and 5 μL Esculetin were added into plate and incubated for 5 min at 37℃, sealed with TopSeal-A384, Clear Adhesive (PE) . Then 5 μL AdoMet was added into the plate. The reaction system contains 1U COMT enzyme, test compound, 4 μM Esculetin, 0.6 mM AdoMet, 50 mM K₃PO₄, and 10 mM MgCl₂. Read plate by using kinetics model (Excitation at 360 nm &emission at 460 nm) . The inhibition was calculated from the slope.

As expect, deuteration did not alter in vitro enzymatic inhbition of the compounds of the present invention.

Table 1: FTO IC50s of the representative compounds

INACTIVE means compounds do not have inhibition dose response curve, even up to 10μM or higher.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and Examples should not be construed as limiting the scope of the invention.

Claims

A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a deuterated analog thereof,

wherein

X¹, X², and X³, are each independently -O-, -S-, -NH-, -N=, -CH=, or -CH₂-, provided that no two -O-and/or -S-are adjacent,

X⁴, X⁵, X⁶ are each independently -CH= or -N=,

X⁷ and X⁸ are each independently nitrogen and carbon;

m and n are each a number of 0 to 3, provided that the valency theory has been met;

R² and R³ are each independently halogen, deuterium, cyano, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1- ₆alkoxy, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1- ₆alkoxyC_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl-S-, C_2-6alkenyl, C_2-6alkynyl, -SO₂R^2a, -COOR^2a, or -NR^2aR^2b,

wherein R^2a and R^2b are each independently hydrogen, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, or C_1-6alkoxyC_1-6alkyl;

R¹ is -C (O) NR^a1R^a2, -C (O) R^a3, or R^a4,

wherein

R^a1 is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, or C_1-6alkoxy;

R^a2 is

a) C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl, wherein each of said C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, -OR^b1, halogen, C_1-6alkyl-S-, cyano, -NR^b2R^b3, -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, -NR^b2C (O) R^b3, phenyl, naphthalenyl, heteroaryl or heterocyclyl, wherein each of said phenyl or naphthalenyl is unsubstituted or substituted with one or more substituents R^c3;

b) C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C_3-8cycloalkyl, phenyl, Heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

wherein

R^b1 is

1) hydrogen;

2) C_1-6alkyl, C_1-6alkoxy, or C_1-6alkoxyC_1-6alkyl-;

3) phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl, -C_1-6alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl; or

4) heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with C_1- ₆alkyl, oxo, or heteroaryl;

R^c1, and R^c2 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^b2 and R^b3 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1-6alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) ;

- C_2-6alkenyl or C_2-6alkynyl;

- hydroxy;

- C_1-6alkyl-S-

- C_1-6alkoxy or phenoxy, wherein each of said C_1-6alkoxy or phenoxy is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclyl;

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- Heterocyclyl, which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, C_1-6alkyl substituted heterocyclyl,

- Heteroaryl, which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl;

- C_3-8cylcoalkyl;

- phenyl; and

R^e1, R^e2, and R^e3 are each independently hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl-substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) ;

alternatively, R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl,

R^b4 is hydroxy; halogen; oxo; cyano; C_1-6alkyl; haloC_1-6alkyl; C_1-6alkoxy; C_1-6alkoxyC_1-6alkyl; haloC_1-6alkoxy; NR^c4R^c5, wherein R^c4 and R^c5 are each independently hydrogen, alkyl, or phenyl; phenyl, heterocyclyl, or heteroaryl, wherein each of said phenyl, heterocyclyl or heteroaryl is unsubstituted or substituted with one or more halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, -NR^e4R^e5, or -COOR^e4, wherein R^e4 and R^e5 are hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl, or C_1- ₆alkyl-substituted heteroaryl;

R^a3 is C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein each of said C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, or haloC_1-6alkoxy;

R^a4 is heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, phenoxy, -NR^c6R^c7, -C (O) NR^c6R^c7, -OC (O) NR^c6R^c7, -C (O) R^c6, or -NR^c6C (O) R^c7,

R^c6 and R^c7 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy,

provided that the bicyclic moietyis aromatic.
The compound of claim 1, wherein X⁴, X⁵, and X⁶ are each -CH=; and , X⁷ and X⁸ are carbon.
The compound of claim 1 or 2, wherein

(a) X¹ is O, S or -NH-, X² is -N= and X³ is -CH=; or

(b) X¹ is -N=, X² is -CH=, and X³ is O, S or -NH-; or

(c) X¹ is O or S, X² is -N= and X³ is -CH=; or

(d) X¹ is -N=, X² is -CH=, and X³ is O or S; or

(e) X¹ is -N=, X² is -N=, and X³ is -NH-; or X¹ is -N=, X² is -NH-, and X³ is -N=; or X¹ is -NH-, X² is -N=, and X³ is -N=.
The compound of any one of claims 1 to 3, wherein

the bicyclic moiety is benzofuranyl, benzo [b] thiophenyl, benzo [d] isoxazolyl, benzo [d] isothiazolyl, benzo [c] isoxazolyl, benzo [c] isothiazolyl, benzo [d] oxazolyl, 1H-benzo [d] imidazolyl, benzo [d] thiazolyl, pyrazolo [1, 5-a] pyridinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 3] triazolo [1, 5-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a] pyridinyl, [1, 2, 4] triazolo [1, 5-a] pyridinyl, benzo [d] [1, 2, 3] oxadiazolyl, benzo [c] [1, 2, 5] oxadiazolyl, benzo [d] [1, 2, 3] thiadiazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, 2H-benzo [d] [1, 2, 3] triazolyl, tetrazolo [1, 5-a] pyridinyl, isoindolinyl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridinyl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridinyl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridinyl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazinyl, or 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidinyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, deuterium, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C_1- ₆alkylSO₂-, NR^2aR^2b, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl, cyano, COOR^2a, or cycloalkyl;

