WO2025162376A1

WO2025162376A1 - Deuterated fto inhibitors

Info

Publication number: WO2025162376A1
Application number: PCT/CN2025/075176
Authority: WO
Inventors: Wei Li; Niu Huang
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 deuterated compound of Formulas (I) and (II) as an FTO inhibitor with improved pharmacokinetic properties with comparable selective FTO inhibition. 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

DEUTERATED FTO INHIBITORS

FILED OF THE INVENTION

Disclosed herein is a deuterated compound of Formulas (I) and (II) as an FTO inhibitor with improved pharmacokinetic properties with comparable selective FTO inhibition. 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. One gene that has been strongly associated with obesity is the fat mass and obesity-associated (FTO) gene. Studies have shown that the FTO gene plays a functional role in obesity, and its effects have been confirmed in transgenic animal models.

US2014/0148383A1 first identified a known FDA-approved drug –entacapone as an FTO inhibitor using a structure-based virtual screening method in combination with biological activity measurements, including enzymatic activity, cellular activity and in high-fat diet-induced obesity (DIO) animal model. Entacapone is a COMT (Catechol-O-methyltransferase) inhibitor used for treating Parkinson's disease.

WO2016206573A1 discloses entacapone analogs showing FTO inhibition.

The unpublished PCT application PCT/CN2023/109849 recites novel FTO inhibitors with improved and selective FTO inhibition by structural tuning.

Deuterated compounds, which are compounds that contain deuterium (astable heavy isotope of hydrogen) , have been found to potentially affect the pharmacokinetic and metabolic profiles of drugs. The impact of deuterium substitution on clearance and pharmacokinetic properties of deuterated compounds has been a subject of interest in drug development and research. The presence of deuterium in a compound can affect its metabolism and elimination processes. Deuterium substitution can alter the rate of enzymatic reactions involved in metabolism, such as oxidation or reduction reactions. These reactions can be slower for deuterated compounds due to the higher mass of deuterium, which can lead to a slower clearance from the body.

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

SUMMARY OF THE INVENTION

Disclosed herein are deuterated compounds used as FTO inhibitors, pharmaceutical compositions comprising the same, and methods of using the same. Different from the previous findings concerning deuteration, the inventors of the instant invention found that the deuterated FTO inhibitors show similar clearance in intravenous injection (i.v. ) in vivo but improved oral administration (p.o. ) pharmacokinetic properties, such as higher p.o. exposure (AUC) , higher p.o. Cmax, longer p.o. half life and higher bioavailability in oral administration (p.o. ) in vivo, which means that deuteration helps FTO inhibitors achieve higher oral administration expoure, while keeping comparable or improved FTO inhibition.

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

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof,

L₁ is -NR_a-or a single bond, wherein R_a is hydrogen, deuterium, C_1-6alkyl or C_1-6alkoxy, each of said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with deuterium, halogen, hydroxy (-OH) , deuterated hydroxy (-OD) , C_1-6alkoxy, deuterated C_1-6alkoxy, C_1-6alkyl-S-, or deuterated C_1-6alkyl-S-;

L₂ is C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, or a single bond, wherein each of said C_1-6alkylene, C_2-6alkenylene, or C_2-6alkynylene is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, or deuterated C_1-6alkyl;

L₃ is a single bond, -O-, -S-, -SO-, -SO₂-, -NR_c-, -C (O) -, -C (O) O-, -C (O) NR_c-, -OC (O) NR_c-, -C (O) ONR_c-, -C (O) N (R_c) O-, -OC (O) NR_c-, or -NR_cC (O) -; wherein R_c is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2- ₆alkynyl, haloC_1-6alkyl, hydrxoyC_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, phenyl, phenylalkyl-, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein the alkyl moiety in each of said C_1-6alkyl, haloC_1- ₆alkyl, hydrxoyC_1-6alkyl, or C_1-6alkoxy-C_1-6alkyl, or each of said C_2-6alkenyl, C_2-6alkynyl, phenyl, phenylalkyl-, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is unsubstituted or substituted with deuterium;

R₁ is hydrogen, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each of said C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl is unsubstituted or substituted with R_b, and each of said C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d;

wherein

R_b is deuterium, halogen, cyano, hydroxy, deuterated hydroxy, C_1-6alkoxy, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with at least one substituents selected from the group consisting of deuterium, cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, hydroxy, deuterated hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, deuterated C_1-6alkyl-S-, C_3- ₆cycloalkyl, deuterated C_3-6cycloalkyl, phenyl, deuterated phenyl, heteroaryl, deuterated heteroaryl, heterocyclyl, or deuterated heterocyclyl;

R_d is selected from deuterium, cyano, halogen, oxo, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f,

wherein

R_m, R_n and R_p are each independently hydrogen, hydroxy, deuterated hydroxy, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, phenyl-C_1-6alkyl-, heteroaryl-C_1-6alkyl-, heterocyclyl-C_1- ₆alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, oxo, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R_e is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloalkoxy, hydroxy, deuterated hydroxy, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1- ₆alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1- ₆alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2- ₆alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1-6alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, deuterated C_1-6alkoxy, C_1-6alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkyl, deuterated C_1- ₆alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R₂ is hydrogen, deuterium, halogen, cyano, C_1-6alkyl, deuterated C_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy;

R₃ is hydrogen, deuterium, halogen, cyano, C_1-6alkyl, deuterated C_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy;

R₄ is cyano; hydrogen; deuterium; halogen; hydroxy; deuterated hydroxy; C_1-6alkoxy; C_1-6alkyl-S-; nitro (-NO₂) ; or -SF₅, each of said C_1-6alkoxy or C_1-6alkyl-S-is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; or C_1-6alkyl, C_2-6alkenyl or C_2- ₆alkynyl, each of said C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkoxy or C_1-6alkyl-S-;

R₅ is hydrogen, deuterium, nitro (-NO₂) , cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, -C (O) OR_5a, -SO₂-R_5a, or -SF₅; wherein R_5a is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

provided that if L₁, L_2, and L₃ are each a single bond, then R₁ is not hydrogen;

further provided that at least one of R₁, R₂, R₃, R₄, R₅, L₁, L₂ and L₃ comprise one or more deuterium.

R₂

In some embodiments, R₂ is hydrogen, deuterium, fluoro, chloro, or bromo. In some embodiments, R₂ is hydrogen or deuterium. In some embodiments, R₂ is -CN, -CH₃, -OH, -OD, -OCH₃, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃.

R₃

In some embodiments, R₃ is hydrogen, deuterium, fluoro, chloro, or bromo. In some embodiments, R₃ is hydrogen or deuterium. In some embodiments, R₃ is -CN, -CH₃, -OH, -OD, -OCH₃, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃.

R₄

In some embodiments, R₄ is hydrogen; deuterium; halogen; hydroxy; deuterated hydroxy; nitro; cyano; -SF₅; C_1-6alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; C_1-6alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; C_1-6alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy or C_1-6alkyl-S-; C_2-6alkenyl; or C_2-6alkynyl.

In some embodiments, R₄ is C_1-4alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-4alkoxy, or deuterated C_1-4alkoxy; C_1-4alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-4alkoxy, or deuterated C_1-4alkoxy; C_1- ₄alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1- ₄alkoxy, deuterated C_1-4alkoxy, or C_1-4alkyl-S-; C_2-4alkenyl; or C_2-4alkynyl.

In some embodiments, R₄ is C_1-2alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-2alkoxy, or deuterated C_1-2alkoxy; C_1-2alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-2alkoxy, or deuterated C_1-2alkoxy; or C_1-2alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1- ₂alkoxy, deuterated C_1-2alkoxy, or C_1-2alkyl-S-.

In some embodiments, R₄ is hydrogen, deuterium, nitro, cyano, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxy, deuterated hydroxy, methoxy, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, methoxy-d3 (i.e., -OCD₃) , -OCHD₂, -OCH₂D, ethoxy, ethoxy-d5 (i.e., -OCD₂CD₃) , -OCH₂CD₃, -OCD₂CH₃, difluoromethoxy, trifluoromethoxy, methylthio, trifluoromethylthio, vinyl, ethynyl, fluoro, chloro, bromo or iodo. In some embodiments, R₄ is hydrogen, deutrium, hydroxy, deuterated hydroxy, methoxy, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, ethoxy, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, fluoro, chloro, methyl, nitro, cyano, difluoromethoxy or trifluoromethoxy.

R₅

In some embodiments, R₅ is deuterium, nitro, cyano, halogen, C_1-4alkyl, deuterated C_1-4alkyl, haloC_1- ₆alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, deuterated C_1-4alkoxy, haloC_1-4alkoxy, -SF₅, -C (O) OR_5a, and -SO₂-R_5a, wherein R_5a is hydrogen, C_1-4alkyl or haloC_1-4alkyl.

In some embodiments, R₅ is deuterium, nitro, cyano, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, ethynyl, vinyl, methoxycarbonyl, carboxyl, methylsulfonyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃. In some embodiments, R₅ is nitro, fluoro, chloro, or cyano.

In some embodiments, themoiety is selected from the group consisting of:

-

L₁, L₂, L₃ and R₁

In some embodiments, L₁ is -NR_a-, wherein R_a is C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_1- ₆alkoxy, deuterated C_1-6alkoxy, or hydroxyC_1-6alkyl.

In some embodiments, L₂ is C_1-6alkylene, C_2-6alkenylene, or C_2-6alkynylene, wherein each of said C_1- ₆alkylene, C_2-6alkenylene, or C_2-6alkynylene is unsubstituted or substituted with deuterium, halogen, or hydroxy.

In some embodiments, L₃ is a single bond, -O-, -S-, -NR_c-or -C (O) -; wherein R_c is hydrogen, C_1- ₆alkyl, or deuterated C_1-6alkyl.

In some embodiments, R₁ is C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each of said C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl is unsubstituted or substituted with R_b, and each of said C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d;

wherein

R_b is deuterium, halogen, cyano, hydroxy, C_1-6alkoxy, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with at least one substituents selected from the group consisting of deuterium, cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, deuterated C_1-6alkyl-S-, C_3-6cycloalkyl, deuterated C_3-6cycloalkyl, phenyl, deuterated phenyl, heteroaryl, deuterated heteroaryl, heterocyclyl or deuterated heterocyclyl;

R_d is selected from deuterium, cyano, halogen, oxo, C_1-6alkyl, C_1-6alkoxy, hydroxy, C_2-6alkenyl, C_2- ₆alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f,

wherein

R_m, R_n and R_p are each independently hydrogen, hydroxy, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxyC_1- ₆alkyl-, phenyl-C_1-6alkyl-, heteroaryl-C_1-6alkyl-, heterocyclyl-C_1-6alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, oxo, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R_e is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloalkoxy, hydroxy, deuterated hydroxy, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1- ₆alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxy, hydroxyC_1- ₆alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy.

In some embodiments, if L₃ is a single bond, and L₂ is any one of C_1-6alkylene, C_2-6alkenylene, or C_2- ₆alkynylene, then R₁ is not any one of C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl.

In some further embodiments, R₄ is halogen (e.g., Cl) , C_1-6alkoxy or deuterated C_1-6alkoxy, . In some even further embodiments, R₄ is Cl. In some even further embodiments, R₄ is methoxy, ethoxy, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃.

In some embodiments,

R₄ is hydroxy, deuterated hydroxy, or halogen (e.g., F, Cl or Br) ,

R₅ is haloC_1-6alkyl (e.g, trifluoromethyl) or SO₂-R_5a, wherein R_5a is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

L₁ is -NR_a-, wherein R_a is C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, deuterated C_1- ₆alkoxy, or hydroxyC_1-6alkyl;

L₂ is C_1-6alkylene, C_2-6alkenylene, or C_2-6alkynylene, wherein each of said C_1-6alkylene, C_2- ₆alkenylene, or C_2-6alkynylene is unsubstituted or substituted with deuterium, halogen, or hydroxy, deuterated hydroxy;

R₁ is hydrogen, deuterium, cyano, C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR_b, -SR_b, -SOR_b, -SO₂R_b, -NR_bR_c, -C (O) R_b, -C (O) OR_b, -C (O) NR_bR_c, -OC (O) NR_bR_c, or -NR_bC (O) R_c, each of which is defined as in Formula (I) .

In some embodiments,

R₄ is hydrogen, halogen (e.g., F, Cl or Br) , nitro, CN, C_1-6alkyl (e.g., C_1-4alkyl, further e.g., methyl) or C_1-6alkoxy (e.g., methoxy) which is unsubstituted or substituted with deuterium, halogen, hydroxy or C_1- ₆alkoxy,

R₅ is nitro, CN or halogen;

R₁ is deuterium, hydrogen, cyano, C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR_b, -SR_b, -SOR_b, -SO₂R_b, -NR_bR_c, -C (O) R_b, -C (O) OR_b, -C (O) NR_bR_c, -OC (O) NR_bR_c, or -NR_bC (O) R_c, wherein each of said C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d;

wherein

R_b and R_c are each independently hydrogen, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- ₈cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein said each of C_1-6alkyl, C_2-6alkenyl or C_2- ₆alkynyl is unsubstituted or substituted with R_b, and each of said C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d; wherein R_b is deuterium, cyano, halogen, hydroxy, C_1-6alkoxy, phenyl, heteroaryl or heterocyclyl, wherein each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d;

wherein

R_m, R_n and R_p are each independently hydrogen, hydroxy, C_1-6alkyl, haloC_1-6alkyl, C_1- ₆alkoxyC_1-6alkyl-, phenyl-C_1-6alkyl-, heteroaryl-C_1-6alkyl-, heterocyclyl-C_1-6alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with deuterium, halogen, hydroxy, oxo, C_1-6alkyl, C_1- ₆alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R_e is deuterium, halogen, C_1-6alkyl, C_1-6alkoxy, haloalkoxy, hydroxy, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1- ₆alkyl or haloC_1-6alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2- ₆alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1-6alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy.

-L₁-L₂-L₃-R₁ wherein L ₁ is -NR_a -

R_a

In some embodiments, R_a is C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, deuterated C_1- ₆alkoxy, or hydroxyC_1-6alkyl. In some embodiments, R_a is C_1-6alkyl, or deuterated C_1-6alkyl. In some embodiments, R_a is C_1-4alkyl, or deuterated C_1-4alkyl. In some embodiments, R_a is methyl, ethyl, propyl, isopropyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -CH₂CH₂CD₃, -CH₂CD₂CD₃, -CD₂CD₂CD₃, -C (D) (CH₃) ₂, -C (D) (CH₃) (CD₃) , -C (D) (CD₃) ₂, -C (H) (CD₃) ₂, or -C (H) (CH₃) (CD₃) .

(a) -L₁-L₂-L₃-R₁ wherein L ₁ is NR_a as defined above, L₂ is a single bond, L₃ is a single bond, and R₁ is C_1-6alkyl, C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl

In some embodiments, R₁ is C_1-6alkyl or deuterated C_1-6alkyl. In some embodiments, R₁ is C_1-4alkyl or deuterated C_1-4alkyl.

In some embodiments, -L₁-L₂-L₃-R₁ is selected from the group consisting of

In some embodiments, R₁ is C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl, each of which is unsubstituted or substituted as defined in Formula (I) . In some embodiments, R₁ is C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl, wherein each of heteroaryl, heterocyclyl, aryl, or C_3-8cycloalkyl is unsubstituted or substituted with R_d,

wherein

R_d is deuterium, cyano, C_1-6alkyl, deuterated C_1-6alkyl, halogen, heteroaryl, heterocyclyl, oxo, -C (O) NR_mR_n, NR_mR_n, -OR_m or -NR_mC (O) NR_nR_p, wherein R_m, R_n and R_p are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy.

In some embodiments, R₁ is methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, butyl, isobutyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, difluoromethyl, cyanomethyl or cyclopropylmethyl.

In some embodiments, R₁ is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl) , triazolyl (e.g., 4H-1, 2, 4-triazol-3-yl) , oxazolyl, isoxazolyl (e.g., isoxazole-3-yl, isoxazole-5-yl) , pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-5-yl) , pyrazolyl, benzoisoxazol-3-yl (e.g., benzo [c] isoxazole-3-yl) , triazolopyridin-3-yl, triazolooxazinyl, tetratriazolopyridin-3-yl (e.g., 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl) , dihydrotriazolooxazinyl (e.g., 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazin-3-yl, 6, 8-dihydro-5H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazin-3-yl) , or isoquinolinyl (i.e., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl) , each which is unsubstituted or substituted with at least one substituents selected from the group consisting of deuterium, C_1-6alkyl, deuterated C_1-6alkyl, halogen, heteroaryl, oxo, -C (O) NR_mR_n, NR_mR_n, -OR_m, -NR_mC (O) R_n, or -NR_mC (O) NR_nR_p, preferably fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, phenyl, pyridinyl, methylureido, acetylamino, amino, oxo, and phenoxy; R₁ is -OR_b or -SR_b, wherein R_b is C_1-6alkyl or phenyl, wherein said C_1-6alkyl is unsubstituted or substituted with R_b, and said phenyl is unsubstituted or substituted with R_d, wherein R_b is deuterium, halogen or hydroxy, deuterated hydroxy, and R_d is deuterium, halogen, hydroxy and C_1-6alkyl; or R₁ is C_1-6alkylamino, diC_1-6alkylamino, N-phyenylamino or N-C_1-6alkyl-N-phenylamino, said phenyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen and C_1-6alkyl; or R₁ is C (O) NR_bR_c or -SO₂R_b, wherein R_b and R_c are each hydrogen or C_1-6alkyl; or R₁ is carbamoyl (i.e., NH₂C (O) -) or methylsulfonyl (CH₃SO₂-) .

In some embodiments, -L₁-L₂-L₃-R₁ is selected from the group consisting of:

(b) -L₁-L₂-L₃-R₁ wherein L₁ is NR_a as defined above, L₂ is C_1-6alkylene, L₃ is a single bond and R₁ is aryl

In some embodiments, L₂ is C_1-6alkylene which is unsubstituted or substituted with deuterium, halogen, or deuteratedC_1-6alkyl, preferably C_1-3alkylene or deuterated C_1-3alkylene, e.g., methylene (CH₂) , -CD₂-, ethylene (-CH₂CH₂-) , -CD₂CD₂-, -CD₂CH₂-, or -CH₂CD₂-, and R₁ is an aryl group, wherein said aryl is unsubstituted or substituted with R_d,

wherein R_d is selected from deuterium, cyano, halogen, oxo, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, C_3-8cycloalkyl, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -NR_mR_n, -C (O) NR_mR_n, -C (O) R_m, -C (O) OR_m, phenyl, heteroaryl or heterocyclyl, wherein each of said C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, C_2-6alkenyl, or C_2-6alkynyl is unsubstituted or substituted with R_e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f,

R_m, R_n and R_p are each independently hydrogen, C_1-6alkyl, haloC_1-6alkyl, heterocyclyl, heteroaryl, or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy,

wherein

R_e is deuterium, halogen, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1- ₆alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1-6alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1- ₆alkyl or haloC_1-6alkoxy.