optionally further wherein the bicyclic moiety is benzofuran-5-yl, benzo [b] thiophen-5-yl, benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [d] isothiazol-5-yl, benzo [c] isoxazol-5-yl, benzo [c] isothiazol-5-yl, benzo [d] oxazol-5-yl, benzo [d] oxazol-6-yl, 1H-benzo [d] imidazol-6-yl, benzo [d] thiazol-6-yl, pyrazolo [1, 5-a] pyridin-5-yl, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 3] triazolo [1, 5-a] pyridin-5-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-7-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-6-yl, benzo [d] [1, 2, 3] oxadiazol-5-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl , benzo [d] [1, 2, 3] oxadiazol-6-yl, benzo [d] [1, 2, 3] thiadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, tetrazolo [1, 5-a] pyridin-7-yl, tetrazolo [1, 5-a] pyridin-6-yl, isoindolin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazin-6-yl, or 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidin-5-yl, each of which is unsubstituted or substituted as defined above;

optionally further wherein the bicyclic moiety is benzofuran-5-yl, benzo [b] thiophen-5-yl, benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [d] isothiazol-5-yl, benzo [c] isoxazol-5-yl, benzo [c] isothiazol-5-yl, benzo [d] oxazol-5-yl, benzo [d] oxazol-6-yl, 1H-benzo [d] imidazol-6-yl, benzo [d] thiazol-6-yl, pyrazolo [1, 5-a] pyridin-5-yl, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 3] triazolo [1, 5-a] pyridin-5-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-7-yl, [1, 2, 4] triazolo [1, 5-a] pyridin-6-yl, benzo [d] [1, 2, 3] oxadiazol-5-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, benzo [d] [1, 2, 3] thiadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, tetrazolo [1, 5-a] pyridin-7-yl, tetrazolo [1, 5-a] pyridin-6-yl, 2-oxo-2, 3-dihydrobenzo [d] oxazol-5-yl, 2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl, 1, 3-dioxoisoindolin-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7-chloro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4- (trifluoromethyl) -1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7- (trifluoromethyl) -3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-cyano-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4-cyano-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 1H- [1, 2, 3] triazolo [4, 5-b] pyrazin-6-yl, 3H- [1, 2, 3] triazolo [4, 5-d] pyrimidin-5-yl, 7-nitro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-methyl-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-methoxy-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 7-hydroxy-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 6-fluoro-3H- [1, 2, 3] triazolo [4, 5-b] pyridin-5-yl, 4-methyl-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 4-methoxy-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 4-hydroxy-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 7-fluoro-1H- [1, 2, 3] triazolo [4, 5-c] pyridin-6-yl, 5-methoxy-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 5-hydroxy-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 7-methyl-1H- [1, 2, 3] triazolo [4, 5-b] pyridin-6-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl;

optionally further wherein the bicyclic moiety is benzo [d] isoxazolyl, benzo [c] [1, 2, 5] oxadiazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, or 2H-benzo [d] [1, 2, 3] triazolyl, each of which is unsubstituted or substituted as defined above;

optionally further wherein the bicyclic moiety is benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-, benzo [d] [1, 2, 3] triazol-5-yl, or 2H-benzo [d] [1, 2, 3] triazol-5-yl, each of which is unsubstituted or substituted as defined above;

optionally further wherein the bicyclic moiety is benzo [d] isoxazol-5-yl, benzo [d] isoxazol-6-yl, benzo [c] [1, 2, 5] oxadiazol-5-yl, benzo [d] [1, 2, 3] oxadiazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-6-yl, 1H-benzo [d] [1, 2, 3] triazol-5-yl, 2H-benzo [d] [1, 2, 3] triazol-5-yl, 4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-nitro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-bromo-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-amino-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylamino) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methylsulfonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methoxycarbonyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-carboxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyclopropyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-cyano-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-dichloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chloro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methyl-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-methoxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-fluoro-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-hydroxy-4- (trifluoromethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-chloro-5-fluoro-7- (methylthio) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (difluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (trifluoromethoxy) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4- (hydroxymethyl) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 5-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 7-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-fluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 4, 5-difluoro-7-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4-methyl-1H-benzo [d] [1, 2, 3] triazol-6-yl, 5, 7-difluoro-4- (methyl-d3) -1H-benzo [d] [1, 2, 3] triazol-6-yl, 2- (4-chloro-1H-benzo [d] [1, 2, 3] triazol-6-yl, 7-chlorobenzo [d] isoxazol-5-yl, 7-methylbenzo [d] isoxazol-5-yl, 7-hydroxybenzo [d] isoxazol-5-yl, 7-methoxybenzo [d] isoxazol-5-yl, or 6-fluorobenzo [d] isoxazol-5-yl.
The compound of any one of claims 1 to 4, wherein R¹ is -C (O) NR^a1R^a2,

wherein

R^a1 is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, or C_1-6alkoxy;

R^a2 is

a) C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl, wherein each of said C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, or C_3-8cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, -OR^b1, halogen, C_1-6alkyl-S-, cyano, -NR^b2R^b3, -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, -NR^b2C (O) R^b3, phenyl, naphthalenyl, heteroaryl or heterocyclyl, wherein each of said phenyl or naphthalenyl is unsubstituted or substituted with one or more substituents R^c3;

b) C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of C_3-8cycloalkyl, phenyl, Heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

Wherein

R^b1 is

1) hydrogen;

2) C_1-6alkyl, C_1-6alkoxy, or C_1-6alkoxyC_1-6alkyl-;

3) phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl (e.g., azetidinyl) , -C_1- ₆alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl (e.g., pyridinyl, pyrazolyl, pyrazinyl) ; or

4) heteroaryl (e.g., pyrimidinyl, pyridinyl, 1H-benzo [d] imidazolyl, 1H-indazolyl) or heterocyclyl (e.g., azetidinyl, pyrrolidinyl) , which is unsubstituted or substituted with C_1-6alkyl, oxo, or pyridinyl;

R^c1 and R^c2 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^b2 and R^b3 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy;

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1-6alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) ;

- C_2-6alkenyl or C_2-6alkynyl;

- hydroxy;

- C_1-6alkyl-S-

- C_1-6alkoxy or phenoxy, wherein each of said C_1-6alkoxy or phenoxy is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl (pyrazolyl) , or alkyl-substituted heterocyclyl (piperidinyl) ;

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- Heterocyclyl (e.g., azetidin-1-yl, piperidin-4-yl, morpholino, piperazinyl, morpholino) , which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, C_1-6alkyl substituted heterocyclyl,

- Heteroaryl (e.g., pyrazinyl, pyridinyl, pyrimidinyl) , which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl (e.g., pyridinyl)

- C_3-8cylcoalkyl;

- phenyl,

R^e1, R^e2, and R^e3 are each independently hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl-substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) .
The compound of any one of claims 1 to 4, wherein R^a1 is C_1-6alkyl, or deuterated C_1-6alkyl.
The compound of any one of claims 1 to 4, wherein R^a1 is hydrogen, methyl, ethyl, CH₃-d₃, CF₃, CHF₂, methoxy.
The compound of any one of claims 1 to 7, wherein

(a) R^a2 is C_1-6alkyl, which is substituted with -OR^b1, wherein R^b1 is hydrogen, methoxy, phenyl which is unsubstituted or substituted with 1, 2, or 3 substituents selected from the groups consisting of fluoro, bromo, chloro, methyl, hydroxymethyl, trifluoromethyl, azetidin-1-yl, 2-amino-2-oxoethyl, acetamido, pyridin-2-yl, 1H-pyrazol-1-yl, pyrazin-2-yl, N, N-dimethylamino, 2- (dimethylamino) -2-oxoethyl, 2-hydroxypropyl, or methylamino; pyrimidinyl, pyridinyl, 1H-benzo [d] imidazolyl, or 1H-indazolyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, oxo, or pyridinyl;

(b) R^a2 is C_1-6alkyl, which is substituted with -NR^b2R^b3, wherein R^b2 is hydrogen, or C_1-6alkyl (e.g., methyl, ethyl, etc) and R^b3 is C_1-6alkyl, phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, oxo, or halogen.

(c) R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a phenyl group which is unsubstituted or substituted with one or more substituents R^c3;

optionally further wherein R^c3 is halogen; hydroxy; cyano; oxo; C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1-6alkoxy, phenyl, or alkyl-substituted heteroaryl (e.g., pyrazolyl) ; C_1-6alkoxy; phenoxy, C_2-6alkenyl; C_2-6alkynyl; hydroxy; C_1-6alkoxy which is unsubstituted or substituted with one or more halogen, C_1- ₆alkoxy, alkyl-substituted heteroaryl (pyrazolyl) , or alkyl-substituted heterocyclyl (piperidinyl) ; -C_1-6alkylC (O) NR^e2R^e3; -C (O) NR^e1R^e2; -NR^e1R^e2; -NR^e1C (O) R^e2; -NR^e1-C (O) -NR^e2R^e3; -NR^e1R^e2; R^e1, R^e2, R^e3 are each independently hydrogen, C_1-6alkyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) ; heterocyclyl (e.g., azetidin-1-yl, piperidin-4-yl, morpholino, piperazinyl, morpholino) , which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, or C_1-6alkyl substituted heterocyclyl; heteroaryl (pyrazinyl, pyridinyl, pyrimidinyl) , which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl (e.g., pyridinyl) ; C_3-8cylcoalkyl; phenyl; or C_1-6alkyl-S-;

optionally further wherein R^c3 is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, ethynyl, vinyl trifluoromethyl, methoxymethyl, (1-methyl-1H-pyrazol-4-yl) methyl, hydroxy, methoxy, (1-methylpiperidin-4-yl) methoxy, trifluoromethoxy, difluoromethoxy, 2, 2, 2-trifluoroethoxy, cyano, oxo, hydroxymethyl, 3-methylureido, thiazol-2-ylamino, (1-methyl-1H-pyrazol-4-yl) amino, azetidin-1-yl, 1-methylpiperidin-4-yl, piperidin-4-yl, 4-methylpiperazin-1-yl, morpholino, pyrazin-2-yl, 3- (hydroxymethyl) pyridin-2-yl, pyridin-3-yl, phenyl, pyrimidin-4-yl, 1, 2, 3, 6-tetrahydropyridin-4-yl, 4'-methyl- [1, 1'-bipiperazin] -4-yl, amino, acetamido, dimethylamino, methylthio, cyclopropyl, 2-amino-2-oxoethyl, or 2- (methylamino) -2-oxoethyl;

(d) R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a heteroaryl or heterocyclyl group which is unsubstituted or substituted with one or more substituents R^c3;

Optionally further wherein the heteroaryl or heterocyclyl group is selected from the group consisting of triazolyl, isoquinolinyl, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, drobenzofuranyl, 2, 3-dihydrodrobenzofuranyl, drobenzofuranyl, 2, 3-dihydrodrobenzofuranyl, benzo [b] [1, 4] dioxinyl, 2, 3-dihydrobenzo [b] [1, 4] dioxinyl, benzo [b] [1, 4] oxazinyl, 2, 3-dihydrobenzo [b] [1, 4] oxazinyl, benzo [b] [1, 4] thiazinyl or 3, 4-dihydro-2H-benzo [b] [1, 4] thiazinyl, 1, 2, 3, 4-tetrahydroquinoxalinyl or 1, 2, 3, 4-tetrahydroquinoxalinl, isochromanyl, or indazolyl;