In some embodiments, R₁ is a phenyl group, wherein said phenyl is unsubstituted or substituted with R_d as defined above. In some further embodiments, R_d is selected from deuterium, cyano, halogen, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -NR_mR_n or phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino is unsubstituted or substituted with R_f, wherein R_m, R_n and R_p are each independently hydrogen or C_1-6alkyl, deuterated C_1- ₆alkyl, wherein R_e is deuterium, halogen, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino, each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino is unsubstituted or substituted with halogen, hydroxy, deuterated hydroxy, C_1-6alkyl or C_1-6alkoxy; R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, or hydroxyC_1-6alkyl-; and R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, or deuterated C_1-6alkyl.

In some embodiments, R₁ is an aryl group, e.g., a phenyl group, said aryl is unsubstituted or substituted with at least one substituents selected from deuterium, chloro, fluoro, bromo, phenyl, methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, deuterated hydroxy, methoxy, ethoxy, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, 1-methyl-d3-1H-pyrazol-4-ylamino, dimethylamino, di (methyl-d3) amino, 3- (hydroxymethyl) pyridin-2-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-methyl-d3-piperazin-1-yl) piperidin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-d3-piperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, 1-methyl-d3-piperidin-4-yl, pyrimidin-4-yl, morpholino, 2, 2, 2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl) methoxy, (1-methyl-d3-piperidin-4-yl) methoxy, (1-methyl-1H-pyrazol-4-yl) methyl, (1-methyl-d3-1H-pyrazol-4-yl) methyl, aminocarbonylmethyl, methylaminocarbonylmethyl or acetamido.

1)

2)

3)

4)

5)

6)

7)

8)

9) or

10)

(c) -L₁-L₂-L₃-R₁ wherein L₁ is NR_a as defined above, L₂ is C_1-6alkylene, L₃ is a single bond and R₁ is C_3-8cycloalkyl, heteroaryl or heterocyclyl

In some embodiments, L₂ is C_1-6alkylene which is unsubstituted or substituted with deuterium, halogen, or deuteratedC_1-6alkyl, preferably C_1-3alkylene or deuterated C_1-3alkylene, e.g., methylene (CH₂) , -CD₂-, ethylene (-CH₂CH₂-) , -CD₂CD₂-, -CD₂CH₂-, or -CH₂CD₂-, and R₁ is heteroaryl or heterocyclyl, wherein each of said heteroaryl or heterocyclyl is unsubstituted or substituted with R_d,

R_d is deuterium, cyano, halogen, oxo, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, hydroxy, deuterated hydroxy, -NR_mR_n, phenyl, heteroaryl or heterocyclyl, wherein said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f, wherein R_m and R_n are each independently hydrogen, C_1- ₆alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy; wherein R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1- ₆alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1- ₆alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy.

In some embodiments, R₁ is heteroaryl or heterocyclyl, wherein said heteroaryl or heterocyclyl is pyridinyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinoliny, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or substituted with R_d as defined above. In some further embodiments, R_d is deuterium, cyano, halogen, oxo, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, hydroxy, deuterated hydroxy, -NR_mR_n; phenyl, heteroaryl, heterocyclyl; halogen or C_1-6alkyl-substituted phenyl; halogen or C_1-6alkyl-substituted heteroaryl; or halogen or C_1-6alkyl-substituted heterocyclyl, wherein R_m and R_n are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl or heterocyclyl.

In some embodiments, R₁ is heteroaryl or heterocyclyl, wherein said heteroaryl or heterocyclyl is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl) , pyrazinyl (e.g., pyrazin-2-yl, pyrazin-4-yl) , dihydrobenzofuranyl (e.g., dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl) , indazolyl (e.g., 1H-indazol-6-yl) , benzodioxinyl, dihydrobenzodioxinyl (e.g., 2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) , isoquinoliny (e.g., isoquinolin-6-y) , triazol-4-yl (e.g., 1H-1, 2, 3-triazol-4-yl, 1H-1, 2, 4-triazol-3-yl) , imidazolyl (e.g., 1H-imidazol-4-yl) , isoxazolyl (e.g., isoxazol-5-yl) , oxazolyl (e.g., oxazol-2-yl) , thiazolyl (e.g., thiazol-2-yl) or triazolyl (e.g., 1H-1, 2, 3-triazol-4-yl or 1H-1, 2, 4-triazol-3-yl) , each of which is unsubstituted or substituted with deuterium, chloro, fluoro, hydroxy, deuterated hydroxy, methyl, -CD₃, -CHD₂, -CH₂D, cyano, oxo, methoxy, -OCD₃, -OCHD₂, -OCH₂D, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl) , pyridin-4-yl, phenyl or NR_mR_n, wherein R_m and R_n are each independently hydrogen, C_1-6alkyl or triazolyl (e.g., 1H-1, 2, 3-triazol-4-yl) .

1)

2)

3)

4) or

5)

(d) -L₁-L₂-L₃-R₁ wherein L₁ is NR_a as defined above, L₂ is C_1-6alkylene and L₃ is -O-, -S-, -SO-, - SO₂-, -NR_c-, -C (O) -, C (O) O-, -C (O) NR_c-, -OC (O) NR_c-, -C (O) ONR_c-or -NR_cC (O) -and R₁ is hydrogen, deuterium, C_1-6alkyl, phenyl or naphthyl, heteroaryl or heterocyclyl

In some embodiments, L₂ is C_1-6alkylene which is unsubstituted or substituted with deuterium, halogen, or deuteratedC_1-6alkyl, preferably C_1-3alkylene or deuterated C_1-3alkylene, e.g., methylene (CH₂) , -CD₂-, ethylene (-CH₂CH₂-) , -CD₂CD₂-, -CD₂CH₂-, or -CH₂CD₂-;

wherein R₁ is C_1-6alkyl, phenyl or naphthyl, heteroaryl or heterocyclyl, wherein said C_1-6alkyl is unsubstituted or substituted with R_b, and said phenyl or heteroaryl or heterocyclyl is unsubstituted or substituted with R_d,

R_b is deuterium, halogen, cyano, hydroxy, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1- ₆alkoxy, phenyl, heteroaryl, or heterocyclyl;

R_d is deuterium, cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, oxo, C_1-6alkoxyC_1-6alkyl-, hydroxyC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, phenyl, heterocyclyl, heteroaryl, -SF₅, -NR_mC (O) NR_nR_p, NR_mR_n, -C (O) NR_nR_n, -NR_mC (O) R_n, -C (O) R_m, or -C (O) OR_m, wherein each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy, wherein R_m and R_n are each independently is hydrogen, C_1-6alkyl or haloC_1- ₆alkyl.

In some embodiments, R₁ is C_1-6alkyl, phenyl or naphthyl or heteroaryl selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl) ; pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl) ; benzo [d] imidazolyl (e.g., benzo [d] imidazole-4-yl) ; indazolyl (e.g., indazol-4-yl) ; or heterocyclyl (e.g., dihydropyridinyl, or azetidinyl) , wherein said C_1-6alkyl is unsubstituted or substituted with R_b, and said phenyl or heteroaryl or heterocyclyl is unsubstituted or substituted with R_d, wherein R_b is deuterium, halogen, cyano, hydroxy or C_1-6alkoxy; R_d is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, oxo, C_1- ₆alkoxyC_1-6alkyl-, hydroxyC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, phenyl, heterocyclyl (e.g., azetidinyl) , heteroaryl (e.g., pyridinyl, pyrazolyl, pyridinyl, pyrazinyl) , NR_mR_n, -C (O) NR_mR_n or -NR_mC (O) R_n, wherein each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-4alkyl, C_1-4alkoxy, haloC_1-4alkyl or haloC_1-4alkoxy, wherein R_m and R_n are each independently is hydrogen or C_1-4alkyl, or deuterated C_1-4alkyl.

1)

2)

3) or

4)

(e) -L₁-L₂-L₃-R₁ wherein L₁ is NR_a as defined above, L₂ is C_2-6alkenylene or C_2-6alkynylene and L₃ is a single bond, -O-, -S-, -SO-, -SO₂-, -NR_c-, -C (O) -, C (O) O-, -C (O) NR_c-, -OC (O) NR_c-, or -NR_cC (O) - and R₁ is hydrogen, deuterium, phenyl or naphthyl, heteroaryl or heterocyclyl

In some embodiments, L₂ is C_2-6alkynylene or C_2-6alkynylene which is unsubstituted or substituted with deuterium, deuterated C_1-6alkyl, or halogen, and R₁ is defined as in Formula (I) . In some embodiments, R₁ is selected from deuterium, hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl, wherein said C_1-6alkyl is unsubstituted or substituted with R_b and each of said C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d, wherein R_b is deuterium, halogen, cyano, hydroxy, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, phenyl, heteroaryl, or heterocyclyl; and R_d is deuterium, cyano, C_1-6alkyl, deuterated C_1-6alkyl, halogen, oxo, C_1-6alkoxy, deuterated C_1-6alkoxy, -OR_m or -NR_mR_n, wherein R_m and R_n are each independently hydrogen, C_1-6alkyl or phenyl, wherein R_m and R_n are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl or phenyl.