Optionally further wherein the heteroaryl or heterocyclyl group is selected from the group consisting of 1H-1, 2, 3-triazol-4-yl, isoquinolin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1H-1, 2, 3-triazol-4-yl, 1H-1, 2, 4-triazol-3-yl, 2H-1, 2, 3-triazol-4-yl, 1H-imidazol-4-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, drobenzofuran-6-yl or 2, 3-dihydrodrobenzofuran-6-yl, drobenzofuran-5-yl or 2, 3-dihydrodrobenzofuran-5-yl, benzo [b] [1, 4] dioxin-6-yl or 2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl, benzo [b] [1, 4] oxazin-7-yl or 2, 3-dihydrobenzo [b] [1, 4] oxazin-7-yl, 2H-benzo [b] [1, 4] thiazin-7-yl or 3, 4-dihydro-2H-benzo [b] [1, 4] thiazin-7-yl, 1, 2, 3, 4-tetrahydroquinoxalin-6-yl or 1, 2, 3, 4-tetrahydroquinoxalin-6-yl, isochroman-7-yl, or 1H-indazol-6-yl;

Optionally further wherein R^c3 is selected from the group consisting of halogen, C_1-6alkyl, C_1- ₆alkoxy; hydroxy, cyano, heterocyclyl, NR^e1R^e2, oxo, heterocyclyl or phenyl;

Optionally further wherein R^c3 is selected from the group consisting of fluoro, bromo, chloro, methyl, ethyl, methoxy, ethoxy, hydroxy, cyano, morpholino, (1-methyl-1H-1, 2, 3-triazol-4-yl) amino, oxo, pyridinyl or phenyl;

(e) R^a2 is C_1-6alkyl (e.g., methyl, ethyl, or propyl) , which is substituted with -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, -NR^b2C (O) R^b3, or -NR^b2R^b3, wherein R^b1 and R^b2 are defined as in Formula (I) ;

(f) R^a2 is C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen; C_1-6alkyl which is unsubstituted or substituted with R^c3,

Optionally further wherein R^a2 is pyridin-2-yl, pyridin-3-yl, isoquinolin-4-yl, pyrimidin-5-yl, isoxazol-5-yl, isoxazol-3-yl, triazol-3-yl, benzo [c] isoxazol-3-yl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridinyl, triazolo [4, 3-a] pyridinyl, 5, 6-dihydro-8H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazinyl, triazolo [3, 4-c] [1, 4] oxazinyl, 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazinyl, triazolo [5, 1-c] [1, 4] oxazinyl, or phenyl, each of which is unsubstituted or substituted with R^c3, Optionally further wherein R^c3 is phenyl; C_1-6alkoxy; cyano; oxo; -NR^e1R^e2; -NR^e1-C (O) -NR^e2R^e3; phenoxy, phenyl, or heteroaryl;

Optionally further wherein R^c3 is fluoro, bromo, chloro, methyl, methoxy, amino, cyano, oxo, acetamido, 3-methylureido, benzyl, phenoxy, pyridin-2-yl, or phenyl; or

(g) R^a2 is alkenyl or alkynyl, each of which is further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more R^c3.
The compound of any one of claims 1 to 8, wherein

(a) R^a2 is 2- (o-tolyloxy) ethyl, 2- (2- (hydroxymethyl) phenoxy) ethyl, 2- (2- (trifluoromethyl) phenoxy) ethyl, 2- (2- (hydroxymethyl) -3-methylphenoxy) ethyl, 2-phenoxyethyl, 2- (3- (azetidin-1-yl) phenoxy) ethyl, 2- (4- (azetidin-1-yl) phenoxy) ethyl, 2- (2- (2-amino-2-oxoethyl) phenoxy) ethyl, 2- (3-acetamidophenoxy) ethyl, 2- (4- (pyridin-2-yl) phenoxy) ethyl, 2- (4-methyl-3- (1H-pyrazol-1-yl) phenoxy) ethyl, 2- (3- (pyrazin-2-yl) phenoxy) ethyl, N, N-dimethylaminophenoxyethyl, 2- (3- (2- (dimethylamino) -2-oxoethyl) phenoxy) ethyl, 2- (3- (2-hydroxypropyl) phenoxy) ethyl, 2- (4-methyl-3-methylaminophenoxy) ethyl, 2- (2-chlorophenoxy) ethyl, 2-fluoro-5-methylphenoxy, 2- (pyrimidin-2-yloxy) ethyl, 2- (pyridin-2-yloxy) ethyl, 2- (pyridin-3-yloxy) ethyl, 2- ( (2-oxo-2H- [1, 2'-bipyridin] -4'-yl) oxy) ethyl, 2- ( (1-methyl-1H-benzo [d] imidazol-4-yl) oxy) ethyl, 2- ( (1-methyl-1H-indazol-4-yl) oxy) ethyl, or 2- ( (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) oxy) ethyl;

(b) R^a2 is 2- ( (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) ethyl, N-methyl-N- (2-fluoro-5-methylphenyl) amino, N- (2-fluoro-5-methylphenyl) amino, or dimethylamino;