In some embodiments, L₂-L₃-R₁ is ethynyl, prop-2-ynyl, but-2-ynyl, but-3-yn-2-yl, pent-2-ynyl, pent-2-ynyl, pent-3-ynyl, pent-3-yn-2-yl, pent-3-yn, hex-2-ynyl, each of which is unsubstituted or substituted with one or two halogen, C_1-6alkyl, deuterated C_1-6alkyl, hydroxy, or deuterated hydroxy or substituted with C_3- ₈cycloalkyl, heteroaryl, heterocyclyl, aryl, and -NR_mR_n, wherein R_m and R_n are each independently hydrogen, C_1-6alkyl or phenyl, and wherein each of said C_3-8cycloalkyl, heteroaryl, heterocyclyl or aryl is unsubstituted or substituted with deuterium, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1- ₆alkoxy, hydroxy, deuterated hydroxy, oxo, halogen, di-C_1-6alkylamino, C_1-6alkylamino or amino; preferably L₂-L₃-R₁ is ethynyl, prop-2-ynyl, but-2-ynyl, but-3-yn-2-yl, pent-2-ynyl, pent-2-ynyl, pent-3-ynyl, pent-3-yn-2-yl, pent-3-yn, hex-2-ynyl, each of which is unsubstituted or substituted with fluoro, chloro, bromo, methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, propyl, isopropyl, butyl, isobutyl, pentyl, hydroxy, deuterated hydroxy, 1-hydroxycyclopropyl, cyclopropyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-2-oxo-1, 2-dihydropyridin-3-yl, 1-methyl-2-oxopiperidin-3-yl, 2-chlorophenyl, 2-cyanophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 3-fluorophenyl, 4-fluorophenyl, pyridin-3-yl, pyridin-4-yl, o-tolyl, phenyl, pyrazin-2-yl, pyridin-2-yl or dimethylamino.

1)

2)

3)

4) or

5)

(f) -L₁-L₂-L₃-R₁ wherein L₁ is NR_a as defined above, L₂ is a single bond, L₃ is -O-, -S-, -NR _c -, C (O) NR _c -or -SO₂-and R₁ is C_1-6alkyl, C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl

In some embodiments, L₃ is -O-, -S-, -NR_c-, C (O) NR_c-or -SO₂-, and R₁ is C_1-6alkyl, C_3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl; wherein said C_1-6alkyl is unsubstituted or substituted with R_b, and each of heteroaryl, heterocyclyl, aryl, or C_3-8cycloalkyl is unsubstituted or substituted with R_d,

wherein

R_d is deuterium, cyano, C_1-6alkyl, deuterated C_1-6alkyl, halogen, heteroaryl, heterocyclyl, oxo, -C (O) NR_mR_n, NR_mR_n, -OR_m or -NR_mC (O) NR_nR_p, wherein R_m, R_n and R_p are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R_b is cyano, halogen, hydroxy, deuterated hydroxy, C_3-6cycloalkyl, or phenyl.

In some embodiments, R₁ is pyridin-3-yl, 3, 4-dimethylisoxazol-5-yl, 3, 4-di (methyl-d3) isoxazol-5-yl, 3-methyl-4-phenylisoxazol-5-yl, 3-methyl-d3-4-phenylisoxazol-5-yl, 4-methyl-3- (pyridin-2-yl) isoxazol-5-yl, 4-methyl-d3-3- (pyridin-2-yl) isoxazol-5-yl, 4-methyl-3-phenylisoxazol-5-yl) , 4-methyl-d3-3-phenylisoxazol- 5-yl) , 4-methyl-4H-1, 2, 4-triazol-3-yl, 4-methyl-d3-4H-1, 2, 4-triazol-3-yl, 4-methyl-6- (methylureido) pyridin-3-yl, 4-methyl-d3-6- (methylureido) pyridin-3-yl, 4-methyl-6-acetylaminopyridin-3-yl, 4-methyl-d3-6-acetylaminopyridin-3-yl, 4-methyl-6-aminopyridin-3-yl, 4-methyl-d3-6-aminopyridin-3-yl, 4-methylisoxazol-3-yl, 4-methyl-d3-isoxazol-3-yl, 4-methylisoxazol-5-yl, 4-methyl-d3-isoxazol-5-yl, 4-methylpyridin-3-yl, 4-methyl-d3-pyridin-3-yl, 4-methylpyrimidin-5-yl, 4-methyl-d3-pyrimidin-5-yl, 4-phenylisoxazol-5-yl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyridin-3-yl, 5-fluoro-4-methylpyridin-3-yl, 5-fluoro-4-methyl-d3-pyridin-3-yl, 5-methyl-2-oxo-1, 2-dihydropyridin-4-yl, 5-phenoxypyridin-3-yl, 6, 7-dihydro-4H- [1, 2, 3] triazolo [5, 1-c] [1, 4] oxazin-3-yl, 6, 8-dihydro-5H- [1, 2, 4] triazolo [3, 4-c] [1, 4] oxazin-3-yl or benzo [c] isoxazol-3-yl.

-L₁-L₂-L₃-R₁

-L₁-L₂-L₃-R₁ wherein L₁ is a single bond, L₂ is a single bond, L₃ is a single bond, -O-or -S-, and R₁ is C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl or C_3-8cycloalkyl

In some embodiments, L₁ is a single bond, L₂ is a single bond, L₃ is a single bond, -O-or -S-, and R₁ is C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl or C_3-8cycloalkyl; each of which is unsubstituted or substituted with deuterium, cyano, halogen, hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, C_1- ₆alkylcarbonylamino, or phenyl which is unsubstituted or substituted with deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1- ₆alkoxy, C_1-6alkyl-S-or cyano; in other embodiments, R₁ is methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, t-butyl, ethynyl, or vinyl.

In some embodiments, L₁ is a single bond, L₂ is a single bond, L₃ is a single bond, and R₁ is C_1-6alkyl, deuterated C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl; in other embodiments, R₁ is methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, t-butyl, ethynyl, or vinyl.

In some embodiments, L₁ is a single bond, L₂ is a single bond, L₃ is -O-or -S-, and R₁ is C_1-6alkyl, deuterated C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl; in other embodiments, R₁ is methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, t-butyl, ethynyl, or vinyl.

In some embodiments, L₁ is a single bond, L₂ is a single bond, L₃ is a single bond, and R₁ is C_3- ₈cycloalkyl, which is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1- ₆alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, C_1-6alkyl-S-or deuterated C_1-6alkyl-S-.

1) Me, Et, CD₃, CD₂CD₃, iPr, -CD (CD₃) ₂, or C (CD₃) ₃;

2)

3)

4)

5)

6) or

7)

In some embodiments, the compound is a deuterated compound of Formula (II)

R_a is hydrogen, deuterium, C_1-6alkyl or C_1-6alkoxy, each of said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, C_1- ₆alkyl-S-, or deuterated C_1-6alkyl-S-;

L₂ is C_1-6alkylene, which is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, or deuterated C_1-6alkyl;

wherein

provided that at least one of R₁, R₂, R₃, R₄, R₅, and L₂ comprise one or more deuterium.

R₂

R₃

R₄

R₅

In some embodiments, themoiety is selected from the group consisting of:

-

R_a

In some embodiments, R_a is defined as in Formula (I) .

In some embodiments, R_a is C_1-6alkyl or deuterated C_1-6alkyl. In some embodiments, R_a is C_1-4alkyl or deuterated C_1-4alkyl. In some embodiments, R_a is methyl, ethyl, propyl, isopropyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -CH₂CH₂CD₃, -CH₂CD₂CD₃, -CD₂CD₂CD₃, -C (D) (CH₃) ₂, -C (D) (CH₃) (CD₃) , -C (D) (CD₃) ₂, -C (H) (CD₃) ₂, or -C (H) (CH₃) (CD₃) .

L₂

In some embodiments, L₂ is defined as in Formula (I) . In some embodiments, L₂ is C_1-6alkylene which is unsubstituted or substituted with deuterium, halogen, or deuteratedC_1-6alkyl, preferably C_1-3alkylene or deuterated C_1-3alkylene, e.g., methylene (CH₂) , -CD₂-, ethylene (-CH₂CH₂-) , -CD₂CD₂-, -CD₂CH₂-, or -CH₂CD₂-.

R₁

In some embodiments, R₁ is defined as in Formula (I) .

In some embodiments, R₁ is hydrogen, deuterium, C_1-6alkyl or deuterated C_1-6alkyl. In some embodiments, R₁ is hydrogen, deuterium, C_1-4alkyl or deuterated C_1-4alkyl. In some embodiments, R₁ is hydrogen, or deuterium.

In some embodiments, L₂-R₁ is C_1-6alkyl or deuterated C_1-6alkyl. In some embodiments, L₂-R₁ is C_1- ₄alkyl or deuterated C_1-4alkyl. In some embodiments, L₂-R₁ is methyl, ethyl, propyl, isopropyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -CH₂CH₂CD₃, -CH₂CD₂CD₃, -CD₂CD₂CD₃, -C (D) (CH₃) ₂, -C (D) (CH₃) (CD₃) , -C (D) (CD₃) ₂, -C (H) (CD₃) ₂, or -C (H) (CH₃) (CD₃) .

In some embodiments, at least one of L₂-R₁ and R_a is deuterated.

In some embodiments, R₁ is aryl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with R_d,

wherein

In some embodiments, R₁ is phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, wherein each of said phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d as defined above. In some further embodiments, R_d is selected from deuterium, cyano, halogen, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -NR_mR_n or phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino is unsubstituted or substituted with R_f, wherein R_m, R_n and R_p are each independently hydrogen or C_1-6alkyl, deuterated C_1-6alkyl, wherein R_e is deuterium, halogen, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino, each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino is unsubstituted or substituted with halogen, hydroxy, deuterated hydroxy, C_1-6alkyl or C_1-6alkoxy; R_f is deuterium, halogen, C_1- ₆alkyl, deuterated C_1-6alkyl, or hydroxyC_1-6alkyl-; and R_e1 and R_e2 are each independently hydrogen, C_1- ₆alkyl, or deuterated C_1-6alkyl.

In some embodiments, R₁ is phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, wherein each of said phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl is unsubstituted or substituted with at least one substituents selected from deuterium, chloro, fluoro, bromo, phenyl, methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, deuterated hydroxy, methoxy, ethoxy, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, 1-methyl-d3-1H-pyrazol-4-ylamino, dimethylamino, di (methyl-d3) amino, 3- (hydroxymethyl) pyridin-2-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-methyl-d3-piperazin-1-yl) piperidin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-d3-piperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, 1-methyl-d3-piperidin-4-yl, pyrimidin-4-yl, morpholino, 2, 2, 2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl) methoxy, (1-methyl-d3-piperidin-4-yl) methoxy, (1-methyl-1H-pyrazol-4-yl) methyl, (1-methyl-d3-1H-pyrazol-4-yl) methyl, aminocarbonylmethyl, methylaminocarbonylmethyl or acetamido.

Themoiety is selected from the group consisting of:

a)

b)

c)

d)

e)

f)

g)

h)

i)

j)

k)

l)

m)

n) or

o)

In some embodiments, disclosed here are the compounds selected from the group consisting of Examples 1 to 717.

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.

Brief descripton of the drawings

The following detailed description, given by way of example, but not intended to limit the invention solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings.

Figure 1 shows animal pharmacokinetics curve of intravenous injection (i.v. ) and oral administration (p.o. ) of Ex. 434 v Ex. P849-486.

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., C2-6 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;

- 7-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.

“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.

Example 82

(Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) -N- (methyl-d3) acrylamide

Step 1: Synthesis of N- (5-chloro-2-fluorobenzyl) methan-d3-amine (2)

The mixture of 5-chloro-2-fluorobenzaldehyde (1.0 g, 6.3 mmol) in MeOH (20 mL) was added methan-d3-amine (428.9 mg, 12.6 mmol) , NaBH₃CN (476.3 mg, 7.6 mmol) and ZnCl₂ (1.7 g, 12.6 mmol) , then the mixture was warmed to 50℃, stirred for 6 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 silica gel chromatography (DCM/MeOH=20/1) to obtain the product (750 mg, 67%) . MS [M+H] ⁺ calcd for C₈H₆D₃ClFN 177.1, found 177.1.

Step 2: Synthesis of N- (5-chloro-2-fluorobenzyl) -2-cyano-N- (methyl-d3) acetamide (3)

The solution of N- (5-chloro-2-fluorobenzyl) methan-d3-amine (700 mg, 4.0 mmol) and 2-cyanoacetic acid (336.9 mg, 4.0 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 (1.9 g, 6.0 mmol) and DIEA (1.5 g, 12.0 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 (350 mg, 36%) . MS [M-H] ⁺ calcd for C₁₁H₇D₃ClFN₂O 243.9, found 243.9.

Step 3: Synthesis of (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) -N- (methyl-d3) acrylamide (Ex. 82)

The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (131.1 mg, 0.6 mmol) in SOCl₂ (50 mL) was heated to 80℃ for 2 hours. Then it was concentrated in vacuo to dryness and used for next step. A solution of N- (5-chloro-2-fluorobenzyl) -2-cyano-N- (methyl-d3) acetamide (150 mg, 0.6 mmol) in THF (30 mL) was stirred at -78℃ for 10 min under N₂ atmosphere, after LiHMDS (1.5 mL, 1.5 mmol) was added, stirred for another 1 hour. 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 (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1%TFA, 2 times) to obtain the product (137.5 mg, HPLC: 96%) . MS [M-H] ⁺ calcd for C₁₉H₁₂D₃ClFN₃O₆ 439.0, found 439.0. ¹HNMR (400 MHz, CDCl3) δ 11.09 (s, 1H) , 8.42 (s, 1H) , 7.70 (s, 1H) , 7.28-7.32 (m, 2H) , 7.07 (t, J = 8.0 Hz, 1H) , 4.78 (s, 2H) , 4.02 (s, 3H) .

Example 83

methyl (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4-hydroxy-3- (methoxy-d3) -5-nitrophenyl) -N-methylacrylamide

Step 1: Synthesis of methyl 4- (benzyloxy) -3-hydroxybenzoate (2)

A mixture of methyl 3, 4-dihydroxybenzoate (2 g, 12.7 mmol) in MeCN (40 mL) was added BnBr (2.0 g, 12.7 mmol) and K₂CO₃ (1.6 g, 12.7 mmol) . The reaction was stirred at 25℃ for overnight. The mixture was evaporated, dried to obtain the product (2.6 g, 86.1%) . MS [M-H] ^- calcd for C₁₅H₁₄O₄ 256.9, found 256.9.

Step 2: Synthesis of methyl 4- (benzyloxy) -3- (methoxy-d3) benzoate (3)

The mixture of methyl 4- (benzyloxy) -3-hydroxybenzoate (2 g, 7.8 mmol) , CD₃OD (0.4 g, 11.7 mmol) and PPh₃ (3.0 g, 11.7 mmol) in DCM (50 mL) was stirred at 0℃ for 10 mins. Then DIAD (2.3 g, 11.7 mmol) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by DCM (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 (1.6 g, 76.6%) . MS [M+H] ^- calcd for C₁₆H₁₃D₃O₄ 276.0, found 276.0.

Step 3: Synthesis of methyl 4-hydroxy-3- (methoxy-d3) benzoate (4)

To a solution of methyl 4- (benzyloxy) -3- (methoxy-d3) benzoate (1.5 g, 5.5 mmol) , 10%Pd/C (0.2 g) and AcOH (adrop) in EtOH stirred under hydrogen at 25℃. The reaction mixture was stirred for overnight. The mixture was filtered and dried to obtain the product (0.9 g, 90.3%) . MS [M-H] ^- calcd for C₉H₇D₃O₄ 184.1, found 184.1.

Step 4: Synthesis of methyl 4-hydroxy-3- (methoxy-d3) -5-nitrobenzoate (5)

A mixture of methyl 4-hydroxy-3- (methoxy-d3) benzoate (0.9 g, 4.9 mmol) in AcOH (20 mL) was stirred at 0℃. HNO₃ (0.5 mL) was added to the mixture and stirred at 0℃ for 30 mins. The reaction was stirred at rt for 1h. The reaction was quenched by ice water (20 ML) , filtered, washed by H₂O. The yellow solid was the desired product (0.9 g, 81.2%) . MS [M-H] ^- calcd for C₉H₆D₃NO₆ 229.0, found 229.0.

Step 5: Synthesis of methyl 4-hydroxy-3- (methoxy-d3) -5-nitrobenzoic acid (6)

A mixture of methyl 4-hydroxy-3- (methoxy-d3) -5-nitrobenzoate (0.9 g, 3.9 mmol) in THF/H₂O (15 mL/15 mL) was added LiOH (0.5 g, 11.7 mmol) . The reaction was stirred at 50℃ for overnight. The mixture was cooled and acidified to pH about 5-6 by HCl, evaporated, dried to obtain the product (0.8 g, 90.1%) . MS [M-H] ^- calcd for C₈H₄D₃NO₆ 214.9, found 214.9.

Step 6: Synthesis of methyl (Z) -N- (5-chloro-2-fluorobenzyl) -2-cyano-3-hydroxy-3- (4-hydroxy-3- (methoxy-d3) -5-nitrophenyl) -N-methylacrylamide (Ex. 83)

The mixture of methyl 4-hydroxy-3- (methoxy-d3) -5-nitrobenzoic acid (100 mg, 0.5 mmol) in SOCl₂ (20 mL) was heated to 80℃ for 2 hours. Then it was concentrated in vacuo to dryness and used for next step. A solution of N- (5-chloro-2-fluorobenzyl) -2-cyano-N-methylacetamide (111 mg, 0.5 mmol) in THF (20 mL) was stirred at -78℃ for 10 min under N₂ atmosphere, after LiHMDS (1.2 mL, 1.2 mmol) was added, stirred for another 1 hour. 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 Prep-HPLC (H2O/MeCN=45/55, 0.1%TFA, 2 times) to obtain the product (61 mg, HPLC: 98.5%) . MS [M-H] ^- calcd for C₁₉H₁₂D₃ClFN₃O₆ 437.0, found 436.9.

¹HNMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H) , 7.65 (s, 1H) , 7.43 (s, 2H) , 7.32 (d, J = 8.0 Hz, 1H) , 4.76 (s, 2H) , 3.17 (s, 3H) .

Example 434

(Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxy-N, N-bis (methyl-d3) acrylamide

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

The solution of bis (methyl-d3) amine (500 mg, 9.8 mmol) and 2-cyanoacetic acid (833 mg, 9.8 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 (4.7 g, 14.7 mmol) and DIEA (3.8 g, 29.4 mmol) . The flask is evacuated and purged with nitrogen. The mixture is stirred for 8 h at 25℃. The reaction was quenched by water (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 (240 mg, 21%) . MS [M-H] ⁺ calcd for C₅H₂D₆N₂O 119.1, found 119.1.