(c) R^a2 is 5-chloro-2-fluorobenzyl, 2-fluoro-5-methylbenzyl, 2-hydroxybenzyl, 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-hydroxy-3-methylbenzyl, 5-cyano-2-fluorobenzyl, 2-fluoro-5- (trifluoromethyl) benzyl, 2-chlorobenzyl, 2, 6-difluorobenzyl, 3-chloro-2-fluorobenzyl, 2, 5-difluorobenzyl, 2-fluoro-4-methoxybenzyl, 1- (5-chloro-2-fluorophenyl) ethyl, 2-fluoro-5-methoxybenzyl, 2, 4, 5-trifluorobenzyl, 2, 4-difluorobenzyl, 2, 4-difluoro-5-methylbenzyl, 2-fluoro-5- (methoxymethyl) benzyl, 2-fluoro-3, 5-dimethylbenzyl, benzyl, 4-chloro-2-fluorobenzyl, 2- (5-chloro-2-fluorophenyl) propan-2-yl, (5-chloro-2-fluorophenyl) fluoromethyl, (5-chloro-2-fluorophenyl) difluoromethyl, 1- (3-chlorophenyl) -2-hydroxyethyl, 1- (5-chloro-2-fluorophenyl) cyclopropyl, 2-fluorobenzyl, 2-fluoro-3-hydroxybenzyl, 2-fluoro-3- (hydroxymethyl) benzyl, 2-fluoro-3- (3-methylureido) benzyl, 2-fluoro-3- (thiazol-2-ylamino) benzyl, 2-fluoro-3- ( (1-methyl-1H-pyrazol-4-yl) amino) benzyl, 4-ethyl-2-fluorobenzyl, 4- (azetidin-1-yl) -2-fluorobenzyl, 5-chloro-2-fluoro-4- (pyrazin-2-yl) benzyl, 2-fluoro-4- (3- (hydroxymethyl) pyridin-2-yl) benzyl, 2-fluoro-4- (1-methylpiperidin-4-yl) benzyl, 2-fluoro-4- (piperidin-4-yl) benzyl, 2-fluoro-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzyl, 2-fluoro-4- (4-methylpiperazin-1-yl) benzyl, 2-fluoro-4- (4'-methyl- [1, 1'-bipiperazin] -4-yl) benzyl, 5-chloro-2-fluoro-4- ( (1-methylpiperidin-4-yl) methoxy) benzyl, 2-fluoro-4- ( (1-methylpiperidin-4-yl) methoxy) benzyl, 2-cyano-N- (4-cyano-2-fluorobenzyl, 3-chloro-2, 6-difluorobenzyl, 5-chloro-2, 4-difluorobenzyl, 3-amino-5-chloro-2-fluorobenzyl, 3-acetamido-5-chloro-2-fluorobenzyl, 5-chloro-2-hydroxybenzyl, 5-cyano-2-hydroxybenzyl, 2-cyano-5-methylbenzyl, 2-fluoro-5- (trifluoromethoxy) benzyl, 5- (difluoromethoxy) -2-fluorobenzyl, 2-fluoro-5- (2, 2, 2-trifluoroethoxy) benzyl, 5- (dimethylamino) -2-fluorobenzyl, 2-fluoro-5- (methylthio) benzyl, 5-ethynyl-2-fluorobenzyl, 2-fluoro-5-vinylbenzyl, 2-fluoro-5- ( (trifluoromethoxy) methyl) benzyl, 2-fluoro-5- (hydroxymethyl) benzyl, 5- (azetidin-1-yl) -2-fluorobenzyl, 5-cyclopropyl-2-fluorobenzyl, 2-fluoro-5-morpholinobenzyl, 2-amino-2-oxoethyl) -2-fluorobenzyl, 2-fluoro-5- (2- (methylamino) -2-oxoethyl) benzyl, 2-fluoro-5- ( (1-methyl-1H-pyrazol-4-yl) methyl) benzyl, 2-fluoro-4- (2- (methylamino) -2-oxoethyl) benzyl, 2-cyanobenzyl, (3-fluoronaphthalen-2-yl) methyl, 2-fluoro-4- (pyridin-3-yl) benzyl, (3-fluoro- [1, 1'-biphenyl] -4-yl) methyl, (4-fluoro- [1, 1'-biphenyl] -3-yl) methyl, 2-fluoro-5- (pyrimidin-4-yl) benzyl, 3-phenylpropyl, 3- (2-cyanophenyl) propyl, 3- (2-chlorophenyl) propyl, 3- (2-methoxyphenyl) propyl, 3- (2-fluorophenyl) propyl, or 3-oxo-3-phenylpropyl;

(d) R^a2 is (1- (pyridin-4-yl) -1H-1, 2, 3-triazol-4-yl) methyl, (7-fluoroisoquinolin-6-yl) methyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrazin-2-ylmethyl, (4-methylpyridin-2-yl) methyl, (4-methoxypyridin-2-yl) methyl, (2-chloro-5-methylpyridin-3-yl) methyl, (2-chloro-5-fluoropyridin-4-yl) methyl, (2-chloro-5-hydroxypyridin-4-yl) methyl, (5-fluoro-2-methylpyridin-4-yl) methyl, (5-fluoro-2-methoxypyridin-4-yl) methyl, (2-cyano-5-fluoropyridin-4-yl) methyl, (2-cyano-5-hydroxypyridin-4-yl) methyl, (5-fluoro-2-morpholinopyridin-4-yl) methyl, (5-fluoro-2- ( (1-methyl-1H-1, 2, 3-triazol-4-yl) amino) pyridin-4-yl) methyl, 5-chloro-2-oxo-1, 2-dihydropyridin-3-yl) methyl, (1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl, (1-phenyl-1H-1, 2, 4-triazol-3-yl) methyl, (2-phenyl-2H-1, 2, 3-triazol-4-yl) methyl, (1-phenyl-1H-imidazol-4-yl) methyl, 1-phenyl-1H-pyrazol-4-yl) methyl, (1-phenyl-1H-pyrazol-3-yl) methyl, (5-fluoro-2, 3-dihydrobenzofuran-6-yl) methyl, (6-fluoro-2, 3-dihydrobenzofuran-5-yl) methyl, (2, 3-dihydrobenzofuran-6-yl) methyl, (7-fluoro-2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) methyl, (6-fluoro-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) methyl, (6-fluoro-4-methyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) methyl, (6-fluoro-4-methyl-3, 4-dihydro-2H-benzo [b] [1, 4] thiazin-7-yl) methyl, (7-fluoro-1, 2, 3, 4-tetrahydroquinoxalin-6-yl) methyl, (6-fluoroisochroman-7-yl) methyl, or (7-fluoro-1H-indazol-6-yl) methyl;