Step 2: Synthesis of (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) -N, N-bis (methyl-d3) acrylamide (3)

The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (397 mg, 1.9 mmol) in SOCl₂ (50 mL) was heated to 80℃ for 2 hours. Then it was concentrated in vacuo to dryness and used for next step. A solution of 2-cyano-N, N-bis (methyl-d3) acetamide (220 mg, 1.9 mmol) in THF (30 mL) was stirred at -78℃ for 10 min under N₂ atmosphere, after LiHMDS (4.8 mL, 4.8 mmol) was added, stirred for another 1 hour. 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 (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1%TFA, 2 times) to obtain the product (300 mg, 47%) . MS [M-H] ^- calcd for C₁₃H₇D₆N₃O₆ 312.1, found 312.1.

Step 3: Synthesis of (Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (Ex. 434)

The mixture of (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) -N, N-bis (methyl-d3) acrylamide (200 mg, 0.6 mmol) in DCM (20 mL) was stirred at -10℃ for 15 mins. Then BBr₃ (0.1 mL) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by DCM (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=45/55, 0.1%TFA, 2 times) to obtain the crude product (120 mg, 63%) . MS [M-H] ^-calcd for C₁₂H₅D₆N₃O₆ 298.2, found 298.2. ¹HNMR (400 MHz, DMSO-d₆) δ 7.78 (s, 1H) , 6.94 (s, 1H) .

Example 435

(Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl-2, 6-d2) -3-hydroxy-N, N-bis (methyl-d3) acrylamide

Step 1: Synthesis of methyl 3, 4-dimethoxy-5-nitrobenzoate (2)

The mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10.0 g, 44.1 mmol) in acetone (150 mL) was added dimethyl sulfate (8.3 g, 66.1 mmol) and K₂CO₃ (9.1 g, 66.1 mmol) , then the mixture was warmed to 65℃, stirred for overnight. The reaction was cooled and quenched by ice water (50 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=2/1) to obtain the product (5.0 g, 47%) . MS [M-H] ⁺ calcd for C₁₀H₁₁NO₆ 242.1, found 242.1.

Step 2: Synthesis of 3, 4-dimethoxy-5-nitrobenzoic acid (3)

A mixture of methyl 3, 4-dimethoxy-5-nitrobenzoate (5.0 g, 20.7 mmol) in THF/H₂O (30 mL/30 mL) was added LiOH (2.6 g, 62.2 mmol) . The reaction was stirred at RT for 6 h. The mixture was acidified to pH about 5-6 by HCl extracted by DCM (150 mL*3) , dried by Na₂SO₄ to obtain the product (3.0 g, 65.0%) . MS [M-H] ^- calcd for C₁₃H₁₀Cl₂N₂O₅ 225.9, found 225.9.

Step 3: Synthesis of 3-amino-4, 5-dimethoxybenzoic-2, 6-d2 acid (4)

A solution of 3, 4-dimethoxy-5-nitrobenzoic acid (3.0 g, 13.2 mmol) and Pd/C (300 mg) in D₂O (50 mL) was stirred under H₂ at 120 ℃ for 16 h. The solvent was removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, DCM/MeOH = 20/1) afforded the desired product (0.9 g, 33%) . MS [M-H] ^- calcd for C₉H₉D₂NO₄ 197.9, found 197.9.

Step 4: Synthesis of 3, 4-dimethoxy-5-nitrobenzoic-2, 6-d2 acid (5)

A mixture of 3-amino-4, 5-dimethoxybenzoic-2, 6-d2 acid (900 mg, 4.5 mmol) in DCM (60 mL) was added Oxone (5.6 g, 9.0 mmol) and H₂O. The reaction was stirred at RT for 16 h.. The reaction was cooled and quenched by ice water (50 mL) , extracted by DCM (200 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/EMeOH=10/1) to obtain the product (673 mg, 65.0%) . MS [M-H] ^- calcd for C₉H₇D₂NO₆ 227.9, found 227.9.

Step 5: Synthesis of (Z) -2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl-2, 6-d2) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (6)

The mixture of 3, 4-dimethoxy-5-nitrobenzoic-2, 6-d2 acid (450 mg, 2.0 mmol) in SOCl₂ (50 mL) was heated to 80℃ for 2 hours. Then it was concentrated in vacuo to dryness and used for next step. A solution of 2-cyano-N, N-bis (methyl-d3) acetamide (306 mg, 2.0 mmol) in THF (30 mL) was stirred at -78℃ for 10 min under N₂ atmosphere, after LiHMDS (4.9 mL, 4.9 mmol) was added, stirred for another 1 hour. 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 (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1%TFA, 2 times) to obtain the product (350 mg, 54%) . MS [M-H] ^- calcd for C₁₄H₇D₂N₃O₆ 328.1, found 328.1.

Step 6: Synthesis of (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl-2, 6-d2) -N, N-bis (methyl-d3) acrylamide (7)

The mixture of (Z) -2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl-2, 6-d2) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (300 mg, 0.9 mmol) in DCM (20 mL) was stirred at -10℃ for 15 mins. Then BBr₃ (0.2 mL) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by DCM (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=45/55, 0.1%TFA, 2 times) to obtain the crude product (190 mg, 66%) . MS [M-H] ^-calcd for C₁₃H₅D₈N₃O₆ 313.9, found 313.9.

Step 7: Synthesis of (Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl-2, 6-d2) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (Ex. 435)

The mixture of (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl-2, 6-d2) -N, N-bis (methyl-d3) acrylamide (190 mg, 0.6 mmol) in DCM (20 mL) was stirred at -10℃ for 15 mins. Then BBr₃ (0.1 mL) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by DCM (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1%TFA, 2 times) to obtain the crude product (100 mg, 55%) . MS [M-H] ^-calcd for C₁₂H₃D₈N₃O₆ 300.2, found 300.2. ¹HNMR (400 MHz, DMSO-d₆) δ.

Example 436

(Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -N, N-bis (ethyl-d5) -3-hydroxyacrylamide

Step 1: Synthesis of 2-cyano-N, N-bis (ethyl-d5) acetamide (2)

The solution of bis (ethyl-d5) amine (500 mg, 6.0 mmol) and 2-cyanoacetic acid (512 mg, 6.0 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 (2.8 g, 9.0 mmol) and DIEA (2.3 g, 18.1 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 (300 mg, 33%) . MS [M-H] ⁺ calcd for C₇H₂D₁₀N₂O 150.9, found 150.9.

Step 2: Synthesis of (Z) -2-cyano-N, N-bis (ethyl-d5) -3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) acrylamide (3)

The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (426 mg, 2.0 mmol) in SOCl₂ (50 mL) was heated to 80℃ for 2 hours. Then it was concentrated in vacuo to dryness and used for next step. A solution of 2-cyano-N, N-bis (ethyl-d5) acetamide (300 mg, 2.0mmol) in THF (30 mL) was stirred at -78℃ for 10 min under N₂ atmosphere, after LiHMDS (5.0 mL, 5.0 mmol) was added, stirred for another 1 hour. 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 (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1%TFA, 2 times) to obtain the crude product (150 mg, 19%) . MS [M-H] ^-calcd for C₁₅H₇D₁₀N₃O₆ 344.1, found 344.1.

Step 3: Synthesis of (Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -N, N-bis (ethyl-d5) -3-hydroxyacrylamide (Ex. 436)

The mixture of (Z) -2-cyano-N, N-bis (ethyl-d5) -3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) acrylamide (130 mg, 0.4 mmol) in DCM (20 mL) was stirred at -10℃ for 15 mins. Then BBr₃ (0.1 mL) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by DCM (150 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1%TFA, 2 times) to obtain the product (49 mg, HPLC: 99.6%) . MS [M-H] ^- calcd for C₁₄H₅D₁₀N₃O₆ 330.2, found 330.2. ¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (s, 1H) , 7.50 (s, 1H) .

Example 442

(Z) -2-cyano-3- (3-cyano-4, 5-dihydroxyphenyl) -3-hydroxy-N, N-bis (methyl-d3) acrylamide

Step 1: Synthesis of 3-bromo-4-hydroxy-5-methoxybenzoic acid (2)

A solution of 4-hydroxy-3-methoxybenzoic acid (8 g, 47.62 mmol) in AcOH (80 mL) was stirred at 0 ℃ for 1 h. The reaction mixture was poured into ice water and filtrated to obtain the product (9.8 g, 83%) . MS [M+H] ⁺ calcd for C₈H₇BrO₄ 247.2, found 247.2.

Step 2: Synthesis of 3-cyano-4-hydroxy-5-methoxybenzoic acid (3)

To a solution of 3-bromo-4-hydroxy-5-methoxybenzoic acid (5 g, 20.24 mmol) in DMF (50 mL) was added CuCN (2.2 g, 24.29 mmol) . After stirring at 150 ℃ for overnight. Cool the reaction mixture to 25 ℃ and add water (60 mL) to the reaction mixture. Extracted by EA (300 mL*3) , dried by Na₂SO₄, further purification by Prep-HPLC (H2O/MeCN=6/4) afforded the desired product (980 mg, 25%) . MS [M+H] ⁺ calcd for C₉H₇NO₄ 194.2, found 194.2.

Step 3: Synthesis of 2-cyano-N, N-bis (methyl-d3) acetamide (5)

To a solution of dimethyl-d6-amine hydrochloride (2.1 g, 23.53 mmol) and 2-cyanoacetic acid (2 g, 23.53 mmol) in DCM (20 mL) was added T₄P (12.7 g, 35.29 mmol) and DIEA (9.1 g, 70.59 mmol) . The mixture is stirred for 3 h at 25 ℃. The reaction mixture was quenched by water (40 mL) , extracted by EA (100 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 (780 mg, 28%) . MS [M+H] ⁺ calcd for C₅H₂D₆N₂O 118.9, found 118.9.