(e) R^a2 is 2- (methylamino) -2-oxoethyl, 2- (methoxyamino) -2-oxoethyl, 2- (dimethylamino) -2-oxoethyl, 2-oxo-2- (phenylamino) ethyl, 2-oxo-2- (pyridin-4-ylamino) ethyl, 2- ( (2-methoxyethyl) amino) -2-oxoethyl, dimethylaminocarbonyloxyethyl, carboxymethyl, mMethoxycarbonylmethyl, methylcarbonylaminoethyl, 3- (azetidin-1-yl) -3-oxopropyl, 2- (methylamino) ethyl, or carbamoyl;

(f) R^a2 is cyclopropyl, pyridin-3-yl, 4-methylpyridin-3-yl, 4, 6-dimethylpyridin-3-yl, 4-methoxypyridin-3-yl, 6-amino-4-cyanopyridin-3-yl, isoquinolin-4-yl, 5-methyl-2-oxo-1, 2-dihydropyridin-4-yl, 4-methylpyrimidin-5-yl, 5-fluoro-4-methylpyridin-3-yl, 6-amino-4-methylpyridin-3-yl, 6-acetamido-4-methylpyridin-3-yl, 4-methyl-6- (3-methylureido) pyridin-3-yl, 5-methoxypyridin-3-yl, 4-benzylpyridin-3-yl, 5-phenoxypyridin-3-yl, isoxazol-5-yl, 4-methylisoxazol-5-yl, 3, 4-dimethylisoxazol-5-yl, 4-methyl-3-phenylisoxazol-5-yl, 4-methyl-3- (pyridin-2-yl) isoxazol-5-yl, isoxazol-3-yl, 4-methyl-4H-1, 2, 4-triazol-3-yl, 4-phenylisoxazol-5-yl, 3-methyl-4-phenylisoxazol-5-yl, benzo [c] isoxazol-3-yl, 1-methyl-2-oxo-1, 2-dihydropyridin-3-yl, 3-fluoro-6-methylpyridin-2-yl, 5-methyl-2-oxo-1, 2-dihydropyridin-3-yl, 4-fluoro-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl, 1-phenyl-1H-1, 2, 3-triazol-4-yl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl, 5, 6-dihydro-8H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazin-3-yl, 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazin-3-yl, 5-fluoro-2-methylphenyl, 2-chloro-5-fluorophenyl, or 2-cyano-5-fluorophenyl; or

(g) R^a2 is but-2-yn-1-yl, 3- (1-methyl-1H-pyrazol-4-yl) prop-2-yn-1-yl, 4, 4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N, N-dimethylaminobut-2-yn-yl, N, N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5, 6-dihydroxyhex-2-yn-1-yl, 5-hydroxy-4-methylpent-2-yn-1-yl, 3- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) prop-2-yn-1-yl, 3- (1-methyl-2-oxopiperidin-3-yl) prop-2-yn-1-yl, 4- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) but-3-yn-2-yl, 4- (1-methyl-2-oxopiperidin-3-yl) but-3-yn-2-yl, 3-phenylprop-2-yn-1-yl, 3- (o-tolyl) prop-2-yn-1-yl, 3- (2-fluorophenyl) prop-2-yn-1-yl, 3- (2-chlorophenyl) prop-2-yn-1-yl, 3- (3-fluorophenyl) prop-2-yn-1-yl, 3- (4-fluorophenyl) prop-2-yn-1-yl, 3- (2-hydroxyphenyl) prop-2-yn-1-yl, 3- (pyridin-3-yl) prop-2-yn-1-yl, 4- (pyridin-3-yl) but-3-yn-2-yl, 3- (pyridin-4-yl) prop-2-yn-1-yl, 3- (2-cyanophenyl) prop-2-yn-1-yl, 4- (pyridin-2-yl) but-2-yn-1-yl, 4- (pyrazin-2-yl) but-2-yn-1-yl, or 4- (pyridin-2-yl) pent-2-yn-1-yl.
The compound of any one of claims 1 to 7, wherein

R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl;

Optionally further wherein R¹ as -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of piperidinyl, 6-azaspiro [2.5] octane-6-yl, 5-azaspiro [2.5] octane-5-yl, piperidinyl, piperazinyl, 1, 2, 3, 6-tetrahydropyridinyl, thiomorpholine, morpholine, azetidine, azepane, azocane, 3-azabicyclo [3.1.0] hexane, and octahydrocyclopenta [c] pyrrole, wherein each of said ring is unsubstituted or substituted as define above;

Optionally further wherein R^b4 is hydroxy; halogen; oxo; cyano; C_1-6alkyl; haloC_1-6alkyl; C_1-6alkoxy; C_1- ₆alkoxyC_1-6alkyl; haloC_1-6alkoxy; NR^c4R^c5 (R^c4 and R^c5 are each independently hydrogen, alkyl, or phenyl) ; phenyl, heterocyclyl (e.g., pyrrolidine, azetidine) , or heteroaryl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenoxy, cyclohexyl, 1H-pyrazol-4-yl, or 1-methyl-1H-pyrazol-4-yl) , wherein each of said phenyl, heterocyclyl or heteroaryl is unsubstituted or substituted with one or more halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, -NR^e4R^e5, or -COOR^e4, wherein R^e4 and R^e5 are hydrogen, C_1-6alkyl, phenyl, C_1- ₆alkyl-substituted phenyl, heteroaryl, or C_1-6alkyl-substituted heteroaryl.