Step 4: Synthesis of (Z) -2-cyano-3- (3-cyano-4-hydroxy-5-methoxyphenyl) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (6)

A solution of 3-cyano-4-hydroxy-5-methoxybenzoic acid (1276 mg, 6.61 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, N-bis (methyl-d3) acetamide (780 mg, 6.61 mmol) in THF (20 mL) was added LiHMDS (16.5 mL, 16.53 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 (100 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 (470 mg, 24%) . MS [M+H] ⁺ calcd for C₁₄H₇D₆N₃O₄ 293.9, found 293.9.

Step 5: Synthesis of (Z) -2-cyano-3- (3-cyano-4, 5-dihydroxyphenyl) -3-hydroxy-N, N-bis (methyl-d3) acrylamide (Ex. 442)

To a solution of (Z) -2-cyano-3- (3-cyano-4-hydroxy-5-methoxyphenyl) -3-hydroxy-N, N-bis (

methyl-d3) acrylamide (470 mg, 1.60 mmol) in DCM (10 mL) was added BBr₃ (0.89 mL, 8.02 mmol) dropwise at 0 ℃ for 30 mins. After addition, the reaction was warmed to RT and stirred for overnight. The mixture was quenched by ice, extracted by EA (100 mL*3) , dried by Na₂SO₄, concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=7/3) to obtain the product (140 mg, 40%) . MS [M+H] ⁺ calcd for C₁₃H₅D₆N₃O₄ 280.1, found 280.1. ¹HNMR (400 MHz, MeOD-d₄) δ 7.14 (s, 1H) , 7.09 (s, 1H) .

Example 541

Ethyl-d5 (Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylate

Step 1: Synthesis of ethyl-d5 2-cyanoacetate (2)

To a solution of ethan-1, 1, 2, 2, 2-d5-1-ol-d (2 g, 38.46 mmol) and 2-cyanoacetic acid (654 mg, 7.69 mmol) in DCM (20 mL) was added conc. H₂SO₄ (0.012 mL, 0.07 mmol) . The mixture is stirred for overnight at 40 ℃. The reaction mixture was quenched by saturated sodium bicarbonate solution (40 mL) , extracted by EA (100 mL x 3) , dried by Na₂SO₄. The combined organic phases were dried by Na₂SO₄ and concentrated in vacuo to obtain the product (450 mg, 10%) . MS [M+H] ⁺ calcd for C₅H₂D₅NO₂ 118.9, found 118.9.

Step 2: Synthesis of ethyl-d5 (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) acrylate (3)

A solution of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (812 mg, 3.81 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 ethyl-d5 2-cyanoacetate (450 mg, 3.81 mmol) in THF (20 mL) was added LiHMDS (9.5 mL, 9.53 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 (100 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 (300 mg, 25%) . MS [M+H] ⁺ calcd for C₁₃H₇D₅N₂O₇ 313.9, found 313.9.

Step 3: Synthesis of ethyl-d5 (Z) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylate (Ex. 541) To a solution of ethyl-d5 (Z) -2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl) acrylate (300 mg, 0.96 mmol) in DCM (10 mL) was added BBr₃ (0.53 mL, 4.79 mmol) dropwise at 0 ℃ for 30 mins. After addition, the reaction was warmed to 40 ℃ 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) to obtain the product (161 mg, 56%) . MS [M-H] ^-calcd for C₁₂H₅D₅N₂O₇ 298.0, found 298.0. ¹HNMR (400 MHz, DMSO-d₆) δ 7.66 (d, J = 2.3 Hz, 1H) , 6.73 (d, J = 2.3 Hz, 1H) .

The following compounds in Table were made by methods analogous the procedures above as indicated.

The compounds of the present invention could be prepared using commercially available reagents and the intermediates in the synthetic methods. The resource of deuterium in preparing for deuterated intermediates includes but not limited of CD₃I, D₂O, CD₃OD, DCO₂D, NaOD, DCl, D₂SO₄, (CD₂O) _n, CD₂O, CD₃S (O) CD₃, D_2, CD₅OD C₂D₅I, CD₃NH₂, NaBD₄, (CD₃) ₂NH, (C₂D₅) ₂HN, (CD₃) ₃COD, CHD₂I, CH₂DI.

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) .

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 as well as the reference compounds

Pharmacokinetic Evaluation in mice. 18 male ICR (Institute of Cancer Research) mice (6～10 weeks old, body weight around 34g) , were divided as Table 2 shown. An intravenous injection (i.v. ) dose of 5 mg/kg and oral administration (p.o. ) dose of 50 mg/kg were prepared for both the reference compound Ex. P849-486 from unpublished PCT application PCT/CN2023/109849 and test compounds. They are administrated via both i.v. and p.o., and the difference in pharmacokinetics between reference compound and the test compounds was compared. Mice were fed with standard feed, and given water ad libitum, and started to fast over night before the test. The drug is dissolved with 0.5%CMC-Na for oral administration and DMA: 30%Solutol HS-15: Saline = 10: 10: 80 (v/v/v) for intravenous injection. Orbital blood collection was conducted at different time points as Table 2 shown before and after administration. At each time point, 100 μL of orbital blood was collected into a test tube with EDTA-K2. After the blood sample was collected, mice were euthanatized. After the blood sample was collected, the tubes were gently inverted several times immediately to ensure adequate mixing, and placed on ice. At 4℃, blood samples were centrifuged at 1500～1600 g for 10 minutes to separate plasma and red blood cells. Plasma was stored at -40 ～ -20 ℃. The concentration of compound of the invention in plasma was determined with LC-MS/MS. The pharmacokinetic parameters were calculated based on the plasma concentration of compound at different time points.

In general, deuteration will slow down clearance of the compound in intravenous injection (i.v. ) in vivo. Unexpectedly, in animal PK study, it can be seen from the data (Table 3 and Figure 1) that, compared with the reference compound Ex. P849-486, compounds of the present invention did not slow down clearance of the compound in intravenous injection (i.v. ) , but they unexpectedly showed better pharmacokinetics in oral administration (p.o. ) , such as higher p.o. exposure (AUC) , higher p.o. Cmax, longer p.o. half life and higher bioavailability, which suggest compounds of the present invention will have better pharmacodynamic and therapeutic effects by oral administration (p.o. ) .

Table 2: Experimental Scheme

Table 3: Summary of animal pharmacokinetics

The reference compound Ex. P849-486 from unpublished PCT application PCT/CN2023/109849 has the structure of

and reference compound Ex. P849-13 from unpublished PCT application PCT/CN2023/109849 has the structure of

and reference compound Ex. P849-Ref1 from unpublished PCT application PCT/CN2023/109849 has the structure of

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 deuterated compound of Formula (II)

R₂ is hydrogen, deuterium, halogen, cyano, C_1-6alkyl, deuterated C_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy;

R₃ is hydrogen, deuterium, halogen, cyano, C_1-6alkyl, deuterated C_1-6alkyl, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy;

R₄ is cyano; hydrogen; deuterium; halogen; hydroxy; deuterated hydroxy; C_1-6alkoxy; C_1-6alkyl-S-; nitro (-NO₂) ; or -SF₅, each of said C_1-6alkoxy or C_1-6alkyl-S-is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; or C_1-6alkyl, C_2-6alkenyl or C_2- ₆alkynyl, each of said C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkoxy or C_1-6alkyl-S-;

R₅ is hydrogen, deuterium, nitro (-NO₂) , cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, -C (O) OR_5a, -SO₂-R_5a, or -SF₅; wherein R_5a is hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

R_a is hydrogen, deuterium, C_1-6alkyl or C_1-6alkoxy, each of said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, C_1- ₆alkyl-S-, or deuterated C_1-6alkyl-S-;

L₂ is C_1-6alkylene, which is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, or deuterated C_1-6alkyl;

R₁ is hydrogen, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each of said C_1-6alkyl, C_2-6alkenyl, or C_2-6alkynyl is unsubstituted or substituted with R_b, and each of said C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d;

wherein

R_b is deuterium, halogen, cyano, hydroxy, deuterated hydroxy, C_1-6alkoxy, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C_3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with at least one substituents selected from the group consisting of deuterium, cyano, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, hydroxy, deuterated hydroxy, deuterated hydroxy, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkyl-S-, deuterated C_1-6alkyl-S-, C_3- ₆cycloalkyl, deuterated C_3-6cycloalkyl, phenyl, deuterated phenyl, heteroaryl, deuterated heteroaryl, heterocyclyl, or deuterated heterocyclyl;

R_d is selected from deuterium, cyano, halogen, oxo, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -C (O) NR_mR_n, -NR_mR_n, -C (O) R_m, -C (O) OR_m, C_3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f,

wherein

R_m, R_n and R_p are each independently hydrogen, hydroxy, deuterated hydroxy, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxyC_1-6alkyl-, phenyl-C_1-6alkyl-, heteroaryl-C_1-6alkyl-, heterocyclyl-C_1- ₆alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, oxo, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