Optionally further wherein R^b4 is 3-chlorophenyl, methoxymethyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, m-tolyl, 3- (trifluoromethyl) phenyl, 3- (N, N-dimethylamino) phenyl, 3- (methylamino) phenyl, 3- (methoxycarbonyl, 3- (carboxy) phenyl) , methoxyphenyl) , phenoxy, cyclohexyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, fluoro, bromo, chloro, azetidine, oxo, pyrrolidine, hydroxy, amino, trifluoromethyl, or phenylamino.

Optionally further wherein R¹ is 4- (3-chlorophenyl) piperidine-1-carbonyl, 6-azaspiro [2.5] octane-6-carbonyl, 5-azaspiro [2.5] octane-5-carbonyl, piperidine-1-carbonyl, 4- (methoxymethyl) piperidine-1-carbonyl, 4-phenylpiperidine-1-carbonyl, 4-phenylpiperazine-1-carbonyl, 4-phenyl-1, 2, 3, 6-tetrahydropyridine-1-carbonyl, 4- (pyridin-2-yl) piperidine-1-carbonyl, 4- (pyridin-3-yl) piperidine-1-carbonyl, 4- (pyridin-4-yl) piperidine-1-carbonyl, 4- (m-tolyl) piperidine-1-carbonyl, 4- (3- (trifluoromethyl) phenyl) piperidine-1-carbonyl, 4- (3- (N, N-dimethylamino) phenyl) piperidin-1-ylcarbonyl, 4- (3- (methylamino) phenyl) piperidin-1-ylcarbonyl, 4- (3- (methoxycarbonyl) phenyl) piperidin-1-ylcarbonyl, 4- (3- (carboxy) phenyl) piperidin-1-ylcarbonyl, 4- (4-methoxyphenyl) piperidine-1-carbonyl, 4-phenoxypiperidine-1-carbonyl, 4-cyclohexylpiperidine-1-carbonyl, 3-phenylpiperidine-1-carbonyl, 3- (1H-pyrazol-4-yl) piperidine-1-carbonyl, 3- (1-methyl-1H-pyrazol-4-yl) piperidine-1-carbonyl, 3- (methoxymethyl) piperidine-1-carbonyl, 4, 4-difluoropiperidine-1-carbonyl, 3, 3-difluoropiperidine-1-carbonyl, 1, 1-dioxidothiomorpholine-4-carbonyl, morpholine-4-carbonyl, azetidine-1-carbonyl, pyrrolidine-1-carbonyl, 3-fluoroazetidine-1-carbonyl, 3, 3-difluoroazetidine-1-carbonyl, 3-hydroxyazetidine-1-carbonyl, 3-aminoazetidine-1-carbonyl, 3- (trifluoromethyl) azetidine-1-carbonyl, azepane-1-carbonyl, azocane-1-carbonyl, 3-azabicyclo [3.1.0] hexane-3-carbonyl, octahydrocyclopenta [c] pyrrole-2-carbonyl, or 4- (phenylamino) piperidine-1-carbonyl.
The compound of any one of claims 1 to 7, wherein R¹ is -C (O) R^a3, wherein R^a3 is C_1-6alkyl, haloC_1- ₆alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein each of said C3-8cycloalkyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, or haloC_1-6alkoxy;

Optionally further wherein R^a3 is methyl, ethyl, isopropyl, propyl, ethynyl, vinyl, methoxy, ethoxy, ethylthiol, 1-methylcyclopropane, 1-fluorocyclopropane, 2, 2-difluorocyclopropane, 1- (trifluoromethyl) cyclopropane, cyclopropyl, cyclobutyl, thiazole-4-carbonyl or 1H-imidazole-1-carbonyl.
The compound of any one of claims 1 to 7, wherein

R¹ is heteroaryl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, phenoxy, -NR^b2R^b3, -C (O) NR^b2R^b3, -OC (O) NR^b2R^b3, -C (O) R^b2, or -NR^b2C (O) R^b3;

Optionally further wherein R¹ is thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, oxidized pyrazinyl, pyrimidinyl, oxidized pyrimidinyl, pyridazinyl, pyrdinyl, or benzo [d] thiazolyl, each of which is unsubstituted or substituted with as defined above;

Optionally further wherein R¹ is thiazol-2-yl, thiazol-4-yl, 1, 2, 4-thiadiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, oxidized pyrazinyl, pyrimidin-2-yl, pyrimidin-4-yl, oxidized pyrimidinyl, pyridazin-3-yl, pyrimidine-5-yl, pyrdin-2-yl, pyrazine-2-yl, pyridazine-3-yl, or benzo [d] thiazol-2-yl;

Optionally further wherein R¹ is thiazol-2-yl, thiazol-4-yl, 1, 2, 4-thiadiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazine 1-oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine 1-oxide, pyridazin-3-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 3- (trifluoromethyl) pyridin-2-yl, 5-bromopyrimidin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5-methylpyrimidin-4-yl, 5- (trifluoromethyl) pyrimidin-4-yl, 3-methylpyrazin-2-yl, 5-fluoropyridin-2-yl, 3, 5-difluoropyridin-2-yl, 5-methylthiazol-4-yl, 1-methyl-1H-imidazol-2-yl, N, N-dimethylaminocarbonylpyrimidine-5-yl, N, N-dimethylaminocarbonylpyrdin-2-yl, N, N-dimethylaminocarbonylpyrazine-2-yl, N, N-dimethylaminocarbonylpyridazine-3-yl, 5-phenoxypyridin-2-yl, 5-phenoxypyrazin-2-yl, or benzo [d] thiazol-2-yl.
A compound of Formula (II)