R_e is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloalkoxy, hydroxy, deuterated hydroxy, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1- ₆alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1- ₆alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, haloC_1-6alkyl, C_2-6alkenyl, C_2- ₆alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1-6alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkoxy, deuterated C_1-6alkoxy, C_1-6alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, deuterated hydroxy, C_1-6alkyl, deuterated C_1- ₆alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy;

provided that at least one of R₁, R₂, R₃, R₄, R₅, and L₂ comprise one or more deuterium.
The compound of claim 1, wherein R₂ is hydrogen, deuterium, fluoro, chloro, bromo, -CN, -CH₃, -OH, -OD, -OCH₃, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃.
The compound of claim 1 or 2, wherein R₃ is hydrogen, deuterium, fluoro, chloro, bromo, -CN, -CH₃, -OH, -OD, -OCH₃, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃.
The compound of any one of claims 1 to 3, wherein R₄ is hydrogen; deuterium; halogen; hydroxy; deuterated hydroxy; nitro; cyano; -SF₅; C_1-6alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; C_1-6alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy, or deuterated C_1-6alkoxy; C_1-6alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-6alkoxy or C_1-6alkyl-S-; C_2-6alkenyl; or C_2-6alkynyl;

optionally further wherein R₄ is C_1-4alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-4alkoxy, or deuterated C_1-4alkoxy; C_1-4alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-4alkoxy, or deuterated C_1-4alkoxy; C_1-4alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-4alkoxy, deuterated C_1-4alkoxy, or C_1-4alkyl-S-; C_2-4alkenyl; or C_2-4alkynyl;

optionally further wherein R₄ is C_1-2alkoxy which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-2alkoxy, or deuterated C_1-2alkoxy; C_1-2alkyl-S-which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-2alkoxy, or deuterated C_1-2alkoxy; or C_1-2alkyl which is unsubstituted or substituted with halogen, deuterium, hydroxy, deuterated hydroxy, C_1-2alkoxy, deuterated C_1-2alkoxy, or C_1-2alkyl-S-;

optionally further wherein R₄ is hydrogen, deuterium, nitro, cyano, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxy, deuterated hydroxy, methoxy, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, methoxy-d3 (i.e., -OCD₃) , -OCHD₂, -OCH₂D, ethoxy, ethoxy-d5 (i.e., -OCD₂CD₃) , -OCH₂CD₃, -OCD₂CH₃, difluoromethoxy, trifluoromethoxy, methylthio, trifluoromethylthio, vinyl, ethynyl, fluoro, chloro, bromo or iodo;

optionally further wherein R₄ is hydrogen, deutrium, hydroxy, deuterated hydroxy, methoxy, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, ethoxy, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, fluoro, chloro, methyl, nitro, cyano, difluoromethoxy or trifluoromethoxy.
The compound of any one of claims 1 to 4, wherein R₅ is deuterium, nitro, cyano, halogen, C_1-4alkyl, deuterated C_1-4alkyl, haloC_1-6alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, deuterated C_1-4alkoxy, haloC_1- ₄alkoxy, -SF₅, -C (O) OR_5a, and -SO₂-R_5a, wherein R_5a is hydrogen, C_1-4alkyl or haloC_1-4alkyl;

Optionally further wherein R₅ is deuterium, nitro, cyano, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, ethynyl, vinyl, methoxycarbonyl, carboxyl, methylsulfonyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, or -OCD₂CH₃. In some embodiments, R₅ is nitro, fluoro, chloro, or cyano.
The compound of any one of claims 1 to 5, wherein themoiety is selected from the group consisting of:

-

-

-

-
The compound of any one of claims 1 to 6, wherein R_a is C_1-6alkyl or deuterated C_1-6alkyl. In some embodiments, R_a is C_1-4alkyl or deuterated C_1-4alkyl;

Optionally further wherein R_a is methyl, ethyl, propyl, isopropyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -CH₂CH₂CD₃, -CH₂CD₂CD₃, -CD₂CD₂CD₃, -C (D) (CH₃) ₂, -C (D) (CH₃) (CD₃) , -C (D) (CD₃) ₂, -C (H) (CD₃) ₂, or -C (H) (CH₃) (CD₃) .
The compound of any one of claims 1 to 7, wherein L₂ is C_1-6alkylene which is unsubstituted or substituted with deuterium, halogen, or deuteratedC_1-6alkyl,

optionally further wherein L₂ is C_1-3alkylene or deuterated C_1-3alkylene;

optionally further wherein L₂ is methylene (CH₂) , -CD₂-, ethylene (-CH₂CH₂-) , -CD₂CD₂-, -CD₂CH₂-, or -CH₂CD₂-.
The compound of any one of claims 1 to 8, wherein R₁ is hydrogen, deuterium, C_1-6alkyl or deuterated C_1-6alkyl;

Optionally further wherein R₁ is hydrogen, deuterium, C_1-4alkyl or deuterated C_1-4alkyl;

Optionally further wherein R₁ is hydrogen, or deuterium.
The compound of claim 9, wherein L₂-R₁ is C_1-6alkyl or deuterated C_1-6alkyl;

Optionally further wherein L₂-R₁ is C_1-4alkyl or deuterated C_1-4alkyl;

Optionally further wherein L₂-R₁ is methyl, ethyl, propyl, isopropyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, -CH₂CH₂CD₃, -CH₂CD₂CD₃, -CD₂CD₂CD₃, -C (D) (CH₃) ₂, -C (D) (CH₃) (CD₃) , -C (D) (CD₃) ₂, -C (H) (CD₃) ₂, or -C (H) (CH₃) (CD₃) .
The compound of any one of claims 7 to 10, wherein at least one of L₂-R₁ and R_a is deuterated.
The compound of any one of claims 1 to 8, wherein

R₁ is aryl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted with R_d,

wherein R_d is selected from deuterium, cyano, halogen, oxo, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, C_3-8cycloalkyl, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -NR_mR_n, -C (O) NR_mR_n, -C (O) R_m, -C (O) OR_m, phenyl, heteroaryl or heterocyclyl, wherein each of said C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, C_2-6alkenyl, or C_2-6alkynyl is unsubstituted or substituted with R_e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_f,

R_m, R_n and R_p are each independently hydrogen, C_1-6alkyl, haloC_1-6alkyl, heterocyclyl, heteroaryl, or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1-6alkoxy,

wherein

R_e is deuterium, halogen, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1-6alkyl or haloC_1- ₆alkoxy; wherein R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, deuterated C_1-6alkyl, or haloC_1-6alkyl;

R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxy, deuterated hydroxy, hydroxyC_1-6alkyl-, C_1-6alkoxy-C_1-6alkyl-, C_1-6alkoxy, deuterated C_1-6alkoxy, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with deuterium, halogen, hydroxy, C_1-6alkyl, deuterated C_1-6alkyl, C_1-6alkoxy, deuterated C_1-6alkoxy, haloC_1- ₆alkyl or haloC_1-6alkoxy.
The compound of any one of claims 1 to 8, wherein R₁ is phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, wherein each of said phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R_d as defined above.
The compound of any one of claims 1 to 8, wherein R_d is selected from deuterium, cyano, halogen, C_1-6alkyl, C_1-6alkoxy, hydroxy, deuterated hydroxy, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl-S-, -SF₅, -NR_mC (O) NR_nR_p, -NR_mC (O) R_n, -NR_mR_n or phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein said C_1-6alkyl or C_1-6alkoxy is unsubstituted or substituted with R_e, and each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino is unsubstituted or substituted with R_f, wherein R_m, R_n and R_p are each independently hydrogen or C_1-6alkyl, deuterated C_1-6alkyl, wherein R_e is deuterium, halogen, -C (O) NR_e1R_e2, -NR_e1C (O) R_e2, -C (O) R_e1, -OR_e1, -SR_e1, -NR_e1R_e2, phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino, each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino is unsubstituted or substituted with halogen, hydroxy, deuterated hydroxy, C_1-6alkyl or C_1-6alkoxy; R_f is deuterium, halogen, C_1-6alkyl, deuterated C_1-6alkyl, or hydroxyC_1-6alkyl-; and R_e1 and R_e2 are each independently hydrogen, C_1-6alkyl, or deuterated C_1-6alkyl.
The compound of any one of claims 1 to 8, wherein R₁ is phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl, wherein each of said phenyl, C_3-8cycloalkyl, heteroaryl or heterocyclyl is unsubstituted or substituted with at least one substituents selected from deuterium, chloro, fluoro, bromo, phenyl, methyl, ethyl, -CD₃, -CHD₂, -CH₂D, -CD₂CD₃, -CH₂CD₃, -CD₂CH₃, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, deuterated hydroxy, methoxy, ethoxy, -OCD₃, -OCHD₂, -OCH₂D, -OCD₂CD₃, -OCH₂CD₃, -OCD₂CH₃, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, 1-methyl-d3-1H-pyrazol-4-ylamino, dimethylamino, di (methyl-d3) amino, 3- (hydroxymethyl) pyridin-2-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-methyl-d3-piperazin-1-yl) piperidin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-d3-piperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, 1-methyl-d3-piperidin-4-yl, pyrimidin-4-yl, morpholino, 2, 2, 2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl) methoxy, (1-methyl-d3-piperidin-4-yl) methoxy, (1-methyl-1H-pyrazol-4-yl) methyl, (1-methyl-d3-1H-pyrazol-4-yl) methyl, aminocarbonylmethyl, methylaminocarbonylmethyl or acetamido.
The compound of any one of claims 1 to 8, wherein themoiety is selected from the group consisting of:

a)

b)

c)

d)

e)

f)

g)

h)

i)

j)

k)

l)

m)

n)

o)

p)
The compound of claim 1, wherein the compounds are selected from the group consisting of Examples 1 to 721.
A pharmaceutical composition comprising the compounds of any one of claims 1-19 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 1-19.
The method of claim 19, wherein the method is characterized by FTO inhibition.