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a deuterated analog thereof,

wherein

X¹ and X³, are each independently -O-, -S-, -NH-, -N=, or -CH=;

m and n are each a number of 0 to 3, provided that the valency theory has been met;

R² and R³ are each independently halogen, deuterium, cyano, oxo, nitro, hydroxy, C_1-6alkoxy, haloC_1- ₆alkoxy, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1- ₆alkoxyC_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl-S-, C_2-6alkenyl, C_2-6alkynyl, -SO₂R^2a, -COOR^2a, or -NR^2aR^2b,

wherein R^2a and R^2b are each independently hydrogen, C_1-6alkyl, haloC_1-6alkyl, deuterated C_1-6alkyl, deuterated haloC_1-6alkyl, hydroxyC_1-6alkyl, or C_1-6alkoxyC_1-6alkyl;

R¹ is

1) -C (O) NR^a1R^a2, wherein R^a1 and R^a2 are each independently C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

2) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_1- ₆alkyl which is unsubstituted or substituted with one or more halogen or hydroxy, and further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more substituents R^c3;

3) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_1- ₆alkyl which is unsubstituted or substituted with one or more halogen or hydroxy, and which is further substituted with -OR^b1, wherein R^b1 is phenyl which is unsubstituted or substituted with halogen, oxo, C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, haloC_1-6alkyl, heterocyclyl, -C_1- ₆alkylC (O) NR^c1R^c2, -C (O) NR^c1R^c2, -NR^c1R^c2, -NR^c1C (O) R^c2, or heteroaryl; or

4) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_2- ₆alkenyl or C_2-6alkynyl, each of which is further substituted with a phenyl group, wherein said phenyl is unsubstituted or substituted with one or more substituents R^c3;

5) -C (O) NR^a1R^a2, wherein R^a1 is C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl; and R^a2 is C_3- ₈cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one or more substituents R^c3;

6) -C (O) NR^a1R^a2, wherein R^a1 and R^a2, together with the nitrogen atom to which they are attached, form a 4 to 9-membered ring comprising one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and said ring is unsubstituted or substituted with one or more substituents R^b4, or two substituents R^b4 on the two adjacent atoms form a 4-to 6-membered fused ring and/or two substituents R^b4 on the same carbon atom form a 3-to 6-membered spiro ring, wherein said fused ring or spiro ring is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C_1-6alkyl,

7) heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, phenoxy, -NR^c6R^c7, -C (O) NR^c6R^c7, -OC (O) NR^c6R^c7, -C (O) R^c6, or -NR^c6C (O) R^c7,

wherein

R^c1, and R^c2 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1-6alkoxy;

R^c3 is

- halogen;

- hydroxy;

- cyano;

- oxo;

- C_1-6alkyl which is unsubstituted or substituted with one or more halogen, hydroxy, C_1-6alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) ;

- C_2-6alkenyl or C_2-6alkynyl;

- hydroxy;

- C_1-6alkyl-S-

- C_1-6alkoxy or phenoxy, wherein each of said C_1-6alkoxy or phenoxy is unsubstituted or substituted with one or more halogen, C_1-6alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclyl;

- -C_1-6alkylC (O) NR^e1R^e2;

- -C (O) NR^e1R^e2;

- -NR^e1R^e2;

- -NR^e1C (O) R^e2;

- -NR^e1-C (O) -NR^e2R^e3;

- -NR^e1R^e2;

- Heterocyclyl, which is unsubstituted or substituted with halogen, C_1-6alkyl or heterocyclyl, C_1-6alkyl substituted heterocyclyl,

- Heteroaryl, which is unsubstituted or substituted with C_1-6alkyl, hydroxy, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, or heteroaryl;

- C_3-8cylcoalkyl;

- phenyl; and

R^e1, R^e2, and R^e3 are each independently hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl) , or C_1-6alkyl-substituted heteroaryl (1-methyl-1H-1, 2, 3-triazol-4-yl) ;

R^b4 is hydroxy; halogen; oxo; cyano; C_1-6alkyl; haloC_1-6alkyl; C_1-6alkoxy; C_1-6alkoxyC_1-6alkyl; haloC_1-6alkoxy; NR^c4R^c5, wherein R^c4 and R^c5 are each independently hydrogen, alkyl, or phenyl; phenyl, heterocyclyl, or heteroaryl, wherein each of said phenyl, heterocyclyl or heteroaryl is unsubstituted or substituted with one or more halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, -NR^e4R^e5, or -COOR^e4, wherein R^e4 and R^e5 are hydrogen, C_1-6alkyl, phenyl, C_1-6alkyl-substituted phenyl, heteroaryl, or C_1- ₆alkyl-substituted heteroaryl;

R^c6 and R^c7 are each independently hydrogen, C_1-6alkyl, phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, oxo, C_1-6alkyl, or C_1- ₆alkoxy,

provided that the bicyclic moietyis aromatic.
The compound of claim 1, wherein the compound is selected from the group consisting of Compound Nos. : 1-549.
A pharmaceutical composition comprising the compounds of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof and a pharmaceutically-acceptable excipient.
A method of inhibiting weight gain; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or an obesity-related disease (especially, obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) , macular degeneration or Alzheimer’s disease; or treating injury or promoting wound healing or tissue regeneration in a subject, comprising administering the subject in need thereof an effective amount of the compounds of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof.
The method of claim 16, wherein the method is characterized by FTO inhibition.